用于III型糖原贮积病的治疗剂的制作方法

相关申请的交叉引用

本申请要求于2017年5月31日提交的美国临时申请序号62/513,350的优先权，所述美国临时申请出于所有目的以全文引用的方式并入本文。

本发明涉及分子生物学和遗传学领域以及由可翻译分子产生的生物药物和治疗剂。更具体地说，本发明涉及用于具有翻译成活性多肽或蛋白的能力以在体内并且作为治疗剂使用的分子的方法、结构和组合物。

对以电子方式提交的文本文件的描述

与本申请一起以电子方式提交的文本文件的内容以全文引用的方式并入本文：序列表的计算机可读格式副本(文件名称：ulpi_041_01wo_seqlist_st25.txt，记录日期：2018年5月30日，文件大小：226千字节)。

背景技术：

iii型糖原贮积病(也称为gsdiii或柯里病(coridisease))是一种由缺乏糖原脱支酶引起的罕见的(发病率1:100,000)先天性糖原代谢缺陷，所述糖原脱支酶被称为淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(amylo-alpha-1,6-glucosidase,4-alpha-glucanotransferase)(agl)。这种常染色体隐性代谢紊乱表征为可变的肝脏、心肌和骨骼肌受累。

基于有缺陷的酶agl在组织表达上的差异，存在四种gsdiii亚型。gsdiiia占所有gsdiii的大约85％并且表现为由于肝脏和肌肉两者中的酶缺乏引起的肝脏和肌肉受累。gsdiiib占大约15％并且通常表现为由于仅肝脏中的酶缺乏引起的仅肝脏受累。同时，gsdiiic和gsdiiid均极为罕见，其中认为gsdiiic是由于缺乏葡萄糖苷酶脱支活性引起的并且认为gsdiiid是由于缺乏转移酶脱支活性引起的。

在婴儿期和儿童早期，肝脏受累表现为酮性低血糖症、肝肿大、高脂血症和肝转氨酶升高。在青少年期和成人期，肝脏疾病变得不那么突出。大多数患有gsdiiia的患者通常在儿童时期期间出现肥厚型心肌病。其临床显著性的范围为大多数的无症状到严重的心功能障碍、充血性心力衰竭和罕见的猝死。表现为无力的骨骼肌病通常在儿童时期并不明显，但缓慢进展，从而通常在成人中变得突出。

与受影响的器官一致，gsdiii患者的血清中经常存在增强的丙氨酸转氨酶(alt)、天冬氨酸转氨酶(ast)、碱性磷酸酶(alp)和/或肌酸磷酸激酶(cpk)活性。

如上所述，gsdiii是由缺乏agl引起的。该缺乏通常归因于agl基因的一种或多种遗传突变，所述一种或多种遗传突变导致患有gsdiii的受试者的agl酶活性部分或全部消除。在几个种族人群中执行了对gsdiii患者的agl蛋白的分子分析，并且描述了100多种不同的agl突变。参见goldstein等人,2010,《医学遗传学(genet.med.)》12:424-430。还参见sentner等人，2013,《遗传性代谢病杂志报道(jimdrep.)》7:19-26。

目前还没有对gsdiii的有效治疗。已经尝试通过频繁摄入碳水化合物含量高的餐食来控制低血糖症，通常通过使用夜间胃滴注喂食或玉米淀粉补充。同时，通过白天期间的高蛋白饮食加上整夜肠内输注对患有肌病的患者进行治疗。已有少数患者的症状得到暂时改善的记载，但尚无长期数据表明高蛋白饮食可预防或治疗进行性肌病。参见chenyt、burchella,《糖原贮积病(glycogenstoragedisease)》于scrivercr、beaudetal、slyws、valled,《遗传性疾病的代谢和分子基础(themetabolicandmolecularbasisofinheriteddisease)》纽约：麦格劳-希尔公司(mcgrawhill),1995:935-65。进行性肌病和/或心肌病是成人发病的主要原因，并且已经报道了有患者表现为进行性肝硬化和肝癌。因此，迫切需要可以解决该疾病的根本原因(即缺乏agl酶活性)的疗法。

迄今为止，在细胞溶质中存在有缺陷的酶的疾病中尚未发现酶置换，如gsdiii中的agl，这可能是由于缺乏跨质膜将外源酶递送到细胞质的有效且特异的细胞摄取机制所致。

本发明通过提供具有在细胞质中进行翻译以提供活性agl的能力的分子、结构和组合物来解决上述需求，所述活性agl可以改善、预防或治疗与agl缺乏相关联的疾病或病状，如gsdiii。

技术实现要素：

本发明提供了包括具有翻译能力的新型分子的组合物，所述分子可以用于提供一种或多种活性多肽和蛋白或其片段。本发明进一步提供了使用包括新型分子的这些组合物来预防或治疗各种病症的方法。更具体地说，本发明的实施例提供了包括用于提供活性淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的可翻译分子的组合物和使用所述组合物来治疗gsdiii的方法。

本发明的可翻译分子可以具有功能性细胞质活性，以用于产生agl多肽或蛋白。所述多肽和蛋白对于治疗方式可以具有活性。

本发明的可翻译分子尤其在细胞的细胞质中可以具有长半衰期。可翻译分子可以可表达为提供对于改善、预防或治疗与agl缺陷相关联的疾病或病状具有活性的产物。

本公开针对可翻译分子提供了一系列结构，以用于产生agl多肽或蛋白。在一些实施例中，可翻译分子可以具有与原生mrna相比增加的翻译能力和/或延长的半衰期。

本发明的可翻译分子可以在医药中使用并且用于用于生产和递送活性多肽和蛋白的方法和组合物。本发明的可翻译分子可以用于在体外、离体地或在体内提供多肽或蛋白质。

本公开的实施例提供了一系列用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段的新型多核苷酸。所述多核苷酸可以包含天然核苷酸和经过化学修饰的核苷酸。所述多核苷酸可以可表达为提供人agl或其具有agl活性的片段。

在另外方面，本发明提供了用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段的包括一个或多个解锁核酸(una)单体的一系列新型可翻译低聚物。可翻译低聚物可以含有一个或多个una单体以及天然核苷酸和经过化学修饰的核苷酸。包括一个或多个una单体的可翻译低聚物可以可表达为提供人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段。

在某些方面，本发明的可翻译分子可以提供对多肽或蛋白质或其片段的高效表达。所述表达可以在体外、离体地或在体内。

在一些实施例中，与对同一多肽或蛋白质进行编码的原生成熟的mrna相比，本发明的分子可以具有增加的细胞质半衰期。相对于原生成熟的mrna，本发明的分子和组合物可以提供增加的功能性细胞活性。

在另外方面，与原生成熟的mrna相比，本发明的可翻译分子作为提供多肽或蛋白产物的药剂可以提供增加的活性。本发明的可翻译分子可以减少有效疗法所需的剂量水平。

本发明的实施例包含以下内容。

附图说明

图1示出了使用本发明的可翻译分子在体外表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl，nm_000028)的结果。图1示出了在相对于参考分子534归一化的aml12和c2c12细胞中的相对agl表达。纵轴反映了相对于参考的倍数增加，例如，10是与参考相比增加了10倍。包含参考分子在内的分子包括烟草蚀纹病毒(tev)5'utr和非洲爪蟾(xenopus)β-珠蛋白(xbg)3'utr。分子在转录期间被封端并且用n^l-甲基假尿苷合成，使得100％的尿苷被n^l-甲基假尿苷置换。在两个细胞系(aml12、c2c12)中转染对agl进行编码的可翻译分子。转染后6小时裂解并收获细胞。通过使用对agl具有特异性的抗体(ab133720，兔)，执行定量蛋白印迹法来检测agl。

图2示出了使用本发明的可翻译分子在体外表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl，nm_000028)的结果。图2示出了在相对于参考分子534归一化的aml12和c2c12细胞中的相对agl表达。纵轴反映了相对于参考的倍数增加，例如，10是与参考相比增加了10倍。包含参考分子在内的分子包括烟草蚀纹病毒(tev)5'utr和非洲爪蟾β-珠蛋白(xbg)3'utr。分子在转录期间被封端并且用n^l-甲基假尿苷合成，使得100％的尿苷被n^l-甲基假尿苷置换。在两个细胞系(aml12、c2c12)中转染对agl进行编码的可翻译分子。转染后24小时裂解并收获细胞。通过使用对agl具有特异性的抗体(ab133720，兔)，执行定量蛋白印迹法来检测agl。

图3示出了使用本发明的可翻译分子在体内表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl，nm_000028)的结果。图3示出了在24小时和48小时的时间点处针对可翻译分子528和534(参考)在wt小鼠体内的相对agl表达。分子包括烟草蚀纹病毒(tev)5'utr和非洲爪蟾β-珠蛋白(xbg)3'utr。分子在转录期间被封端并且用n^l-甲基假尿苷合成，使得100％的尿苷被n^l-甲基假尿苷置换。在脂质纳米颗粒调配物中各自制备对agl进行编码的可翻译分子，并且以10mg/kg将其静脉注射到wt小鼠体内。在24小时和48小时时收获小鼠肝脏，并且通过使用对agl具有特异性的抗体(ab133720，兔)，执行定量蛋白印迹法来检测agl。

图4示出了使用本发明的可翻译分子在体内表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl，nm_000028)的结果。图4示出了与基线pbs(100)相比，在经过可翻译分子525、527、528、529和546给药后的wt小鼠体内的相对肝脏agl表达。在脂质纳米颗粒调配物中制备对agl进行编码的经过合成的可翻译分子525、527、528、529和546，并将其ip注射到wt小鼠体内。注射的剂量为10mpk，并且在6小时时收集肝脏，以供进一步分析。通过使用对agl具有特异性的抗体(ab133720，兔)，执行定量蛋白印迹法来检测agl。

图5示出了从以下三个可翻译分子中表达人agl的结果：546、1783和1784。用密码子优化的mrna来转染人原代肝细胞，并且在转染后6小时、24小时、48小时和72小时时通过in-cellwestern^tm测量agl蛋白表达。将mrna序列的表达与未处理对照物(“unt”)进行比较。

图6示出了在野生型c57bl/6小鼠中人agl从用脂质纳米颗粒调配的各种mrna分子的表达。通过多重反应监测测定来确定在肝脏活检样品的匀浆中从mrna分子表达的外源人agl的蛋白浓度(ng/mg)。在曲线图中示出为546.1、736.1、738.1、737.1、731.1和1783.1的可翻译分子分别与实例2中描述的546、736、738、737、731和1783相同。同时，可翻译分子546.7的核碱基序列与实例2中描述的546的核碱基序列相同，但用5-甲氧基尿苷代替尿苷而非用于合成可翻译分子546的n¹-甲基假尿苷合成。

图7示出了在用脂质纳米颗粒调配的各种mrna分子治疗的野生型c57bl/6小鼠中的内源性小鼠agl表达。通过多重反应监测测定来确定表达在肝脏活检样品的匀浆中的内源性小鼠agl的蛋白浓度(ng/mg)。在曲线图中示出为546.1、736.1、738.1、737.1、731.1和1783.1的可翻译分子分别与实例2中描述的546、736、738、737、731和1783相同。同时，可翻译分子546.7的核碱基序列与实例2中描述的546的核碱基序列相同，但用5-甲氧基尿苷代替尿苷而非用于合成可翻译分子546的n¹-甲基假尿苷合成。

图8示出了来自用媒剂(“veh”)治疗的agl敲除小鼠的肝脏的组织病理学。在用媒剂治疗的肝细胞内观察到显著到严重肝细胞空泡化和中度到显著糖原累积增加。

图9示出了来自用atx2脂质纳米颗粒调配的可翻译分子546治疗的agl敲除小鼠的肝脏的组织病理学。在用atx2脂质纳米颗粒调配的可翻译分子546治疗的肝细胞内，观察到在肝细胞有仅轻度到中度肝细胞空泡化和仅轻度到中度糖原累积增加。

具体实施方式

本发明提供了一系列用于治疗性应用的新型药剂和组合物。本发明的分子和组合物可以用于改善、预防和治疗gsdiii和/或与受试者的淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的存在或功能的减少相关联的疾病。

在一些实施例中，本发明包含用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶的合成的经过纯化的可翻译多核苷酸分子。所述分子可以含有天然核苷酸和经过化学修饰的核苷酸并且对人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段进行编码。

在某些实施例中，本公开包含用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段的包括一个或多个una单体的合成的经过纯化的可翻译低聚物分子。可翻译低聚物可以含有一个或多个una单体以及天然核苷酸和经过化学修饰的核苷酸。包括一个或多个una单体的可翻译低聚物可以可表达为提供人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)或其具有agl活性的片段。

如本文所使用的，术语“可翻译”可以与术语“可表达”可互换地使用并且是指多核苷酸或其一部分能够被宿主细胞转化为多肽。如本领域所理解的，翻译是细胞的细胞质中的核糖体产生多肽的过程。在翻译中，由核糖体复合物中的trna对信使rna(mrna)进行解码以产生特异性氨基酸链或多肽。此外，当在本说明书中关于低聚物使用时，术语“可翻译”意味着低聚物的至少一部分，例如低聚物序列的编码区(也称为编码序列或cds)能够转化为蛋白质或其片段。

如本文所使用的，术语“单体”是指可以与相同或不同类型的另一种分子连接以形成低聚物的单个单元，例如单个核酸。在一些实施例中，单体可以是解锁核酸，即una单体。

同时，术语“低聚物”可以与“多核苷酸”可互换地使用并且是指包括至少两个单体的分子并且包含如dna和rna等寡核苷酸。在含有rna单体和/或解锁核酸(una)单体的低聚物的情况下，本发明的低聚物除了编码序列(cds)之外可以另外含有序列。这些另外的序列可以是非翻译序列，即未被宿主细胞转化为蛋白质的序列。这些非翻译序列可以包含5'端帽、5'非翻译区(5'utr)、3'非翻译区(3'utr)和尾区，例如polya尾区。如本文进一步详细描述的，这些非翻译序列中的任何非翻译序列均可以含有一个或多个una单体—这些una单体无法被宿主细胞的机器翻译。在本发明的上下文中，“可翻译低聚物”、“可翻译分子”、“可翻译多核苷酸”或“可翻译化合物”是指包括能够转换成蛋白质或其片段(例如人agl蛋白质或其片段)的区域(例如rna的编码区)的序列(例如人agl的编码序列或其密码子优化版本)。

如本文所使用的，术语“密码子优化”意指天然编码序列(或天然编码序列的有目的地设计的变体)通过在不改变经过编码的蛋白质氨基酸序列的情况下选择不同的密码子而被重新设计从而提高蛋白质表达水平(gustafsson等人,《密码子偏倚和异源蛋白表达(codonbiasandheterologousproteinexpression)》2004,《生物科技趋势(trendsbiotechnol)》,22:346-53)。已经显示，如高密码子适应指数(cai)、lowu法、mrna二级结构、顺式调控序列、gc含量等变量以及许多其它类似的变量在一定程度上与蛋白表达水平相关(villalobos等人,《基因设计器：用于构建人工dna区段的合成生物学工具(genedesigner:asyntheticbiologytoolforconstructingartificialdnasegments)》2006,《bmc生物信息学(bmcbioinformatics)》7:285)。高cai(密码子适应指数)法为整个蛋白质编码序列挑选最常用的同义密码子。从人类基因组的74218个蛋白质编码基因中推导出每个氨基酸的最常用密码子。lowu法针对可以用具有较少u部分的同义密码子置换的仅含u密码子。如果存在几种替换选择，则将选择更常用的密码子。lowu法不会改变序列中其余的密码子。该方法可以与公开的mrna结合使用，以设计用5-甲氧基尿苷合成的编码序列。

如配备有本公开的技术人员将了解的，本发明的可翻译分子可以用于改善、预防或治疗与受试者的淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的活性降低(例如由于浓度、存在和/或功能的减少引起的)相关联的任何疾病或病症。在一些实施例中，本发明的可翻译分子可以在用于改善、预防或治疗gsdiiia、gsdiiib、gsdiiic和gsdiiid(在本文中统一地或单独地称为“gsdiii”或“iii型糖原贮积病”)中的一种或多种的方法中使用。本文要治疗的疾病或病症(例如gsdiiia、gsdiiib、gsdiiic和gsdiiid)可以与以下相关联：低血糖(低血糖症)、肝脏增大(肝肿大)、血液中脂肪过量(高脂血症)、肝酶血液水平升高、慢性肝病(肝硬化)、肝衰竭、生长缓慢、身材矮小、良性肿瘤(腺瘤)、肥厚型心肌病、心功能障碍、充血性心力衰竭、骨骼肌病和/或肌张力低下(张力减退)。在一些实施例中，本发明的可翻译分子可以用于改善、预防或治疗这些上述症状中的任何或全部症状。

如技术人员所理解的，gsdiii在本领域可以由许多替代名称来指代，包含但不限于agl缺乏症、柯里病、柯里氏病(cori'sdisease)、脱支酶缺乏症、福布斯病(forbesdisease)、糖原脱支酶缺乏症、gsd3或极限糊精糖增多症(由于细胞溶质中的极限糊精样结构)。因此，gsdiii可以与本说明书、实例、附图和权利要求书中的这些替代名称中的任何替代名称可互换地使用。

本发明的对功能性agl部分进行编码的可翻译分子可以递送到有需要的患者(例如gsdiii患者)的肝脏，尤其是肝细胞，并且可以提升患者的活性agl水平。可翻译分子可以用于预防、治疗、减轻或逆转患者的gsdiii的任何症状。

在另外方面，本发明的可翻译分子还可以用于减少gsdiii患者对特定饮食的依赖，以控制疾病。例如，本发明的可翻译分子可以用于减少gsdiii患者对频繁摄入碳水化合物含量高的餐食和/或蛋白质异常高的饮食的依赖。

本发明的实施例进一步涵盖用于制备用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的可翻译分子的方法。所述方法包含：在天然核苷三磷酸和经过化学修饰的核苷三磷酸存在的情况下在体外转录agldna模板以形成产物混合物；以及纯化所述产物混合物以分离出可翻译分子。还可以通过本领域已知的方法来制备可翻译分子。

本发明的分子可以是含有rna和/或una单体的可翻译分子。这些可翻译分子尤其在细胞质中可以具有长半衰期。长持续时间可翻译分子可以用于改善、预防或治疗与受试者的淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的活性降低(例如由于浓度、存在和/或功能的减少引起的)相关联的疾病或病症。

本发明的可翻译分子的性质是根据其分子结构产生的，并且基于那些性质，整个分子的结构作为整体可以提供显著的益处。本发明的实施例可以提供具有有利地提供提高的蛋白浓度或增加的蛋白活性的一种或多种性质的可翻译分子。本发明的分子和组合物可以提供包括用于改善、预防或治疗与受试者的淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的活性降低(例如由于浓度、存在和/或功能的减少引起的)相关联的任何疾病或病症的治疗剂的调配物。

本发明提供了令人惊讶地可翻译以在体外、离体地以及在体内提供活性多肽或蛋白的一系列可翻译分子。

本发明的可翻译分子可表达为提供一种或多种活性多肽或蛋白或其片段。

可翻译结构和组合物可以具有增加的翻译活性或细胞质半衰期。在这些实施例中，与原生mrna相比，可翻译结构和组合物可以在哺乳动物细胞的细胞质中提供增加的功能性半衰期。

如本文所使用的，术语“半衰期”是量(如核酸或蛋白浓度或活性)下降到其在时间段开始时测量的值的一半所需的时间。

本文提供了本发明的可翻译分子的一系列结构，所述一系列结构包含含有一个或多个una单体的低聚物。含有一个或多个una单体的低聚物可以合并专门的连接子基团。连接子基团可以在可翻译分子中的链中附接。还可以将每个连接子基团附接到核碱基。

在一些方面，连接子基团可以是单体。单体可以附接以形成链分子。在本发明的链分子中，连接子基团单体可以附接在链中的任何点处。

在某些方面，连接子基团单体可以在本发明的链分子中附接，使得连接子基团单体驻留在链的末端附近或链中的任何位置处。

在另外方面，链分子的连接子基团可以各自附接到核碱基。链分子中存在核碱基可以在链分子中提供核碱基序列。

在某些实施例中，本发明提供了具有合并连接子基团单体与某些天然核苷酸或非天然核苷酸或经过修饰的核苷酸或经过化学修饰的核苷酸的新型组合的链结构的可翻译低聚物分子。

本发明的低聚物分子可以展示核碱基序列并且可以被设计成在体外、离体地或在体内表达多肽或蛋白质。表达的多肽或蛋白质可以具有各种形式的活性，包含与从天然mrna、原生mrna或野生型mrna表达的蛋白质相对应的活性或与阴性蛋白质或显性阴性蛋白质相对应的活性。

在一些方面，本发明可以提供具有与细胞的原生核酸分子的至少片段相同的碱基序列的活性可翻译低聚物分子。

在一些实施例中，细胞可以是真核细胞、哺乳动物细胞或人细胞。

本发明提供了用于合并连接子基团单体的可翻译低聚剂的结构、方法和组合物。本发明的低聚分子可以在用于治疗的调配物中用作活性剂。

本发明提供了由于其能够表达为受试者的细胞中的多肽或蛋白质而因此可用于提供治疗效果的一系列可翻译分子。

在某些实施例中，可翻译分子可以被构造为由单体构成的低聚物。本发明的低聚结构可以含有一个或多个连接子基团单体连同某些核苷酸。

在某些实施例中，可翻译分子可以含有核碱基序列并且可以被设计成部分地通过与原生多核苷酸序列具有足够的同源性来表达任何同种型的肽或蛋白质。

在一些实施例中，可翻译分子的长度可以为约200到约12,000个单体或更多。在某些实施例中，可翻译分子可以为1,000到9,000个单体长、3,000到7,000个单体长、或4,000到6,000个单体长。在一个示例性实施例中，可翻译分子的长度为4,500到5,500个单体。在另外的示例性实施例中，可翻译分子的长度为约5,000个单体。

在一些实施例中，可翻译分子可以含有1到约800个una单体。在某些实施例中，可翻译分子可以含有1到600个una单体、或1到100个una单体、或1到12个una单体。

在一些实施例中，可翻译分子可以含有1到约800个锁核酸(lna)单体。在某些实施例中，可翻译分子可以含有1到600个lna单体、或1到100个lna单体、或1到12个lna单体。

本发明的可翻译分子可以包括5'端帽、单体的5'非翻译区、单体的编码区、单体的3'非翻译区和单体的尾区。

本发明的可翻译分子可以包括含有一个或多个una单体的单体的3'非翻译区。

本发明的可翻译分子可以包括含有一个或多个una单体的单体的尾区。

本发明的可翻译分子可以包括序列或结构的区域，所述区域可操作以用于在细胞中翻译或者具有mrna的包含例如5'端帽、5'非翻译区、编码区、3'非翻译区和polya尾在内的区域的功能。

本发明进一步设想了用于向细胞递送包括一个或多个可翻译分子的一个或多个载体的方法。在另外的实施例中，本发明还设想了向细胞递送一个或多个可翻译分子。

在一些实施例中，可以将一个或多个可翻译分子在体外、离体地或在体内递送到细胞。可以使用如本领域已知的病毒和非病毒转移方法来将可翻译分子引入哺乳动物细胞中。可翻译分子可以与药学上可接受媒剂或者例如与纳米颗粒或脂质体一起递送。

在一些实施例中，与利用原生组合物相比，本发明的可翻译结构和组合物可以减少在培养物中进行细胞命运操纵所需的转染的数量和频率。

在另外方面，与利用原生mrna相比，本发明针对作为活性剂的可翻译分子提供了增加的活性。

在一些方面，本发明可以提供与有原生核酸、多肽或蛋白质诱导的分子相比可以减少细胞的固有免疫应答的可翻译分子。

本发明可以提供与原生分子相比难以脱腺苷酸化的合成可翻译分子。

在某些实施例中，本发明可以提供具有与原生分子相比增加的比活性和更长的功能半衰期的合成可翻译分子。本发明的合成可翻译分子可以提供提高的异位蛋白表达水平。当使用载体表达可翻译分子时，细胞递送可以处于提高的水平，并且细胞毒素的固有免疫应答可以是有限的，从而使得可以实现更高的异位蛋白表达水平。与原生mrna相比，本发明的可翻译分子可以具有增加的比活性和更长的功能半衰期。

在某些方面，可翻译分子可以具有许多相对于原生mrna的突变。

在另外的实施例中，本发明可以提供具有可裂解递送并且靶向附接在3'端和/或5'端的部分的可翻译分子。

通常，可以将通过转染递送的合成可翻译分子的比活性视为每单位时间内每个递送的转录物表达的蛋白质的分子的数量。

如本文所使用的，翻译效率是指通过在体外或在体内翻译可翻译分子来产生蛋白质或多肽的量度。

本发明提供了可以含有一个或多个una单体和许多核酸单体的一系列可翻译低聚物分子，其中所述可翻译分子可以可表达为提供多肽或蛋白质。

在一些实施例中，本发明包含可以在一个或多个非翻译区中含有一个或多个una单体以及许多核酸单体的一系列可翻译低聚物分子，其中所述可翻译分子可以可表达为提供多肽或蛋白质。

在一些实施例中，本发明包含在尾区中含有一个或多个una单体以及许多核酸单体的一系列可翻译分子，其中所述可翻译分子可以可表达为提供多肽或蛋白质。

在一些实施例中，可翻译分子可以含有经过修饰的5'端帽。

在另外的实施例中，可翻译分子可以含有单体的翻译增强性5'非翻译区。

在另外的实施例中，可翻译分子可以含有单体的翻译增强性3'非翻译区。

在另外的实施例中，可翻译分子在单体的3'非翻译区中可以含有一个或多个una单体。

在另外的实施例中，可翻译分子在单体的尾区中可以含有一个或多个una单体。

在另外的实施例中，可翻译分子在polya尾中可以含有一个或多个una单体。

在一些实施例中，可翻译分子在单体的3'非翻译区中或在单体的尾区中(例如在polya尾中)可以含有一个或多个lna单体。

另一方面，与对同一翻译产物进行编码的原生mrna相比，本发明的可翻译分子在体内可以表现出提高至少2倍、3倍、5倍或10倍的翻译效率。

在另外方面，与对同一多肽或蛋白质进行编码的原生mrna相比，可翻译分子在体内可以产生提高至少2倍、3倍、5倍或10倍的多肽或蛋白质水平。

在某些实施例中，与对同一多肽或蛋白质进行编码的原生mrna相比，可翻译分子在体内可以提供提高的多肽或蛋白质水平。例如，多肽或蛋白质的水平可以提高10％、或20％、或30％、或40％、或50％或更多。

在另外的实施例中，本发明提供了用于通过向受试者施用含有本发明的可翻译分子的组合物来治疗受试者的疾病或病状的方法。

本发明的可翻译分子可以用于改善、预防或治疗疾病或病症，例如与受试者的淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的活性降低(例如由于浓度、存在和/或功能的减少引起的)相关联的疾病或病症。在这些实施例中，可以施用包括本发明的可翻译分子的组合物，以调控、调节或增加agl酶在受试者体内的浓度或有效性。在一些方面，所述酶可以是未经过修饰的天然酶，患者具有异常量的未经过修饰的天然酶(例如患者具有部分地或完全地消除agl活性的agl突变版本)。在一些方面，所述酶可以是可以用于治疗携带agl突变版本的患者的未经过修饰的天然agl酶。在示例性实施例中，本发明的可翻译分子可以用于改善、预防或治疗gsdiii。

在一些实施例中，可翻译分子可以递送到细胞或受试者并且被翻译以提高细胞或受试者中的agl水平。

如本文所使用的，术语“受试者”是指人类或任何非人类动物(例如小鼠、大鼠、兔、狗、猫、牛、猪、绵羊、马或灵长类动物)。人类包含出生前形式和出生后形式。在许多实施例中，受试者是人类。受试者可以是患者，所述患者是指呈现给医疗提供者以进行疾病的诊断或治疗的人类。术语“受试者”在本文中与“个体”或“患者”可互换地使用。受试者可以患有或易于患上疾病或病症，但是可以或可以不展示出疾病或病症的症状。

在示例性实施例中，本发明的受试者是淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的活性降低(例如由于浓度、存在和/或功能的减少引起的)的受试者。在另外的示例性实施例中，受试者是人类。

在一些实施例中，施用包括本发明的可翻译分子的组合物可以使经过治疗的受试者的肝脏agl蛋白水平提高。在一些实施例中，施用包括本发明的可翻译分子的组合物使肝脏agl蛋白水平相对于在治疗之前受试者的基线agl蛋白水平提高5％、10％、20％、30％、40％、50％、60％、70％、80％、90％或95％。在一个示例性实施例中，施用包括本发明的可翻译分子的组合物使肝脏agl水平相对于治疗之前的受试者体内的基线agl水平提高。在一些实施例中，肝脏agl水平可以提高至少约5％、10％、20％、30％、40％、50％、100％、200％或更多。

在一些实施例中，从本发明的可翻译分子表达的agl蛋白可在肝脏、血清、血浆、肾脏、心脏、肌肉、大脑、脑脊液或淋巴结中检测。在示例性实施例中，agl蛋白表达在肝细胞，例如经过治疗的受试者的肝细胞中。

在一些实施例中，施用包括本发明的可翻译分子的组合物使天然的未突变的人agl(即与异常或突变agl相反的正常或野生型agl)蛋白表达水平处于或高于经过治疗的受试者的肝脏中总蛋白的约10ng/mg、约20ng/mg、约50ng/mg、约100ng/mg、约150ng/mg、约200ng/mg、约250ng/mg、约300ng/mg、约350ng/mg、约400ng/mg、约450ng/mg、约500ng/mg、约600ng/mg、约700ng/mg、约800ng/mg、约900ng/mg、约1000ng/mg、约1200ng/mg或约1500ng/mg。

如本文使用的，如应用于一个或多个感兴趣的值的术语“约”或“大约”是指与规定的参考值类似的值。在某些实施例中，除非另有规定或另外从上下文显而易见(除了此些数字将会超过可能值的100％的情况)，否则术语“大约”或“约”是指在规定的参考值的在任一方向(大于或小于)的10％、9％、8％、7％、6％、5％、4％、3％、2％、1％或更小的值的范围。

在一些实施例中，可在施用包括本发明的可翻译分子的组合物之后6小时、12小时、18小时、24小时、30小时、36小时、48小时、60小时和/或72小时检测天然的未突变的人agl蛋白的表达。在一些实施例中，可在施用包括本发明的可翻译分子的组合物之后1天、2天、3天、4天、5天、6天和/或7天检测天然的未突变的人agl蛋白的表达。在一些实施例中，可在施用后1周、2周、3周和/或4周检测天然的未突变的人agl蛋白的表达。在一些实施例中，可在施用包括本发明的可翻译分子的组合物之后检测天然的未突变人agl蛋白的表达。在一些实施例中，可在施用包括本发明的可翻译分子的组合物之后在肝脏例如肝细胞中检测天然的未突变的人agl蛋白的表达。

用于制备可翻译分子的变体模板

在本文描述的各个实施例中，可翻译低聚物可以包括mrna编码的agl，其中所述mrna编码agl是密码子优化的。在一些实施例中，agl是人agl(即hagl)。在一些实施例中，人agl包括氨基酸序列seqidno:2。在一些实施例中，人agl由氨基酸序列seqidno:2组成。

在一些实施例中，可以利用变体dna模板来制备能够对agl进行编码的可翻译分子。本公开的变体dna模板在用于制备可翻译分子的方法和可翻译分子的效率方面可以表现出优势。可以利用改变模板来增强经过修饰的核苷酸或单体在本发明的可翻译分子中的合并。在某些方面，可以利用改变模板来增强可翻译分子的结构特征。可翻译分子的增强的结构特征可以提供意想不到的有利性质，包含用于提供多肽或蛋白产物的翻译效率。

在本发明的一些方面，改变模板可以包含减少某些核苷酸在模板链中的出现或出现频率。减少某种核苷酸的出现可以改变本公开的结构和方法以提供非原生形式，这令人惊奇地实现了改善对agl进行编码的可翻译rna产物的性质。

本发明的各方面在用于制备可翻译分子的方法中可能需要变体dna模板。dna分子可以具有可以转录以提供对agl进行编码的靶可翻译分子的核苷酸的非编码模板链。

靶可翻译分子可以是任何rna，无论是原生的或经过修饰的、合成的或源自天然来源。

在一些实施例中，可以使用变体dna模板，所述变体dna模板的模板链的开放阅读框被转化成替代形式，同时维持了密码子分配。

在某些实施例中，可以使用dna模板，所述dna模板的替代性核苷酸是基于替代性密码子优化和/或序列简并使用的。

在另外的实施例中，dna模板可以具有在维持密码子分配的同时用替代性核苷酸置换的某些核苷酸。

本发明的实施例有利地利用了本发明的dna模板中的替代性密码子以在用于制备对agl进行编码的可翻译分子的方法中使用。与在许多方法中可能需要优选密码子的细胞和生物体相比，可以在本发明的dna模板中实现的改变的范围要大得多。在本发明中，可以在dna模板中使用广泛范围的替代性密码子和位置以用于转录可翻译分子。

在本发明的另外方面，改变模板可以包含减少某些核苷酸在模板链中的出现或出现频率。例如，可以将核苷酸在模板中的出现减少到低于模板中核苷酸的25％的水平。在另外的实例中，可以将核苷酸在模板中的出现减少到低于模板中核苷酸的20％的水平。在一些实例中，可以将核苷酸在模板中的出现减少到低于模板中核苷酸的16％的水平。在某些实例中，可以将核苷酸在模板中的出现减少到低于模板中核苷酸的12％的水平。

人agl

人agl基因对分子质量为大约174.8kda的1532个氨基酸蛋白质进行编码。agl是在糖原降解时充当1,4-α-d-葡聚糖:1,4-α-d-葡聚糖-4-α-d-糖基转移酶和淀粉-1,6-葡萄糖苷酶的多功能酶。如上所述，正常agl活性的遗传缺陷引起糖原贮积病iii。

共有人agl编码序列的rna序列具有seqidno:1中示出的4,599个核碱基。

共有人agl编码序列—见于ncbi登录号np_000019.2—翻译成seqidno:2。

在一些实施例中，可以制备可翻译分子并将其用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(hagl)，所述可翻译分子与hagl的原生mrna相比具有有利地增加的翻译效率。表达hagl的可翻译分子可以表现出适合于用于改善、预防或治疗疾病的方法的活性。在一些实施例中，可翻译分子可以包括一个或多个una单体。

在一些实施例中，可翻译分子可以包含5'端帽、5'utr、翻译起始序列(例如kozak序列)、人aglcds、3'utr和/或尾区。在示例性实施例中，可翻译分子可以包含5'端帽(m7gpppgm)、烟草蚀纹病毒(tev)的5'utr、kozak序列、人aglcds、非洲爪蟾β-珠蛋白的3'utr和尾区。在另外的示例性实施例中，人aglcds可以包括下文进一步详细描述的seqidno:7-32或seqidno:41-45中的密码子优化序列。在本文所描述的这些和其它实施例中的任何实施例中，可翻译分子可以包括一个或多个una单体。在本文所描述的这些和其它实施例中的任何实施例中，可翻译分子可以包括一个或多个lna单体。

与agl的原生mrna相比，分子的翻译效率可以提高。具体地说，在48小时后，与agl的原生mrna相比，分子的翻译效率可以提高了多于一倍。

在一些实施例中，本发明的适合的mrna序列包括对人agl蛋白进行编码的mrna序列。seqidno:2中示出了天然存在的人agl蛋白的序列。

在一些实施例中，适合的mrna序列可以是对人agl的同系物或变体进行编码的mrna序列。如本文所使用的，人agl蛋白的同系物或变体可以是经过修饰的人agl蛋白，所述经过修饰的人agl蛋白与野生型人agl蛋白或天然存在的人agl蛋白相比，在保留基本的agl蛋白活性的同时含有一个或多个氨基酸取代、缺失和/或插入。在一些实施例中，适合于本发明的mrna对与人agl蛋白基本上相同的蛋白质进行编码。在一些实施例中，适合于本发明的mrna对与seqidno:2的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大的氨基酸序列进行编码。在一些实施例中，适合于本发明的mrna对人agl蛋白的片段或一部分进行编码。

在一些实施例中，适合于本发明的mrna对人agl蛋白的片段或一部分进行编码，其中所述蛋白质的所述片段或所述部分仍维持与野生型蛋白的活性类似的agl活性。

在一些实施例中，适合于本发明的mrna包括与seqidno:7-32或seqidno:41-45的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大的序列。

在一些实施例中，本发明的可翻译低聚分子包括与seqidno:7-32或seqidno:41-45的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大的编码序列。在一些实施例中，包括与seqidno:7-32或seqidno:41-45的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大的编码序列的可翻译低聚分子进一步包括选自5'端帽、5'utr、翻译起始序列、3'utr和尾区的一个或多个序列。

在一些实施例中，本发明的可翻译低聚分子包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％或99％的编码序列并且表达功能性人agl蛋白。在一个示例性实施例中，本发明的可翻译低聚分子包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的编码序列并且表达功能性人agl蛋白质。在另一个示例性实施例中，本发明的可翻译低聚分子包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的编码序列并且表达功能性人agl蛋白，其中所述编码序列与选自seqidno:7-32或seqidno:41-45的序列的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大。在又一个示例性实施例中，本发明的可翻译低聚分子包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的编码序列并且表达功能性人agl蛋白，其中所述编码序列与选自seqidno:7-32或seqidno:41-45的序列的一致性为至少95％。在又一个示例性实施例中，本发明的可翻译低聚分子包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的编码序列并且表达功能性人agl蛋白，其中所述编码序列与选自seqidno:19、seqidno:31或seqidno:45的序列的一致性为至少95％或更大。因此，在一些实施例中，本申请提供了包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的核碱基序列或由其组成的多核苷酸，并且其中所述人agl编码序列与选自seqidno:7-32或seqidno:41-45的序列的一致性为至少80％、85％、90％、91％、92％、93％、94％、95％、96％、97％、98％、99％或更大。在示例性实施例中，本申请提供了包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的核碱基序列或由其组成的多核苷酸，并且其中所述人agl编码序列与选自seqidno:19、seqidno:31或seqidno:45的序列的一致性为至少95％。在一个具体实施例中，本申请提供了包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的核碱基序列的多核苷酸，并且其中所述人agl编码序列与seqidno:19的一致性为至少95％。在另一个具体实施例中，本申请提供了包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的核碱基序列的多核苷酸，并且其中所述人agl编码序列与seqidno:31的一致性为至少95％。在另一个具体实施例中，本申请提供了包括在全长人agl编码序列seqidno:1上与野生型人agl编码序列的一致性小于80％的核碱基序列的多核苷酸，并且其中所述人agl编码序列与seqidno:45的一致性为至少95％。

在一些实施例中，本发明的可翻译低聚分子对融合蛋白进行编码，所述融合蛋白包括与另一个序列融合(例如n或c末端融合)的agl蛋白的全长、片段或一部分。在一些实施例中，n或c末端序列是信号序列或细胞靶向序列。

una单体和低聚物

在一些实施例中，连接子基团单体可以是解锁核单体(una单体)，所述una单体是基于如下所示的丙烷-1,2,3-三-基-三氧基结构的小有机分子：

其中r¹和r²是h，并且r¹和r²可以是磷酸二酯键，碱基可以是核碱基，并且r³是下文描述的官能团。

在另一个视图中，una单体的主要原子可以以iupac表示法绘制如下：

其中低聚物链行进的方向是从丙烷残基的1-端到3-端。

核碱基的实例包含尿嘧啶、胸腺嘧啶、胞嘧啶、5-甲基胞嘧啶、腺嘌呤、鸟嘌呤、肌苷以及天然和非天然核碱基类似物。

核碱基的实例包含假尿嘧啶、1-甲基假尿嘧啶(m1ψ)，即n¹-甲基假尿嘧啶和5-甲氧基尿嘧啶。

不是核苷酸的una单体通常可以是低聚物中的内部连接子单体。低聚物中的内部una单体两侧的侧翼是其它单体。

例如，当低聚物形成复合物或双链体时，una单体可以参与碱基配对，并且所述复合物或双链体中存在具有核碱基的其它单体。

以下示出了作为内部单体侧翼在丙烷-1-基位置和丙烷-3-基位置两者处的una单体的实例，其中r³是-oh。

una单体可以是低聚物的末端单体，其中所述una单体附接到丙烷1-基位置或丙烷3-基位置处的仅一个单体。因为una单体是柔性有机结构，与核苷酸不同，所以末端una单体可以是低聚物的柔性终止子。

下文示出作为附接在丙烷-3-基位置处的末端单体的una单体的实例。

因为una单体可以是柔性分子，所以作为末端单体的una单体可以设想大为不同的构象。下文示出连接在丙烷-3-基位置处作为末端单体的能量最小化una单体构象的实例。

una-a末端形式：虚线键示出了丙烷-3-基附接

除其它事项外，una单体的结构允许其附接到天然存在的核苷酸。

una低聚物可以是由una单体以及可以基于天然存在的核苷酸的各种核苷酸够构成的链。

在一些实施例中，una单体的官能团r³可以是-or⁴、-sr⁴、-nr⁴2、-nh(c＝o)r⁴、吗啉基、吗啉-1-基、哌嗪-1-基或4-烷酰基-哌嗪-1-基，其中r⁴每次出现时是相同或不同的并且可以是h、烷基、胆固醇、脂质分子、多胺、氨基酸或多肽。

una单体是有机分子。una单体不是核酸单体或核苷酸，也不是天然存在的核苷或经过修饰的天然存在的核苷。

本发明的una低聚物是合成链分子。

在一些实施例中，如上所示，una单体可以是una-a(指定为)、una-u(指定为)、una-c(指定为)和una-g(指定为)。

本文可以使用的代号包含指代2'-o-甲基修饰的核糖核苷酸的ma、mg、mc和mu。

本文可以使用的代号包含指代2'-脱氧t核苷酸的dt。

如本文所使用的，在低聚物序列的上下文中，符号n可以表示任何天然核苷酸单体或任何经过修饰的核苷酸单体。

如本文所使用的，在低聚物序列的上下文中，符号q表示非天然的、经过修饰的或经过化学修饰的核苷酸单体。

如本文所使用的，在低聚物序列的上下文中，符号x可以用于表示una单体。

经过修饰的核苷酸和经过化学修饰的核苷酸

在本文的经过修饰的或经过化学修饰的核苷酸的实例中，烷基、环烷基或苯基取代基可以是未取代的或者进一步由一个或多个烷基、卤素、卤代烷基、氨基或硝基取代基取代。

核酸单体的实例包含非天然的、经过修饰的和经过化学修饰的核苷酸，所述核苷酸包含本领域已知的任何此类核苷酸。

经过修饰的或经过化学修饰的核苷酸的实例包含5-羟基胞苷、5-烷基胞苷、5-羟烷基胞苷、5-羧基胞苷、5-甲酰基胞苷、5-烷氧基胞苷、5-炔基胞苷、5-卤代胞苷、2-硫代胞苷、n⁴-烷基胞苷，n⁴-氨基胞苷、n⁴-乙酰基胞苷和n⁴,n⁴-二烷基胞苷。

经过修饰的或经过化学修饰的核苷酸的实例包含5-羟基胞苷、5-甲基胞苷、5-羟甲基胞苷、5-羧基胞苷、5-甲酰基胞苷、5-甲氧基胞苷、5-丙炔基胞苷、5-溴代胞苷、5-碘代胞苷、2-硫代胞苷、n⁴-甲基胞苷、n⁴-氨基胞苷、n⁴-乙酰基胞苷和n⁴,n⁴-二甲苯胞苷。

经过修饰的或经过化学修饰的核苷酸的实例包含5-羟基尿苷、5-烷基尿苷、5-羟烷基尿苷、5-羧基尿苷、5-羧烷基酯尿苷、5-甲酰基尿苷、5-烷氧基尿苷、5-炔基尿苷、5-卤代尿苷、2-硫代尿苷和6-烷基尿苷。

经过修饰的或经过化学修饰的核苷酸的实例包含5-羟基尿苷、5-甲基尿苷、5-羟甲基尿苷、5-羧基尿苷、5-羧甲基酯尿苷、5-甲酰基尿苷、5-甲氧基尿苷、5-丙炔基尿苷、5-溴代尿苷、5-氟代尿苷、5-碘代尿苷、2-硫代尿苷和6-甲基尿苷。

经过修饰的或经过化学修饰的核苷酸的实例包含5-甲氧基羰基甲基-2-硫代尿苷、5-甲基氨甲基-2-硫代尿苷，5-氨基甲酰基甲基尿苷、5-氨基甲酰基甲基-2'-o-甲基尿苷、1-甲基-3-(3-氨基-3-羧基丙基)假尿苷、5-甲基氨甲基-2-硒基尿苷、5-羧甲基尿苷、5-甲基二氢尿苷、5-牛磺甲基尿苷(5-taurinomethyluridine)、5-牛磺甲基-2-硫代尿苷、5-(异戊烯基氨甲基)尿苷、2'-o-甲基假尿苷、2-硫代-2'o-甲基尿苷和3,2'-o-二甲基尿苷。

经过修饰的或经过化学修饰的核苷酸的实例包含n⁶-甲基腺苷、2-氨基腺苷、3-甲基腺苷、8-氮腺苷、7-脱氮腺苷、8-氧代腺苷、8-溴代腺苷、2-甲硫基-n⁶-甲基腺苷、n⁶-异戊烯基腺苷、2-甲硫基-n⁶-异戊烯基腺苷、n⁶-(顺式-羟基异戊烯基)腺苷、2-甲硫基-n⁶-(顺式-羟基异戊烯基)腺苷、n⁶-甘氨酰基氨基甲酰基腺苷、n6-苏氨酰基氨基甲酰基-腺苷、n⁶-甲基-n⁶-苏氨酰基氨基甲酰基-腺苷、2-甲硫基-n⁶-苏氨酰基氨基甲酰基-腺苷、n⁶,n⁶-二甲基腺苷、n6-羟基正缬氨酰基氨基甲酰基腺苷、2-甲硫基-n⁶-羟基正缬氨酰基氨基甲酰基-腺苷、n⁶-乙酰基-腺苷、7-甲基-腺嘌呤、2-甲硫基-腺嘌呤、2-甲氧基-腺嘌呤、α-硫代-腺苷、2'-o-甲基-腺苷、n⁶,2'-o-二甲基-腺苷、n⁶,n⁶,2'-o-三甲基-腺苷、1,2'-o-二甲基-腺苷、2'-o-腺嘌呤核糖苷、2-氨基-n⁶-甲基-嘌呤、1-硫代-腺苷、2'-f-阿糖-腺苷、2'-f-腺苷、2'-oh-阿糖-腺苷和n⁶-(19-氨基-五氧杂十九基)-腺苷。

经过修饰的或经过化学修饰的核苷酸的实例包含n^l-烷基鸟苷、n²-烷基鸟苷、噻吩并鸟苷、7-脱氮鸟苷、8-氧代鸟苷、8-溴代鸟苷、o⁶-烷基鸟苷、黄嘌呤核苷、肌苷和n^l-烷基肌苷。

经过修饰的或经过化学修饰的核苷酸的实例包含n^l-甲基鸟苷、n²-甲基鸟苷、噻吩并鸟苷、7-脱氮鸟苷、8-氧代鸟苷、8-溴代鸟苷、o⁶-甲基鸟苷、黄嘌呤核苷、肌苷和n^l-甲基肌苷。

经过修饰的或经过化学修饰的核苷酸的实例包含假尿苷。假尿苷的实例包含n^l-烷基假尿苷、n^l-环烷基假尿苷、n¹-羟基假尿苷、n¹-羟烷基假尿苷、n^l-苯基假尿苷、n^l-苯基烷基假尿苷、n^l-氨烷基假尿苷、n³-烷基假尿苷、n⁶-烷基假尿苷、n⁶-烷氧基假尿苷、n⁶-羟基假尿苷、n⁶-羟烷基假尿苷、n⁶-吗啉基假尿苷、n⁶-苯基假尿苷和n⁶-卤代假尿苷。假尿苷的实例包含n^l-烷基-n⁶-烷基假尿苷、n^l-烷基-n⁶-烷氧基假尿苷、n^l-烷基-n⁶-羟基假尿苷、n^l-烷基-n⁶-羟烷基假尿苷、n^l-烷基-n⁶-吗啉基假尿苷、n^l-烷基-n⁶-苯基假尿苷和n^l-烷基-n⁶-卤代假尿苷。在这些实例中，烷基、环烷基和苯基取代基可以是未取代的或者进一步由烷基、卤素、卤代烷基、氨基或硝基取代基取代。

假尿苷的实例包含n^l-甲基假尿苷、n^l-乙基假尿苷、n^l-丙基假尿苷、n^l-环丙基假尿苷、n^l-苯基假尿苷、n^l-氨甲基假尿苷、n³-甲基假尿苷、n¹-羟基假尿苷和n¹-羟甲基假尿苷。

核酸单体的实例包含经过修饰的和经过化学修饰的核苷酸，所述核苷酸包含本领域已知的任何此类核苷酸。

经过修饰的和经过化学修饰的核苷酸单体的实例包含本领域已知的任何此类核苷酸，例如，2'-o-甲基核糖核苷酸、2'-o-甲基嘌呤核苷酸、2'-脱氧-2'-氟核糖核苷酸、2'-脱氧-2'-氟嘧啶核苷酸、2'-脱氧核糖核苷酸、2'-脱氧嘌呤核苷酸、通用碱基核苷酸、5-c-甲基-核苷酸和反向脱氧碱基单体残基。

经过修饰的和经过化学修饰的核苷酸单体的实例包含3'端稳定的核苷酸、3'-甘油基核苷酸、3'-反向碱基核苷酸和3'-反向胸苷。

经过修饰的和经过化学修饰的核苷酸单体的实例包含锁核酸核苷酸(lna)、2'-o,4'-c-亚甲基-(d-呋喃核糖基)核苷酸、2'-甲氧基乙氧基(moe)核苷酸、2'-甲基-硫代-乙基、2'-脱氧-2'-氟核苷酸和2'-o-甲基核苷酸。在示例性实施例中，经过修饰的单体是锁核酸核苷酸(lna)。

经过修饰的和经过化学修饰的核苷酸单体的实例包含2',4'-约束的2'-o-甲氧乙基(cmoe)和2'-o-乙基(cet)修饰的dna。

经过修饰的和经过化学修饰的核苷酸单体的实例包含2'-氨基核苷酸、2'-o-氨基核苷酸、2'-c-烯丙基核苷酸和2'-o-烯丙基核苷酸。

经过修饰的和经过化学修饰的核苷酸单体的实例包含n⁶-甲基腺苷核苷酸。

经过修饰的和经过化学修饰的核苷酸单体的实例包含具有经过修饰的碱基的核苷酸单体5-(3-氨基)丙基尿苷、5-(2-巯基)乙基尿苷、5-溴代尿苷、8-溴代鸟苷或7-脱氮腺苷。

经过修饰的和经过化学修饰的核苷酸单体的实例包含2'-o-氨丙基取代的核苷酸。

经过修饰的和经过化学修饰的核苷酸单体的实例包含用2'-r、2'-or、2'-卤素、2'-sr或2'-氨基置换核苷酸的2'-oh基团，其中r可以是h、烷基、烯基或炔基。

saenger,《核酸结构原理(principlesofnucleicacidstructure)》,施普林格出版社(springer-verlag),1984中给出了经过修饰的核苷酸的一些实例。

可以将上文描述的碱基修饰的实例与核苷或核苷酸结构的另外的修饰组合，所述另外的修饰包含糖修饰和键修饰。

在自然界中可以发现某些经过修饰的或经过化学修饰的核苷酸单体。

含有一个或多个una单体的可翻译分子

本发明的各方面提供了是含有一个或多个una单体的低聚化合物的可翻译分子的结构和组合物。可翻译低聚物可以是药物组合物的活性剂。在一些实施例中，可翻译低聚物对人agl或其变体进行编码。

本发明的低聚可翻译分子可以含有一个或多个una单体。本发明的低聚分子可以用作用于供应肽和蛋白质治疗剂的调配物的活性剂。在一些实施例中，可翻译低聚物对人agl或其变体进行编码。

在一些实施例中，本发明提供了具有并入una单体与某些天然核苷酸、非天然核苷酸、经过修饰的核苷酸或经过化学修饰的核苷酸的新型组合的结构的低聚可翻译化合物。

本发明的可翻译低聚化合物的长度可以为约200到约12,000个碱基。本发明的可翻译低聚化合物的长度可以为约1000个、2000个、3000个、4000个、5000个、6000个、7000个、8000个或约9000个碱基。在一些实施例中，本发明的可翻译低聚化合物的长度可以为约4000个、4100个、4200个、4300个、4400个、4500个、4600个、4700个、4800个、4900个、5000个、5100个、5200个、5300个、5400个或约5500个碱基。在示例性实施例中，本发明的可翻译低聚化合物的长度为约5000个碱基。

在另外方面，本发明的包括一个或多个una单体的低聚可翻译化合物可以是药理学活性分子。可翻译低聚分子可以用作用于在体外、在体内或离体地产生肽或蛋白质活性剂的活性药物成分。在示例性实施例中，本发明的可翻译低聚化合物对人agl或其变体进行编码。

本发明的可翻译低聚分子可以具有式i的结构：

其中l¹是键，n为200到12,000，并且每次出现时，l²是具有式-c¹-c²-c³-的una连接子基团，其中r附接到c²并且具有式-och(ch2r³)r⁵，其中r³是-or⁴、-sr⁴、-nr⁴2、-nh(c＝o)r⁴、吗啉基、吗啉-1-基、哌嗪-1-基或4-烷酰基哌嗪-1-基，其中r⁴在每次出现时是相同或不同的并且是h、烷基、胆固醇、脂质分子、多胺、氨基酸或多肽，并且其中r⁵是核碱基，或者l²(r)是如核糖等糖并且r是核碱基，或者l²是如经过修饰的核糖等经过修饰的糖并且r是核碱基。在某些实施例中，核碱基可以是经过修饰的核碱基。l¹可以是磷酸二酯键。

可翻译低聚分子的碱基序列可以是任何核碱基序列。

在一些方面，本发明的可翻译低聚分子在任何单体间(intermonomer)位置处可以具有任何数量的硫代磷酸酯单体间键。

在一些实施例中，可翻译低聚分子的单体间键中的任何一个或多个单体间键可以是磷酸二酯、包括二硫酸酯的硫代磷酸酯、手性硫代磷酸酯和其它经过化学修饰的形式。

当可翻译低聚分子在una单体中终止时，根据上文所示的位置编号，末端位置具有1-端，或者末端位置具有3-端。

增强的翻译

本发明的可翻译分子可以并入增强分子的翻译效率的区域。

通常，可以将本领域已知的翻译增强子区并入可翻译分子的结构中，以增加肽或蛋白质产率。

含有翻译增强子区的可翻译分子可以增加肽或蛋白质的产生。

在一些实施例中，翻译增强子区可以包括或位于可翻译分子的5'非翻译区或3'非翻译区。

翻译增强子区的实例包含来自tev5'utr和非洲爪蟾β-珠蛋白3'utr的天然存在的增强子区。

分子结构和序列

可翻译分子可以被设计成表达靶肽或蛋白。在一些实施例中，靶肽或蛋白可以与受试者的病状或疾病相关联。

在一些方面，可翻译分子的碱基序列可以包含与mrna的碱基序列的至少有效部分或结构域相同的部分，其中有效部分足以向可翻译分子的翻译产物赋予治疗活性。

在一些方面，本发明提供了具有与细胞的原生核酸分子的至少片段相同的碱基序列的活性可翻译分子。

在某些实施例中，可翻译分子的碱基序列可以包含除了一个或多个碱基突变外与mrna的碱基序列相同的部分。可翻译分子的突变数量应当不超过将会产生可翻译分子的具有基本上低于mrna的活性的翻译产物的量。

本发明的低聚可翻译una分子可以展示核碱基序列并且可以被设计成在体外、离体地或在体内表达肽或蛋白质。所表达的肽或蛋白质可以具有各种形式的活性，所述活性包含与从原生或天然mrna表达的蛋白质相对应的活性。

在一些实施例中，本发明的可翻译分子的链长可以为约400到15,000个单体，其中不是una单体的任何单体可以是n单体或q单体。

分子端帽结构

本发明的可翻译分子可以具有5'端，所述5'端被本领域已知的各种基团及其类似物封端。在示例性实施例中，所述5'端帽可以是m7gpppgm端帽。在另外的实施例中，所述5'端帽可以选自m7gpppa、m7gpppc；非甲基化的端帽类似物(例如，gpppg)；二甲基化的端帽类似物(例如，m2,7gpppg)、三甲基化的端帽类似物(例如，m2,2,7gpppg)、二甲基化的对称端帽类似物(例如，m7gpppm7g)或抗-反向端帽类似物(例如，arca；m7、2'omegpppg、m72'dgpppg、m7,3'omegpppg、m7,3'dgpppg及其四核糖基衍生物)(参见，例如，jemelity,j.等人,《rna》9:1108-1122(2003))。在其它实施例中，所述5'端帽可以是arca端帽(3'-ome-m7g(5')pppg)。所述5'端帽可以是mcap(m7g(5')ppp(5')g、n⁷-甲基-鸟苷-5'-三磷酸-5'-鸟苷)。所述5'端帽可以抗水解。

wo2015/051169a2、wo/2015/061491以及美国专利第8,093,367号和第8,304,529号中给出了5'端帽结构的一些实例。

尾区

在一些实施例中，对agl进行编码的可翻译低聚物包括尾区，所述尾区能够用于保护mrna免受外切核酸酶降解。在一些实施例中，所述尾区可以是polya尾。

可以使用本领域已知的各种方法添加polya尾，例如，使用polya聚合酶将尾添加到合成的或体外转录的rna。其它方法包含使用转录载体对polya尾进行编码或使用连接酶(例如，通过使用t4rna连接酶和/或t4dna连接酶的配体)，其中polya可以连接到有义rna的3'端。在一些实施例中，使用上述方法中任一种方法的组合。

在一些实施例中，可翻译低聚物包括3'polya尾结构。在一些实施例中，所述polya尾的长度可以为至少约5个、10个、15个、20个、25个、30个、35个、40个、45个、50个、100个、200个或300个核苷酸。在一些实施例中，3'polya尾含有约5到300个腺苷核苷酸(例如，约30到250个腺苷核苷酸、约60到220个腺苷核苷酸、约80到200个腺苷核苷酸、约90到约150个腺苷核苷酸或约100到约120个腺苷核苷酸)。在示例性实施例中，所述3'polya尾的长度为约100个核苷酸。在另一个示例性实施例中，所述3'polya尾的长度为约115个核苷酸。在另一个示例性实施例中，所述3'polya尾的长度为约250个核苷酸。

在一些实施例中，所述3'polya尾包括一个或多个una单体。在一些实施例中，所述3'polya尾含有2个、3个、4个、5个、10个、15个、20个或更多个una单体。在示例性实施例中，所述3'polya尾含有2个una单体。在另一个示例性实施例中，所述3'polya尾含有连续发现的2个una单体，即，二者在所述3'polya尾中彼此相邻。

在示例性实施例中，所述3'polya尾包括seqidno:6中所示的序列或由其组成。在另一个示例性实施例中，所述3'polya尾包括seqidno:38中所示的序列或由其组成。在又一个示例性实施例中，所述3'polya尾包括seqidno:39中所示的序列或由其组成。

在一些实施例中，所述可翻译低聚物包括3'polyc尾结构。在一些实施例中，所述polyc尾的长度可以为至少约5个、10个、15个、20个、25个、30个、35个、40个、45个、50个、100个、200个或300个核苷酸。在一些实施例中，3'polyc尾含有约5到300个胞嘧啶核苷酸(例如，约30到250个胞嘧啶核苷酸、约60到220个胞嘧啶核苷酸、约80到200个胞嘧啶核苷酸、约90到约150个胞嘧啶核苷酸或约100到约120个胞嘧啶核苷酸)。在示例性实施例中，所述3'polyc尾的长度为约100个核苷酸。在另一个示例性实施例中，所述3'polyc尾的长度为约115个核苷酸。所述polyc尾可以添加至所述polya尾，或者可以取代所述polya尾。所述polyc尾可以添加至所述polya尾的5'端或所述polya尾的3'端。

在一些实施例中，调节所述polya尾和/或所述polyc尾的长度以控制本发明的经过修饰的可翻译低聚分子的稳定性，从而控制蛋白质的转录。例如，由于polya尾的长度可能影响可翻译分子的半衰期，因此可以调整所述polya尾的长度以改变mrna对核酸酶的抗性水平，从而控制靶细胞中多核苷酸表达和/或多肽生成的时间进程。

5'和3'非翻译区(utr)

在一些实施例中，对agl进行编码的可翻译低聚物可以包括5'非翻译区和/或3'非翻译区。如本领域所理解的，5'utr和/或3'utr可能影响mrna的稳定性或翻译的效率。在示例性实施例中，所述可翻译低聚物包括5'utr和3'utr。

在一些实施例中，所述可翻译低聚物可以包括至少有约25个、50个、75个、100个、125个、150个、175个、200个、300个、400个或500个核苷酸的5'utr。在一些实施例中，5'utr含有约50到300个核苷酸(例如，约75到250个核苷酸、约100到200个核苷酸、约120到约150个核苷酸或约135个核苷酸)。在示例性实施例中，所述5'utr的长度为约135个核苷酸。

在一些实施例中，所述5'utr源自本领域已知相对稳定的mrna分子(例如，组蛋白、微管蛋白、珠蛋白、gapdh、肌动蛋白或柠檬酸循环酶)，以提高所述可翻译低聚物的稳定性。在其它实施例中，5'utr序列可以包含cmv即刻早期1(ie1)基因的部分序列。5'utr序列的实例可以在美国专利第9,149,506号中找到。在一些实施例中，所述5'utr包括选自以下的序列：人il-6、丙氨酸氨基转移酶1、人载脂蛋白e、人纤维蛋白原α链、人转甲状腺素蛋白、人触珠蛋白、人α-1-抗糜蛋白酶、人抗凝血酶、人α-1-抗胰蛋白酶、人白蛋白、人β珠蛋白、人补体c3、人补体c5、synk、at1g58420、小鼠β珠蛋白、小鼠白蛋白和烟草蚀纹病毒的5'utr或前述任何一种的片段。在示例性实施例中，所述5'utr源自烟草蚀纹病毒(tev)。在另一个示例性实施例中，所述5'utr包括seqidno:3中阐述的序列或由其组成。在又一个示例性实施例中，所述5'utr是seqidno:3中阐述的序列的片段，如seqidno:3中的至少10个、20个、30个、40个、50个、60个、70个、80个、90个、100个、110个、120个或125个相邻核苷酸的片段。

在一些实施例中，所述可翻译低聚分子包括内部核糖体进入位点(ires)。如本领域所理解的，ires是允许以不依赖末端的方式启动翻译的rna元件。在示例性实施例中，所述ires位于所述5'utr中。在其它实施例中，所述ires可以位于所述5'utr之外。

在一些实施例中,所述可翻译低聚物可以包括至少有约25个、50个、75个、100个、125个、150个、175个、200个、300个、400个或500个核苷酸的3'utr。在一些实施例中，3'utr含有约50到300个核苷酸(例如，约75到250个核苷酸、约100到200个核苷酸、约140到约175个核苷酸或约160个核苷酸)。在示例性实施例中，所述3'utr的长度为约160个核苷酸。

在一些实施例中，所述3'utr包括一个或多个una单体。在一些实施例中，所述3'utr含有2个、3个、4个、5个、10个、15个、20个或更多个una单体。

3'utr序列的实例可以在美国专利第9,149,506号中找到。在一些实施例中，所述3'utr包括选自以下的序列：丙氨酸氨基转移酶1、人载脂蛋白e、人纤维蛋白原α链、人触珠蛋白、人抗凝血酶、人α珠蛋白、人β珠蛋白、人补体c3、人生长因子、人七肽、malat-1、小鼠β珠蛋白、小鼠白蛋白和非洲爪蟾β珠蛋白的3'utr或前述任何一种的片段。在示例性实施例中，所述3'utr源自非洲爪蟾β珠蛋白。在另一个示例性实施例中，所述3'utr源自非洲爪蟾β珠蛋白并含有一个或多个una单体。在另一个示例性实施例中，所述3'utr包括seqidno:5和33-37中阐述的序列或由其组成。在又一个示例性实施例中，所述3'utr是seqidno:5和33-37中阐述的序列的片段，如seqidno:5和33-37中的至少10个、20个、30个、40个、50个、60个、70个、80个、90个、100个、110个、120个、130个、140个或150个相邻核苷酸的片段。

在某些示例性实施例中，对agl进行编码的可翻译低聚物包括seqidno:3的5'utr序列和选自seqidno:5和33-37的3'utr序列。在一些实施例中，对agl进行编码的可翻译低聚物进一步包括seqidno:6、seqidno:38或seqidno:39中所示的polya尾。在一些实施例中，agl的mrna编码序列包括选自seqidno:7-32或seqidno:41-45的序列。

三联终止密码子

在一些实施例中，对agl进行编码的可翻译低聚物可以包括紧邻cds下游的序列，所述序列产生三联终止密码子。可以引入所述三联终止密码子以提高翻译效率。在一些实施例中，所述可翻译低聚物可以包括紧邻本文所述的pahcds下游的序列auaagugaa(seqidno:40)，如seqidno:7-32或seqidno:41-45所示。

翻译起始位点

在一些实施例中，对agl进行编码的可翻译低聚物可以包括翻译起始位点。此类序列在本领域中是已知的，并且包含kozak序列。参见，例如kozak,marilyn(1988)《分子和细胞生物学(mol.andcellbiol.)》,8:2737-2744；kozak,marilyn(1991)《生物化学杂志(j.biol.chem.)》,266:19867-19870；kozak,marilyn(1990)《美国国家科学院院刊(procnatl.acad.sci.usa)》,87:8301-8305；和kozak,marilyn(1989)《细胞生物学杂志(j.cellbiol.)》,108:229–241；以及其中引用的参考文献。如本领域所理解的，kozak序列是围绕真核mrna的翻译起始位点为中心的短共有序列，所述短共有序列允许有效地启动mrna的翻译。核糖体翻译机器在kozak序列的背景下识别aug起始密码子。

在一些实施例中，翻译起始位点，例如kozak序列，被插入到agl的编码序列的上游。在一些实施例中，翻译起始位点被插入到5'utr的下游。在某些示例性实施例中，翻译起始位点被插入到agl的编码序列的上游和5'utr的下游。

如本领域所理解的，kozak序列的长度可以变化。通常，增加前导序列的长度会增强翻译。

在一些实施例中，对agl进行编码的可翻译低聚物包括具有seqidno:4的序列的kozak序列。在某些示例性实施例中，对agl进行编码的可翻译低聚物包括具有seqidno:4的序列的kozak序列,其中所述kozak序列紧邻5'utr的下游且紧邻agl的编码序列的上游。

合成方法

在各个方面，本发明提供了用于合成可翻译信使分子的方法。

可以使用本文公开的方法以及本领域已知的任何相关技术来合成和分离本发明的可翻译分子。

一些用于制备核酸的方法在下列文献中给出：例如，merino,《核苷酸类似物的化学合成(chemicalsynthesisofnucleosideanalogues)》,(2013)；gait,《寡核苷酸合成：一种实用的方法(oligonucleotidesynthesis:apracticalapproach)》(1984)；herdewijn,《寡核苷酸合成，分子生物学方法(oligonucleotidesynthesis,methodsinmolecularbiology)》,第288卷(2005)。

在一些实施例中，可翻译分子可以通过体外转录(ivt)反应生成。可以使用t7试剂聚合核苷三磷酸酯(ntp)的混合物以便，例如，从dna模板产生rna。可以用无rnase的dnase降解dna模板，并且对rna进行柱分离。

在一些实施例中，可以使用连接酶将合成的低聚物连接到rna分子或rna转录物的3'端以形成可翻译分子。连接到3'端的合成的低聚物可以提供polya尾的功能，并有利地提供了抵抗其被3'-外切核糖核酸酶去除的能力。连接产物可翻译分子可以具有提高的比活性，并提供增加水平的异位蛋白表达。

在某些实施例中，本发明的可翻译分子的连接产物可以通过具有原生特异性的rna转录物生成。连接产物可以是合成分子，所述合成分子保留了在5'端的rna转录物的结构以确保与原生特异性相容。

在另外的实施例中，本发明的可翻译分子的连接产物可以通过外源性rna转录物或者非天然rna生成。连接产物可以是保留了rna的结构的合成分子。

在不希望受到理论约束的情况下，细胞中规范的mrna降解途径包含以下步骤：(i)通过3'外切核酸酶将polya尾逐渐切回到末端，从而终止了有效翻译所需的环相互作用，并使端帽易受到攻击；(ii)使复合物去端化(decapping)以去除5'端帽；(iii)通过5'和3'外切核酸酶活性降解转录物的未受保护且翻译能力低的残基。

本发明的实施例涉及新的可翻译结构，其可以具有比原生转录物的翻译活性更高的翻译活性。除其它外，本文的可翻译分子可以防止外切核酸酶在去腺苷酸化过程中修剪polya尾。

本发明的实施例提供了可翻译分子的结构、组合物和方法。本发明的实施例可以提供含有一个或多个una单体且功能半衰期增长的可翻译分子。

已经发现，通过将mrna转录物高度转化为连接产物，可以出人意料地完成合成的低聚物与mrna转录物的3'端的连接。

如本文所用，术语polya尾和polya低聚物是指单体的低聚物，其中单体可以包含基于腺嘌呤的核苷酸、una单体、天然存在的核苷酸、经过修饰的核苷酸或核苷酸类似物。

用于连接至rna的3'端的低聚物的长度可以为2到120个单体、或长度为3到120个单体、或长度为4到120个单体、或长度为5到120个单体或更长。在示例性实施例中，用于连接的低聚物的长度为约30个单体。

脂基制剂

脂基制剂由于其生物相容性和易于大规模生产而越来越多地被视为是最有希望的rna递送系统之一。阳离子脂质作为递送rna的合成材料已经得到广泛的研究。混合在一起后，核酸被阳离子脂质凝聚而形成被称为阳离子脂质体的脂质/核酸复合物。这些脂质复合物能够保护遗传物质免受核酸酶的作用，并通过与带负电荷的细胞膜相互作用而将所述遗传物质递送到细胞中。通过直接将生理ph值下的带正电荷的脂质与带负电荷的核酸混合，可以制备出阳离子脂质体。

常规的脂质体由脂质双层组成，所述脂质双层可以由阳离子、阴离子或中性(磷)脂质和胆固醇构成并且包含水核。脂质双层和水空间均可以分别掺入疏水性或亲水性化合物。可以通过在脂质体表面添加亲水性聚合物涂层，例如聚乙二醇(peg)来改变脂质体特性和体内行为，从而获得立体稳定。此外，通过将配体(例如，抗体、肽和碳水化合物)附接到其表面或附接的peg链的末端，脂质体可以用于特异性靶向(《前沿药理学(frontpharmacol.)》2015年12月1日；6:286)。

脂质体是胶体脂质基和基于表面活性剂的递送系统，其由围绕水性隔室的磷脂双层构成。脂质体可以呈现为球形小泡，并且大小范围为20纳米到几微米。基于阳离子脂质的脂质体能够通过静电相互作用与带负电荷的核酸结合，从而形成具有生物相容性、低毒性和能够大规模生产以用于体内临床应用的复合物。脂质体可以与质膜融合，从而被摄取；一旦进入细胞内，脂质体就会通过内吞途径被处理，然后遗传物质从内体/载剂释放到细胞质中。因为脂质体基本上是生物膜的类似物且可以由天然和合成的磷脂制备，所以脂质体因其优越的生物相容性而长期以来被视为药物递送媒剂。(《国家纳米医学杂志(intjnanomedicine.)》2014；9:1833-1843)。

阳离子脂质体传统上是寡核苷酸最常用的非病毒递送系统，包含质粒dna、反义寡核苷酸和sirna/小发夹ra-shrna)。阳离子脂质，如dotap(1,2-二烯酰-3-三甲基丙烷)和dotma(n-[l-(2,3-二烯酰氧基)丙基]-n,n,n-三甲基硫酸铵)可以与带负电荷的核酸形成复合物或阳离子脂质体，以通过静电相互作用形成纳米颗粒，从而提供较高的体外转染效率。此外，还开发了用于rna递送的中性脂基纳米脂质体，例如中性l,2-二油酰基-sn-甘油-3-磷脂酰胆碱(dopc)基纳米脂质体。(《高级药物递送综述(advdrugdelivrev.)》2014年2月；66:110-116)

根据一些实施例，本文描述的可表达的多核苷酸和异源mrna结构是脂质配制的。脂质制剂优选地选自但不限于脂质体、阳离子脂质体、共聚物(如plga)和脂质纳米颗粒。在一个优选的实施例中，脂质纳米颗粒(lnp)包括：

(a)核酸；

(b)阳离子脂质；

(c)聚合还原剂(如聚乙二醇(peg)脂质或经过peg修饰的脂质)；

(d)任选地，非阳离子脂质(如中性脂质)；以及

(e)任选地，固醇。

在一个实施例中，脂质纳米颗粒制剂由以下组成：(i)至少一个阳离子脂质；(ii)中性脂质；(iii)固醇，例如，胆固醇；以及(iv)peg-脂质，摩尔比约为：20-60％阳离子脂质：5-25％中性脂质：25-55％固醇；0.5-15％peg-脂质。

含硫代氨基甲酸酯和氨基甲酸酯的脂质制剂

wo/2015/074085和ussn15/387,067中给出了用于递送本发明的活性分子的脂质和脂质组合物的一些实例，所述文献中的每一个均通过引用整体并入本文。在某些实施例中，脂质是下式的化合物：

其中

r1和r2均包括由1至14个碳组成的直链烷基或由2至14个碳组成的烯基或炔基；

l1和l2均包括由5至18个碳组成的或与n形成杂环的直链亚烷基或亚烯基；

x是s；

l3包括键或由1至6个碳组成的或与n形成杂环的直链亚烷基；

r3包括由1至6个碳组成的直链或支链亚烷基；并且

r4和r5相同或不同，各自包括氢或由1至6个碳组成的直链或支链烷基；

或其药学上可接受的盐。

脂质制剂可以含有一个或多个选自以下的可电离阳离子脂质：

阳离子脂质

脂质纳米颗粒优选地包含适于形成脂质纳米颗粒的阳离子脂质。优选地，所述阳离子脂质在接近生理ph值下携带净正电荷。

例如，所述阳离子脂质可以为n,n-二油基-n,n-二甲基氯化铵(dodac)、n,n-二硬脂基-n,n-二甲基溴化铵(ddab)、1,2-二油基三甲基氯化铵(dotap)(也被称为n-(2,3-二油基氧基)丙基)-n,n,n-三甲基氯化铵和1,2-二油酰氧基-3-三甲基氨基丙烷氯盐)、n-(1-(2,3-二油酰氧基)丙基)-n,n,n-三甲基氯化铵(dotma)、n,n-二甲基-2,3-二油酰氧基)丙基胺(dodma)、1,2-二亚油酰氧基-n,n-二甲基氨基丙烷(dlindma)、1,2-二氢亚油酰氧基-n,n-二甲基氨基丙烷(dlendma)、1,2-二氢亚油酰氧基-n,n-二甲基氨基丙烷(γ-dlendma)、1,2-二烷基氨基甲酰氨基甲酰氧基-3-二甲基氨基丙烷(dlin-c-dap)、1,2-二烷基氨基甲酰氧基-3-(二甲基氨基)乙酰氧基丙烷(dlin-dac)、1,2-二烷基氨基甲酰氧基-3-吗啉丙烷(dlin-ma)、1,2-二氢油酰基-3-二甲基氨基丙烷(dlindap)、1,2-二氢油酰基硫代-3-二甲基氨基丙烷(dlin-s-dma)、1-亚油酰基-2-亚油酰基-3-二甲基氨基丙烷(dlin-2-dmap)、1,2-二氢油酰氧基-3-三甲氨基丙烷氯盐(dlin-tma.ci)、1,2-二氢油酰-3-三甲氨基丙烷氯盐(dlin-tap.ci)、1,2-二氢油酰氧基-3-(n-甲基哌嗪)丙烷(dlin-mpz)、或3-(n,n-二油基氨基)-1,2-丙二醇(dlinap)、3-(n,n-二油基氨基)-1,2-丙二醇(doap)、1,2-二油基氧代-3-(2-n,n-二甲基氨基)乙氧基丙烷(dlin-eg-dma)、2,2-二苯基-4-二甲基氨基甲基-[1,3]-二氧戊烷(dlin-k-dma)或其类似物、(3ar,5s,6as)-n,n-二甲基-2,2-二((9z,12z)-十八烷基-9,12-二烯基)四氢-3ah-环戊烯[d][1,3]二噁醇-5-胺、(6z,9z,28z,31z)-三十七碳-6,9,28,31-四烯-19-基4-(二甲基氨基)丁酸甲酯(mc3)、1,1'-(2-(4-(2-((2-(双(2-羟基十二烷基)氨基)乙基)(2-羟基十二烷基)氨基)乙基)哌嗪-1-基)乙基氮杂二基)二十二烷-2-醇(c12-200)、2,2-二氢吲哚基-4-(2-二甲基氨基乙基)-[1,3]-二氧戊环(dlin-k-c2-dma)、2,2-二氢吲哚基-4-二甲基氨基甲基-[1,3]-二氧戊环(dlin-k-dma)、(6z,9z,28z,31z)-三十七碳6,9,28,31-四烯-19-基4-(二甲基氨基)丁酸(dlin-m-c3-dma)、3-((6z,9z,28z,31z)-三十七碳-6,9,28,31-四烯-19-氧基)-n,n-二甲基丙-1-胺(mc3醚)、4-((6z,9z,28z,31z)-三十七碳-6,9,28,31-四烯-19-氧基)-n,n-二甲基丁-1-胺(mc4醚)或前述任何一种的任何组合。其它阳离子脂质包含但不限于n,n-二硬脂基-n,n-二甲基溴化铵(ddab)、3p-(n-(n',n'-二甲基氨基乙烷)-氨基甲酰基)胆固醇(dc-choi)、n-(l-(2,3-二油酰氧基)丙基)-n-2-(精胺)乙基)-n,n-二甲基三氟乙酸铵(dospa)、二十八烷基酰胺基糖基羧精胺(dogs)、1,2-二亮氨酰-sn-3-磷酸乙醇胺(dope)、1,2-二油酰-3-二甲基氨丙烷(dodap)、n-(1,2-二异丙基-3-基)-n,n-二甲基-n-羟乙基溴化铵(dmrie)和2,2-二苯基-4-二甲基氨基乙基-[1,3]-二氧戊环(xtc)。此外，还可以使用阳离子脂质的商业制剂，例如脂质体(lipofectin)(包含dotma和dope，可从gibco/brl获得)和脂质体(lipofectamine)(包括dospa和dope，可从gibco/brl获得)。

其它合适的阳离子脂质公开于以下文献中：国际出版物第wo09/086558、wo09/127060、wo10/048536、wo10/054406、wo10/088537、wo10/129709和wo2011/153493号；美国专利出版物第2011/0256175、2012/0128760和2012/0027803号；美国专利第8,158,601号；以及love等人,《美国科学院院报(pnas)》,107(5),1864-69,2010。其它合适的氨基脂质包含具有替代脂肪酸基团和其它二烷基氨基的脂质，包含烷基取代基不同的脂质(例如，n-乙基-n-甲基氨基和n-丙基-n-乙基氨基)。通常，具有较少饱和酰基链的氨基脂质更易于调整大小，尤其是当出于过滤灭菌的目的，复合物的大小必须小于约0.3微米时。可以使用含有碳链长度在c14到c22范围内的不饱和脂肪酸的氨基脂质。也可以使用其它支架来分离氨基脂质的氨基基团和脂肪酸或脂肪烷基部分。

在另外的优选实施例中，根据专利申请pct/ep2017/064066，lnp包括具有式(iii)的阳离子脂质。在此上下文中，pct/ep2017/064066的公开内容也通过引用并入本文。

在某些实施例中，本发明的氨基或阳离子脂质具有至少一个可质子化或可去质子化基团，使得脂质在等于或低于生理ph值(例如ph7.4)的ph值下带正电荷，且在第二ph值下为中性，所述第二ph值优选地等于或高于生理ph值。当然，应当理解的是，作为ph的函数的质子的添加或去除是平衡过程，并且对带电或中性脂质的提及是指占优势物种的性质，而不要求所有的脂质都以带电或中性形式存在。不排除在本发明中使用具有多个可质子化或可去质子化基团的脂质或两性离子脂质。在某些实施例中，可质子化脂质的可质子化基团的pka在约4到约11的范围内，例如，pka为约5到约7。

阳离子脂质可以包括存在于颗粒中的总脂质的约20mol％到约70或75mol％、或约45到约65mol％、或约20、25、30、35、40、45、50、55、60、65或约70mol％。在另一个实施例中，脂质纳米颗粒包含摩尔占比为约25％到约75％的阳离子脂质，例如，摩尔占比为约20％到约70％、约35％到约65％、约45％到约65％、约60％、约57.5％、约57.1％、约50％或约40％(基于脂质纳米颗粒中脂质的100％摩尔百分比)。在一个实施例中，阳离子脂质与核酸的比率为约3到约15，例如约5到约13或约7到约11。

药物组合物

在一些方面，本发明提供了含有可翻译化合物和药学上可接受的载剂的药物组合物。

药物组合物能够进行局部或全身施用。在一些方面，药物组合物可以具有任何施用方式。在某些方面，可以通过任何途径进行施用，包含静脉内、皮下、肺脏、肌内、腹膜内、皮肤、口服、吸入或鼻腔施用。

本发明的实施例包含含有脂质制剂中的可翻译化合物的药物组合物。

在一些实施例中，药物组合物可以包括选自阳离子脂质、阴离子脂质、固醇、聚乙二醇脂质和前述任何组合的一种或多种脂质。在一些实施例中，含有可翻译化合物的药物组合物包括阳离子脂质、磷脂、胆固醇和聚乙二醇脂质。

在某些实施例中，药物组合物可以基本上不含脂质体。

在另外的实施例中，药物组合物可以包含纳米颗粒。

wo/2015/074085中给出了用于递送本发明的活性分子的脂质和脂质组合物的一些实例，所述文献通过引用整体并入本文。在某些实施例中，脂质是阳离子。在一些实施例中，阳离子脂质包括式ii的化合物：

其中r1和r2相同或不同，各自为直链或支链烷基、烯基或炔基，l1和l2相同或不同，各自为具有至少五个碳原子的直链烷基，或与n形成杂环，x1为键或为--co--o--，通过其形成l2--co--o--r2，x2为s或o，l3为键或低级烷基，r3为低级烷基，r4和r5相同或不同，各自为低级烷基。本文还描述了式ii的化合物，其中不存在l3，r1和r2各由至少7个碳原子组成，r3为乙烯或正丙烯，r4和r5为甲基或乙基，并且l1和l2各由具有至少5个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中不存在l3，r1和r2各由至少7个碳原子组成，r3为乙烯或正丙烯，r4和r5为甲基或乙基，并且l1和l2各由具有至少5个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中不存在l3，r1和r2各由具有至少9个碳原子的烯基组成，r3为乙烯或正丙烯，r4和r5为甲基或乙基，并且l1和l2各由具有至少5个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中是l3为亚甲基，r1和r2各由至少7个碳原子组成，r3为乙烯或正丙烯，r4和r5为甲基或乙基，并且l1和l2各由具有至少5个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中是l3为亚甲基，r1和r2各由至少9个碳原子组成，r3为乙烯或正丙烯，r4和r5各为甲基，l1和l2各由具有至少7个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中是l3为亚甲基，r1由具有至少9个碳原子的烯基组成且r2由具有至少7个碳原子的烯基组成，r3为正丙烯，r4和r5各为甲基，l1和l2各由具有至少7个碳原子的直链烷基组成。本文还描述了式ii的化合物，其中是l3为亚甲基，r1和r2各由具有至少9个碳原子的烯基组成，r3为乙烯，r4和r5各为甲基，l1和l2各由具有至少7个碳原子的直链烷基组成。

在示例性实施例中，所述阳离子脂质包括选自由以下组成的组的化合物：atx-001、atx-002、atx-003、atx-004、atx-005、atx-006、atx-007、atx-008、atx-009、atx-010、atx-011、atx-012、atx-013、atx-014、atx-015、atx-016、atx-017、atx-018、atx-019、atx-020、atx-021、atx-022、atx-023、atx-024、atx-025、atx-026、atx-027、atx-028、atx-029、atx-030、atx-031、atx-032、atx-081、atx-095和atx-126或其药学上可接受的盐。

在某些示例性实施例中，所述阳离子脂质包括atx-002、atx-081、atx-095或atx-126。

在一些实施例中，所述阳离子脂质或其药学上可接受的盐可以呈现为包括纳米颗粒或脂质分子双层的脂质组合物。优选地，所述脂质双层进一步包括中性脂质或聚合物。优选地，所述脂质组合物包括液体介质。优选地，所述组合物进一步包含本发明的可翻译化合物。优选地，所述脂质组合物进一步包括本发明的可翻译化合物和中性脂质或聚合物。优选地，所述脂质组合物包含该可翻译化合物。

在另外的实施例中，所述阳离子脂质包括式iii的化合物：

其中r1和r2相同或不同，各自为由1至9个碳组成的直链或支链烷基、由2至11个碳组成的烯基或炔基或胆甾醇基，l1和l2相同或不同，各自为由5至18个碳组成的直链亚烷基或烯基，x1为--co--o--，通过其形成-l2-co--o--r2，x2为s或o，x3为--co--o--，通过其形成-l1-co--o--r1，l3为键，r3为由1至6个碳组成的直链或支链亚烷基，并且r4和r5相同或不同，各自为氢或由1至6个碳组成的直链或支链烷基；或其药学上可接受的盐。在一个实施例中，x2为s。在另一个实施例中，r3选自乙烯、正丙烯或异丁烯。在又一个实施例中，r4和r5分别为甲基、乙基或异丙基。在又一个实施例中，l1和l2是相同的。在又一个实施例中，l1和l2是不同的。在又一个实施例中，l1或l2由具有7个碳的直链亚烷基组成。在又一个实施例中，l1或l2由具有9个碳的直链亚烷基组成。在又一个实施例中，r1和r2是相同的。在又一个实施例中，r1和r2是不同的。在又一个实施例中，r1和r2各自由烯基组成。在又一个实施例中，r1和r2各自由烷基组成。在又一个实施例中，烯基由单个双键组成。在又一个实施例中，r1或r2由9个碳组成。在又一个实施例中，r1或r2由11个碳组成。在又一个实施例中，r1或r2由7个碳组成。在又一个实施例中，l3为键，r3为乙烯，x2为s，并且r4和r5各自为甲基。在又一个实施例中，l3为键，r3为正丙烯，x2为s，r4和r5各自为甲基。在又一个实施例中，l3为键，r3为乙烯，x2为s，并且r4和r5各自为乙基。

如本领域技术人员所了解的，式ii和式iii的化合物形成的盐也属于本公开范围内。除非另外说明，否则本文中对式ii和式iii的化合物的提及应理解为包含对其盐的提及。如本文所用，术语“盐”是指由无机和/或有机酸形成的酸性盐，以及由无机和/或有机碱形成的碱性盐。此外，当式ii或式iii的化合物同时包含有碱性部分(如但不限于吡啶或咪唑)和酸性部分(如但不限于羧酸)时，两性离子(“内盐”)可以形成并包含在本文所用的术语“盐”中。这些盐可以是药学上可接受的(即，无毒的、生理学上可接受的)盐，尽管其它盐也是有用的。式ii或式iii的化合物的盐可以通过以下形成：例如，使式ⅱ或式ⅲ化合物与一定量(如当量)的酸或碱在盐沉淀的介质中或在水性介质中反应，然后冻干。

示例性的酸加成盐包含乙酸盐、己二酸盐、藻酸盐、抗坏血酸盐、天冬氨酸盐、苯甲酸盐、苯磺酸盐、硫酸氢盐、硼酸盐、丁酸盐、柠檬酸盐、樟脑酸盐、樟脑磺酸盐、环戊烷丙酸盐、双葡萄糖酸盐、十二烷基硫酸盐、乙磺酸盐、富马酸盐、葡萄糖庚烷酸盐、甘油磷酸酯、半硫酸盐、庚烷酸盐、己酸盐、盐酸盐、氢溴酸盐、氢碘酸盐、2-羟乙烷磺酸盐、乳酸盐、马来酸盐、甲烷磺酸盐、2-萘磺酸盐、烟碱酸盐、硝酸盐、草酸盐、果胶酸盐、过硫酸盐、3-苯基丙酸盐、磷酸盐、苦味酸盐、新戊酸盐、丙酸盐、水杨酸盐、琥珀酸盐、硫酸盐、磺酸盐(如本文所述)、酒石酸盐、硫氰酸盐、甲苯磺酸盐(也被称为甲苯磺酸盐)十一烷酸盐等。此外，下列文献中讨论了通常被认为适于从碱性药物化合物中形成药学上有用的盐的酸：例如，s.berge等人,《药学期刊(j.pharmaceuticalsciences)》(1977)66(1)1-19；p.gould,《国际药学期刊(internationalj.pharmaceutics)》(1986)33201-217；anderson等人,《医学化学实践(thepracticeofmedicinalchemistry)》(1996),学术出版社(academicpress),纽约；以及《橙皮书(theorangebook)》(华盛顿特区食品和药物管理局(food&drugadministration)网站)。这些公开内容通过引用并入本文。

示例性的碱性盐包含铵盐、碱金属盐(如钠盐、锂盐和钾盐)、碱土金属盐(如钙盐和镁盐)、含有机碱(例如，有机胺)的盐(如苄星青霉素、二环己基胺、肼类(由n,n-双(脱氢异己基)乙二胺形成)、n-甲基-d-葡糖胺、n-甲基-d-葡糖酰胺、叔丁基胺)和含氨基酸(如精氨酸、赖氨酸)的盐等。可以用如低级烷基卤化物(例如，甲基、乙基、丙基和丁基氯化物、溴化物和碘化物)、硫酸二烷基酯(例如，二甲基、二乙基、二丁基和二烷基硫酸盐)、长链卤化物(例如，癸基、月桂基、肉豆蔻基和硬脂基氯化物、溴化物和碘化物)、芳基烷基卤化物(例如，苄基和苯乙基溴化物)等试剂对碱性含氮基团进行四分之一化。

在本公开的范围内，所有此类酸盐和碱盐都旨在是药学上可接受的盐，并且出于本公开的目的，所有酸盐和碱盐均被视为等同于对应化合物的自由形式。式ii或式iii的化合物可以以非溶剂化和溶剂化形式存在，包含水合形式。通常，出于本公开的目的，具有药学上可接受的溶剂(如水、乙醇等)的溶剂化形式等同于非溶剂化形式。式ii或iii的化合物及其盐和溶剂可能以其互变异构形式存在(例如，作为酰胺或亚胺醚)。本文中所有此类互变异构形式都被视为本公开的一部分。

本文所述的阳离子脂质化合物可以与本发明的可翻译化合物组合以形成微粒、纳米颗粒、脂质体或胶束。由颗粒、脂质体或胶束递送的本发明的可翻译化合物可以是气体、液体或固体的形式。所述阳离子脂质化合物和可翻译化合物可以与其它阳离子脂质化合物、聚合物(合成的或天然的)、表面活性剂、胆固醇、碳水化合物、蛋白质、脂质等组合形成颗粒。然后，可以将这些颗粒任选地与药物赋形剂组合以形成药物组合物。

在某些实施例中，所述阳离子脂质化合物相对无细胞毒性。所述阳离子脂质化合物可以具有生物相容性和生物降解性。阳离子脂质的pka可以在约5.5到约7.5范围内，更优选地在约6.0到约7.0范围内。可以将其设计为具有在约3.0到约9.0之间或在约5.0到约8.0之间的期望pka。

含有阳离子脂质化合物的组合物可以为30-70％阳离子脂质化合物、0-60％胆固醇、0-30％磷脂和1-10％聚乙二醇(peg)。优选地，所述组合物为30-40％阳离子脂质化合物、40-50％胆固醇和10-20％peg。在其它优选实施例中，所述组合物为50-75％阳离子脂质化合物、20-40％胆固醇、5-10％磷脂和1-10％peg。所述组合物可以含有60-70％阳离子脂质化合物、25-35％胆固醇和5-10％peg。所述组合物可以含有多达90％阳离子脂质化合物和2-15％辅助脂。制剂可以是脂质颗粒制剂，例如含有8-30％化合物、5-30％辅助脂和0-20％胆固醇；4-25％阳离子脂质、4-25％辅助脂、2-25％胆固醇、10-35％胆固醇-peg和5％胆固醇-胺；或2-30％阳离子脂质、2-30％辅助脂、1-15％胆固醇、2-35％胆固醇-peg和1-20％胆固醇-胺；或多达90％阳离子脂质和2-10％辅助脂或甚至100％阳离子脂质。

在一些实施例中，所述一个或多个基于胆固醇的脂质选自胆固醇、聚乙二醇化的胆固醇和dc-chol(n,n-二甲基-n-乙基羧基酰胺胆固醇)和1,4-双(3-n-油酰氨基-丙基)哌嗪。在示例性实施例中，所述基于胆固醇的脂质是胆固醇。

在一些实施例中，所述一个或多个聚乙二醇化的脂质，即，经过peg修饰的脂质。在一些实施例中，所述一个或多个经过peg修饰的脂质包括长度多达5kda的聚(乙烯)乙二醇链，所述聚(乙烯)乙二醇链共价附接到具有一个或多个长度为c6-c20的烷基链的脂质上。在一些实施例中，经过peg修饰的脂质是衍生的神经酰胺，如n-辛酰基鞘氨醇-1-[琥珀酰(甲氧基聚乙二醇)-2000]。在一些实施例中，经过peg修饰的或聚乙二醇化的脂质是聚乙二醇化的胆固醇或二肉豆蔻酰甘油(dmg)-peg-2k。在示例性实施例中，经过peg修饰的脂质是聚乙二醇化的胆固醇。

在另外的实施例中，药物组合物可以含有病毒或细菌载体内的低聚化合物。

本公开的药物组合物可以包含本领域已知的载剂、稀释剂或赋形剂。药物组合物和方法的实例描述于以下文献中：例如，《雷明顿药物科学(remington'spharmaceuticalsciences)》,麦克出版公司(mackpublishingco.)(编辑：a.r.gennaro1985)和《雷明顿药学技术与实践(remington,thescienceandpracticeofpharmacy)》,第21版(2005)。

药物组合物的赋形剂的实例包含抗氧化剂、悬浮剂、分散剂、防腐剂、缓冲剂、强力剂和表面活性剂。

本发明的试剂或药物制剂的有效剂量可以是足以在细胞中引起可翻译分子的翻译的量。

治疗有效剂量可以是足以达到治疗效果的试剂或制剂的量。治疗有效剂量可以一次或多次分开施用并通过不同的途径进行施用。如本领域所理解的，治疗有效剂量或治疗有效量在很大程度上取决于本发明的药物组合物中所含的治疗剂的总量。通常，治疗有效量足以对受试者产生有意义的益处(例如，治疗、调节、固化、预防和/或改善gsdiii)。例如，治疗有效量可以是足以达到期望的治疗和/或预防效果的量。通常，施用给需要治疗的受试者的治疗剂(例如，对agl进行编码的可翻译低聚物)的量将取决于所述受试者的特征。这些特征包含所述受试者的病状、疾病严重程度、总体健康、年龄、性别和体重。本领域的普通技术人员将能够容易地根据这些和其它相关因素确定合适的剂量。此外，可以任选地使用客观和主观分析来鉴定最佳剂量范围。。

本文提供的方法设想单次和多次施用治疗有效量的本文所述的可翻译化合物(例如，对agl进行编码的可翻译低聚物)。可以定期施用包括对agl进行编码的可翻译化合物的药物组合物，着具体取决于受试者病状的性质、严重性和程度(例如，受试者的gsdiii疾病状态的严重性和gsdiii的相关症状和/或受试者的agl活性水平)。在一些实施例中，可以每隔一段时间(例如，一年一次、六个月一次、四个月一次、三个月一次、两个月一次、每月一次)、每两周一次、每周一次、每天一次、一天两次、一天三次、一天四次、一天五次、一天六次或者不间断地定期施用治疗有效量的本发明的可翻译化合物(例如，对agl进行编码的可翻译低聚物)。

在一些实施例中，本发明的药物组合物的配方使其适用于其中所包含的对agl进行编码的可翻译化合物的缓释。可以以延长的给药间隔将此类缓释组合物方便地施用于受试者。例如，在一个实施例中，每天两次、每天一次或每隔一天向受试者施用本发明的药物组合物。在一些实施例中，每周两次、一周一次、每10天一次、每两周一次、每28天一次、每月一次、每六周一次、每八周一次、每隔一月、每三个月一次、每四个月一次、每六个月一次、每九个月一次或一年一次向受试者施用本发明的药物组合物。本文还设想了被配制用于补给施用(例如，皮下、肌肉注射)以在延长的时间段内递送或释放对agl进行编码的可翻译化合物的药物组合物。优选地，所使用的缓释手段与对agl进行编码的可翻译化合物的修饰相结合，以增强稳定性。

在一些实施例中，施用后，治疗有效剂量可能导致agl的血清或血浆水平为1-1000pg/ml、或1-1000ng/ml，或1-1000μg/ml或更多。

在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物可能导致经过治疗的受试者的肝脏agl蛋白质水平提高。在一些实施例中，施用包括本发明的可翻译分子的组合物导致肝脏agl蛋白质水平相对于治疗之前的受试者体内的基线agl蛋白质水平提高5％、10％、20％、30％、40％、50％、60％、70％、80％、90％或95％。在某些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物会导致肝脏agl水平相对于治疗之前的受试者体内的基线肝脏agl水平提高。在一些实施例中，肝脏agl水平相对于基线肝脏agl水平增加至少约5％、10％、20％、30％、40％、50％、100％、200％或更多。

在一些实施例中，与治疗前的基线水平相比，定期施用治疗有效剂量导致肝脏中agl的表达增加。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致agl蛋白质水平的表达处于或高于经过治疗的受试者的肝脏中总蛋白的约10ng/mg、约20ng/mg、约50ng/mg、约100ng/mg、约150ng/mg、约200ng/mg、约250ng/mg、约300ng/mg、约350ng/mg、约400ng/mg、约450ng/mg、约500ng/mg、约600ng/mg、约700ng/mg、约800ng/mg、约900ng/mg、约1000ng/mg、约1200ng/mg或约1500ng/mg。

在一些实施例中，施用治疗有效剂量的包括对agl进行编码的可翻译低聚物的组合物会导致选自丙氨酸转氨酶(alt)、天冬氨酸转氨酶(ast)、碱性磷酸酶(alp)、肌酸磷酸激酶(cpk)、糖原和极限糊精(即糖原水解产生的低分子碳水化合物)的一个或多个标志物的水平降低。

在一些实施例中，定期施用治疗有效剂量导致生物样品中alt、ast、alp和/或cpk水平降低。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，血浆或血清样品)中的alt、ast、alp和/或cpk水平相对于治疗前的基线alt、ast、alp和/或cpk水平降低至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％或至少约95％。在一些实施例中，生物样品选自血浆、血清、全血、尿液或脑脊液。

在某些示例性实施例中，定期施用治疗有效剂量导致血清或血浆样品中的alt水平降低，例如，以alt活性/升(u/l)为单位测量。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，血浆或血清样品)中的alt水平相对于治疗前的基线alt水平降低至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％或至少约95％。在示例性实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，血浆或血清样品)中的alt水平相对于治疗前的基线alt水平降低至少约50％。在另一个示例性实施例中，在空腹后测量alt水平，例如在空腹6小时、8小时、10小时、12小时、18或24小时后测量。

在其它示例性实施例中，定期施用治疗有效剂量导致血清或血浆样品中的ast水平降低，例如，以ast活性/升(u/l)为单位测量。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，血浆或血清样品)中的ast水平相对于治疗前的基线ast水平降低至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％或至少约95％。在示例性实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，血浆或血清样品)中的ast水平相对于治疗前的基线ast水平降低至少约50％。在另一个示例性实施例中，在空腹后测量ast水平，例如在空腹6小时、8小时、10小时、12小时、18小时或24小时后测量。

可以使用本领域已知的任何方法进行alt、ast、alp和/或cpk水平的测量，例如，使用liu等人,2014,《分子遗传与代谢(molgenetandmetabolism)》111:467-76中所描述的富士dri-chem临床化学分析仪fdc3500。

在其它示例性实施例中，定期施用治疗有效剂量导致生物样品中的糖原水平降低。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，肝脏样品)中的糖原累积相对于治疗前的基线糖原水平降低至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％或至少约95％。在一些实施例中，生物样品是选自肝脏、心脏、膈肌、四头肌和腓肠肌的器官的一部分。在示例性实施例中，生物样品是肝脏切片，例如肝细胞切片。

在其它示例性实施例中，定期施用治疗有效剂量导致生物样品中的极限糊精水平降低。在一些实施例中，施用治疗有效剂量的包括本发明的可翻译分子的组合物导致生物样品(例如，肝脏样品)中的极限糊精累积相对于治疗前的基线糊精水平降低至少约5％、至少约10％、至少约15％、至少约20％、至少约25％、至少约30％、至少约35％、至少约40％、至少约45％、至少约50％、至少约55％、至少约60％、至少约65％、至少约70％、至少约75％、至少约80％、至少约85％、至少约90％或至少约95％。在一些实施例中，生物样品是选自肝脏、心脏、膈肌、四头肌和腓肠肌的器官的一部分。在示例性实施例中，生物样品是肝脏切片，例如肝细胞切片。在另一个示例性实施例中，定期施用治疗有效剂量导致肝脏样品中的极限糊精水平相对于治疗前的基线极限糊精水平降低至少50％、60％、70％或80％。

在另外的实施例中，定期施用治疗有效剂量会延迟经过治疗的受试者体内的肝纤维化的发作。在一些实施例中，定期施用治疗有效剂量会减缓肝纤维化的发展或减少患gsdiii的受试者体内的肝纤维化的数量。

体内活性剂(例如，对agl进行编码的可翻译低聚物)的治疗有效剂量可以是约0.001到约500mg/kg体重的剂量。例如，治疗有效剂量可以为0.001-0.01mg/kg体重、或0.01-0.1mg/kg、或0.1-1mg/kg、或1-10mg/kg或10-100mg/kg。在一些实施例中，以约0.1到约10mg/kg体重(例如，约0.5到约5mg/kg、约1至到4.5mg/kg或约2到约4mg/kg)的剂量提供对agl进行编码的可翻译低聚物。

体内活性剂(例如，对agl进行编码的可翻译低聚物)的治疗有效剂量可以是至少约0.001mg/kg体重、或至少约0.01mg/kg、或至少约0.1mg/kg、或至少约1mg/kg、或至少约2mg/kg、或至少约3mg/kg、或至少约4mg/kg、或至少约5mg/kg、至少约10mg/kg、至少约20mg/kg、至少约50mg/kg或更多的剂量。在一些实施例中，以约0.1mg/kg、约0.5mg/kg、约1mg/kg、约1.5mg/kg、约2mg/kg、约2.5mg/kg、约3mg/kg、约3.5mg/kg、约4mg/kg、约5mg/kg或约6mg/kg、7mg/kg、8mg/kg、9mg/kg、10mg/kg、15mg/kg、20mg/kg、25mg/kg、50mg/kg、75mg/kg或100mg/kg的剂量提供对agl进行编码的可翻译低聚物。

除非另外说明，否则本文所示的核酸酶序列是从左到右，5'到3'。

转染

在一些实验中，将可翻译信使分子转染到96孔板中的hepa1-6或aml12细胞中。所有转染均按照制造说明使用messengermax转染试剂(赛默飞世尔科技(thermofisherscientific))。其它合适的细胞系包含hek293和hep3b细胞。

体外转染方案实例如下：

在转染前至少8小时，将肝细胞hepa1-6细胞以每孔5000个细胞平板接种到96孔板中。

置换含有10％fbs和非必需氨基酸的90μl的dmem培养基，并在96孔板的每一个孔中分装90μl，然后立即开始转染实验。

根据生产商的指示制备messengermax转染试剂(赛默飞世尔科技)可翻译分子复合物。

将10μl所述复合物转移到96孔板中含有所述细胞的孔中。

在期望的时间点后收集培养基，并在每个孔中加入100μl新鲜培养基。在采用标准生产商方案进行agl的elisa分析之前，培养基将保持在-80℃。

体内转染方案的实例如下：

用纳米颗粒配制可翻译分子。

通过侧尾静脉中的标准静脉注射将纳米颗粒配制的可翻译分子(1mg/kg)注入bl57bl/c小鼠(4～6周龄)的体内。

在注射后的适当时间，在肝素包被的微离心管中收集约50μl血液。

在4℃下以3,000xg离心10分钟。

将上清液(血浆)转移到新鲜的微离心管中。在采用标准生产商方案进行agl的elisa分析之前，血浆将保持在-80℃。

纳米颗粒制剂

可以使用含有mrna的乙醇/缓冲液中的适当体积的脂质来制备含有mrna的脂质纳米颗粒。为此，可以使用nanossemblr微流体装置，然后进行下游处理。例如，为了制备纳米颗粒，可以将期望量的目标mrna溶解在5mm柠檬酸缓冲液(ph3.5)中。脂质可以以适当的摩尔比溶解在乙醇中。组成脂质的摩尔百分比可以是，例如，50％离子化脂质、7％dspc(1,2-二硬脂基-sn-甘油-3-磷酸胆碱；avanti极性脂质)、40％胆固醇(avanti极性脂质)和3％dmg-peg(1,2-二肉豆蔻酰基-sn-甘油，甲氧基聚乙二醇，peg链分子量：2000；nof美国公司)。接着，脂质和mrna溶液可以在微流体装置(precisionnanosystems)中以1:3(乙醇：水相)的流量比混合。总混流速度可达12毫升/分钟。可以形成脂质纳米颗粒，然后通过在透析装置(float-a-lyzer，仕必纯(spectrumlabs))中使用磷酸盐缓冲液进行过夜透析将所述脂质纳米颗粒纯化，然后使用amiconultra-15离心过滤器(默克密里博(merckmillipore))对其进行浓缩。可以通过动态光散射(zen3600，马尔文仪器公司(malverninstruments))来确定颗粒大小。可以通过确定将ribogreen(分子探针(molecularprobes))添加到lnp浆液(fi)时通过荧光测量的未封装的mrna含量来计算“封装”效率；然后，将该值与通过1％tritonx-100(ft)裂解lnp所获得的总mrna含量进行比较，其中“封装”百分比＝(ft-fi)/ft×100。包封可以指在纳米颗粒中包含mrna，无论其形式如何。

in-cellwestern

使用96孔胶原板以适当的密度将细胞接种在dmem/fbs培养基中。在最佳交汇处，用在转染试剂混合液(messengermax和opti-mem)中稀释的目标mrnas转染细胞。将细胞置于co2培养箱中，并使其生长。在所需时间点，去除培养基，并将细胞在4％新鲜的pfa上固定20分钟。然后去除固定剂，并将细胞在tbst中多次渗透5分钟。当渗透洗涤完成后，将细胞与封闭缓冲液一起孵育45分钟。然后加入一抗，并在室温下孵育1小时。之后，将细胞在tbst中洗涤数次，然后与稀释于封闭缓冲液中且含有celltag700染色的二抗一起孵育1小时。最后，将细胞在tbst中洗涤数次，然后在tbs中洗涤最后一次。然后，使用licor检测系统对板进行成像，并将数据相对于celltag700标记的细胞总数归一化。

生成尾pcr产物

根据生产商的说明，含有每个mrna表达载体的质粒dna(10ng)可以用于在50μl的pcr反应中与2xkapahifipcr混合物(kr0370)一起生成polya尾120pcr产物。然后，可以在来自赛默飞世尔科技的2％凝胶上检查该产物，并根据低分子量阶梯的强度(赛默飞世尔科技，10068-013)进行近似定量，然后用凯杰(qiagen)pcr纯化试剂盒清洗产物并将其重新悬浮于50ul的水中。

体外合成转录(ivt)

以下方案针对使用nebhiscribet7rna聚合酶试剂进行200μlivt反应，所述试剂应该产生约1mgrna。通过解冻单个100mmntp储备液(atp、gtp、ctp和utp核苷酸或经过化学修饰的相应物)并将其合并在一起来根据需要制备2.5xntp混合物。对于ivt反应，200μl的反应使用约2-4μg的模板。通过移液将10xivt反应缓冲液、2.5xdntp混合液、模板dna和t7rna聚合酶充分混合，并在37℃下孵育4小时。为了降解dna模板，用700ul不含核酸酶的水稀释ivt反应，然后在ivt混合液中加入10xdnaseⅰ缓冲液和20ul不含rnase的dnaseⅰ，并在在37℃下孵育15分钟。然后，根据生产商的说明，使用凯杰rneasymaxi色谱柱将稀释后(至1ml)且经过dnase处理的反应纯化，最后在不含rnase水中洗脱。然后，通过uv吸光度对纯化的rna进行定量，其中a260/a280应该约为1.8-2.2，这取决于所用的重悬缓冲液。

ivtrna的酶促封端

对于酶促封端，可以使用50倍放大版本的neb的一步封端和2'o-甲基化反应，其适用于处理多达1mg的ivt转录物。根据转录物长度短至100nt的假设，建议在20μl反应中使用10μgrna。然而，对于转录物来说，较高的底物-反应体积是可以接受的，其长度通常可以更长(约300-600nt)。在开始封端反应之前，将rna在65℃下变性5分钟，然后快速冷却以消除任何二级构象。对于总共1ml的封端反应，将700μl不含核酸酶的水中的1mg变性rna与100μl(10x)封端缓冲液一起使用，将50μl(10mm)gtp、50μl(4mm)sam、50μl(10u/μl)牛痘封端酶和50μl(50u/μl)mrna端帽2'-o-甲基转移酶混合，并在37℃下孵育1小时。使用不含rnase的水洗脱所得的封端的mrna，在rneasy柱上再次纯化，通过分光光度计进行定量。在变性以及快速冷却以去除二级结构后，通过在变性凝胶中每通道运行500ng纯化产物，还可以在该凝胶上显示mrna。

实例

实例1：参考可翻译分子534。

在本实例中，制备了参考可翻译分子534，并将其用于表达人wt淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)。可翻译分子包括5'端帽(7mgpppg)、tev的5'utr、kozak序列、wtaglcds(seqidno:1)、非洲爪蟾β-珠蛋白的3'utr和由114as组成的poly(a)尾区(即，“poly(a)114尾区”)。参考可翻译分子进一步包括紧邻aglcds下游的seqidno:40的序列。这个参考可翻译分子是用n¹-甲基假尿苷代替尿苷合成的。

这个参考可翻译分子的结构细节如下：seqidno:3的烟草蚀纹病毒(tev)5'utr、seqidno:4的kozak序列、seqidno:5的非洲爪蟾β-珠蛋白(xbg)3'utr和seqidno:6的poly(a)114尾。

可以以5'端帽作为m7gpppgm端帽来合成以下实例中的可翻译分子。以下实例中的可翻译分子可以含有5'-utr(例如，tev的5'utr(seqidno:3))、翻译起始序列(例如，seqidno:4的kozak序列)、seqidno:40的序列、3'utr(例如，非洲爪蟾β-珠蛋白的3'utr(seqidno:5))和poly(a)尾(例如，seqidno:6、seqidno:38或seqidno:39的polya尾)。

实例2：对agl进行编码的可翻译分子。

在本实例中，制备了翻译效率提高的可翻译分子522-533、546、730-740和1783-1784，并将其用于表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)。这些表达人淀粉-α-1,6-葡萄糖苷酶,4-α-葡聚糖转移酶(agl)的可翻译分子表现出适合在用于改善或治疗gsdiii的方法中使用的活性。这些可翻译分子包括5'端帽(7mgpppg)、tev的5'utr、kozak序列、aglcds和非洲爪蟾β-珠蛋白的3'utr。可翻译分子522-533、546和1783-1784进一步包括poly(a)114尾区。可翻译分子730进一步包括poly(a)100尾区，而可翻译分子731-740进一步包括poly(a)110尾区。可翻译分子522-533、546、730-740和1783-1784进一步包括紧邻aglcds下游的seqidno:40的序列。开发了分别与546和1783相同的另外两个可翻译分子2258和2259，不同之处在于其包含poly(a)100尾区而不是poly(a)114尾区。可以任选地修改1783和2259的编码序列以包含12个核苷酸差异，如seqidno:45所示。本实例中描述的可翻译分子是用n¹-甲基假尿苷代替尿苷合成的。

每个可翻译分子中的aglcds由以下序列构成：

将本实例中的可翻译分子在aml12和c2c12细胞中翻译以产生人agl。

实例3：基于非洲爪蟾β-珠蛋白3'utr的翻译增强子。

在本实例中，示出了用于增强可翻译分子的翻译效率的3'utr序列的结构。

seqidno:33-37所示的碱基序列是可翻译分子的部分，其在功能上可以与非洲爪蟾β-珠蛋白的3'-utr相对应。完整的可翻译分子包括以下序列上游的5'端帽(m7gpppgm)、5'-utr、和编码区(cds)以及以下序列下游的polya尾，其中每一个都对应于原生人mrna的结构。如上所示，可以任选地使用kozak序列。因此，掺入以下片段的可翻译分子可以具有增强的翻译效率。非洲爪蟾β-珠蛋白基因序列显示在登录号nm_001096347.1中。

实例4：人原代肝细胞中的agl表达

在本实例中，用密码子优化的mrna分子546、1783和1784转染人原代肝细胞。转染后6小时、24小时、48小时和72小时，通过in-cellwestern^tm检测agl蛋白表达。图5示出了与未处理对照(“unt”)比较的mrna序列的表达。

实例5：野生型小鼠agl蛋白表达的体内分析

在本实例中，向野生型c57bl/6小鼠注射了用脂质纳米颗粒配制的人aglmrna。注射后6小时处死小鼠。取小鼠肝脏活检样品，并分析肝匀浆中人和小鼠agl蛋白的表达。图6示出了来自各个mrna分子的人agl蛋白的异位表达。图7示出了小鼠agl蛋白水平，表明其与经过处理的小鼠中的小鼠agl蛋白的内源性表达水平相似。可翻译分子546.7—如图6和7所示—具有与可翻译分子546相同的核碱基序列，但其是用5-甲氧基尿苷代替尿苷合成的，而不是用n¹-甲基假尿苷代替尿苷合成的。

实例6：mrna处理降低了gsd3小鼠体内的糖原累积

在本实例中，用使用atx2脂质纳米颗粒配制的媒剂或可翻译分子546治疗agl基因敲除小鼠。经媒剂(“veh”)处理的基因敲除小鼠的肝脏显示出显著至重度的肝细胞空泡化以及中度至显著的肝细胞内糖原累积增加(图8)。相反，经使用atx2脂质纳米颗粒配制的可翻译分子546处理的基因敲除小鼠的肝脏仅有轻度至中度的肝细胞空泡化以及仅轻度至中度的肝细胞内糖原累积增加(图9)。根据本实例所示的组织病理学结果，与用媒剂处理的ko小鼠相比，用mrna处理的基因敲除小鼠的肝脏中的肝细胞空泡化和糖原累积的严重程度似乎有所降低。

实例7：表达agl的其它可翻译分子

设计了具有经过另外修饰的密码子优化的人agl编码序列的另外四个可翻译分子1970、1987、sd1和sd2，所述编码序列分别示于seqidno:41、42、43和44中。可翻译分子1970、1987、sd1和sd2进一步包括5'端帽(7mgpppg)、tev的5'utr、kozak序列、紧邻编码序列下游的seqidno:40的序列、非洲爪蟾β-珠蛋白的3'utr和poly(a)尾区(例如，poly(a)100、110或114尾区)。这些可翻译分子可以任选地用n¹-甲基假尿苷或5-甲氧基尿苷代替尿苷而合成。

本文具体提到的所有出版物、专利和文献均通过引用并入本文用于所有目的。

应理解的是，本发明不限于所描述的特定方法、方案、材料和试剂，因为所述特定方法、方案、材料和试剂可以变化。还应理解的是，本文所使用的术语仅出于描述特定实施例的目的，并非旨在限制将由所附权利要求书涵盖的本发明的范围。

必须注意的是，除非上下文另外明确指示，否则如本文和所附权利要求中所使用，单数形式“一个/种(a/an)”和“所述”包含复数引用。同样，术语“一个(a或an)”、“一个或多个”和“至少一个”在本文中可以互换使用。还应注意的是，术语“包括(comprises/comprising)”、“含有”、“包含”和“具有”可以互换使用。

在不作进一步阐述的情况下，相信本领域的技术人员能够基于上述描述，最大限度地利用本发明。因此，以下具体实施例应被理解为仅仅是说明性的，而不以任何方式限制本公开的其余部分。

在本说明书中公开的所有特征可以以任何组合来组合。本说明书中公开的每个特征都可以由具有相同、等同或相似目的的替代特征代替。

序列表

<110>ultragenyxpharmaceuticalinc.

tachikawa,kiyoshi

perez-garcia,carlosgustavo

chivukula,padmanabh

bhaskaran,hariprakash

cobaugh,christianw.

daugherty,seanchristopher

<120>用于iii型糖原贮积病的治疗剂

<130>ulpi-041/01wo315613-2474

<150>us62/513,350

<151>2017-05-31

<160>45

<170>patentinversion3.5

<210>1

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>共有人agl编码序列

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auauacaaagauaguuauggagcuucaaguccuuggugugacuaucagcucaggccuaau4140

uuuaccauagcaaugguuguggccccugagcucuuuacuacagaaaaagcauggaaagcu4200

uuggagauugcagaaaaaaaauugcuugguccccuuggcaugaaaacuuuagauccagau4260

gauaugguuuacuguggaauuuaugacaaugcauuagacaaugacaacuacaaucuugcu4320

aaagguuucaauuaucaccaaggaccugaguggcuguggccuauuggguauuuucuucgu4380

gcaaaauuauauuuuuccagauugaugggcccggagacuacugcaaagacuauaguuuug4440

guuaaaaauguucuuucccgacauuauguucaucuugagagauccccuuggaaaggacuu4500

ccagaacugaccaaugagaaugcccaguacuguccuuucagcugugaaacacaagccugg4560

ucaauugcuacuauucuugagacacuuuaugauuuauag4599

<210>2

<211>1532

<212>prt

<213>patentin版本3.5

<220>

<223>共有人agl氨基酸序列

<400>2

metglyhisserlysglnileargileleuleuleuasnglumetglu

151015

lysleuglulysthrleupheargleugluglnglytyrgluleugln

202530

pheargleuglyprothrleuglnglylysalavalthrvaltyrthr

354045

asntyrpropheproglygluthrpheasnargglulyspheargser

505560

leuasptrpgluasnprothrgluarggluaspaspserasplystyr

65707580

cyslysleuasnleuglnglnserglyserpheglntyrtyrpheleu

859095

glnglyasnglulysserglyglyglytyrilevalvalaspproile

100105110

leuargvalglyalaaspasnhisvalleuproleuaspcysvalthr

115120125

leuglnthrpheleualalyscysleuglypropheaspglutrpglu

130135140

serargleuargvalalalysgluserglytyrasnmetilehisphe

145150155160

thrproleuglnthrleuglyleuserargsercystyrserleuala

165170175

asnglnleugluleuasnproasppheserargproasnarglystyr

180185190

thrtrpasnaspvalglyglnleuvalglulysleulyslysglutrp

195200205

asnvalilecysilethraspvalvaltyrasnhisthralaalaasn

210215220

serlystrpileglngluhisproglucysalatyrasnleuvalasn

225230235240

serprohisleulysproalatrpvalleuaspargalaleutrparg

245250255

phesercysaspvalalagluglylystyrlysglulysglyilepro

260265270

alaleuilegluasnasphishismetasnserilearglysileile

275280285

trpgluaspilepheprolysleulysleutrpgluphepheglnval

290295300

aspvalasnlysalavalgluglnpheargargleuleuthrglnglu

305310315320

asnargargvalthrlysseraspproasnglnhisleuthrileile

325330335

glnaspproglutyrargargpheglycysthrvalaspmetasnile

340345350

alaleuthrthrpheileprohisasplysglyproalaalaileglu

355360365

glucyscysasntrpphehislysargmetglugluleuasnserglu

370375380

lyshisargleuileasntyrhisglngluglnalavalasncysleu

385390395400

leuglyasnvalphetyrgluargleualaglyhisglyprolysleu

405410415

glyprovalthrarglyshisproleuvalthrargtyrphethrphe

420425430

propheglugluileaspphesermetgluglusermetilehisleu

435440445

proasnlysalacyspheleumetalahisasnglytrpvalmetgly

450455460

aspaspproleuargasnphealagluproglysergluvaltyrleu

465470475480

argarggluleuilecystrpglyaspservallysleuargtyrgly

485490495

asnlysprogluaspcysprotyrleutrpalahismetlyslystyr

500505510

thrgluilethralathrtyrpheglnglyvalargleuaspasncys

515520525

hisserthrproleuhisvalalaglutyrmetleuaspalaalaarg

530535540

asnleuglnproasnleutyrvalvalalagluleuphethrglyser

545550555560

gluaspleuaspasnvalphevalthrargleuglyileserserleu

565570575

ileargglualametseralatyrasnserhisglugluglyargleu

580585590

valtyrargtyrglyglygluprovalglyserphevalglnprocys

595600605

leuargproleumetproalailealahisalaleuphemetaspile

610615620

thrhisaspasnglucysproilevalhisargseralatyraspala

625630635640

leuproserthrthrilevalsermetalacyscysalaserglyser

645650655

thrargglytyraspgluleuvalprohisglnileservalvalser

660665670

glugluargphetyrthrlystrpasnproglualaleuproserasn

675680685

thrglygluvalasnpheglnserglyileilealaalaargcysala

690695700

ileserlysleuhisglngluleuglyalalysglypheileglnval

705710715720

tyrvalaspglnvalaspgluaspilevalalavalthrarghisser

725730735

proserilehisglnservalvalalavalserargthralaphearg

740745750

asnprolysthrserphetyrserlysgluvalproglnmetcysile

755760765

proglylysileglugluvalvalleuglualaargthrilegluarg

770775780

asnthrlysprotyrarglysaspgluasnserileasnglythrpro

785790795800

aspilethrvalgluilearggluhisileglnleuasngluserlys

805810815

ilevallysglnalaglyvalalathrlysglyproasnglutyrile

820825830

glngluilegluphegluasnleuserproglyservalileilephe

835840845

argvalserleuaspprohisalaglnvalalavalglyileleuarg

850855860

asnhisleuthrglnpheserprohisphelysserglyserleuala

865870875880

valaspasnalaaspproileleulysileprophealaserleuala

885890895

serargleuthrleualagluleuasnglnileleutyrargcysglu

900905910

sergluglulysgluaspglyglyglycystyraspileproasntrp

915920925

seralaleulystyralaglyleuglnglyleumetservalleuala

930935940

gluileargprolysasnaspleuglyhisprophecysasnasnleu

945950955960

argserglyasptrpmetileasptyrvalserasnargleuileser

965970975

argserglythrilealagluvalglylystrpleuglnalametphe

980985990

phetyrleulysglnileproargtyrleuileprocystyrpheasp

99510001005

alaileleuileglyalatyrthrthrleuleuaspthralatrp

101010151020

lysglnmetserserphevalglnasnglyserthrphevallys

102510301035

hisleuserleuglyservalglnleucysglyvalglylysphe

104010451050

proserleuproileleuserproalaleumetaspvalprotyr

105510601065

argleuasngluilethrlysglulysgluglncyscysvalser

107010751080

leualaalaglyleuprohispheserserglyilepheargcys

108510901095

trpglyargaspthrpheilealaleuargglyileleuleuile

110011051110

thrglyargtyrvalglualaargasnileileleualapheala

111511201125

glythrleuarghisglyleuileproasnleuleuglyglugly

113011351140

iletyralaargtyrasncysargaspalavaltrptrptrpleu

114511501155

glncysileglnasptyrcyslysmetvalproasnglyleuasp

116011651170

ileleulyscysprovalserargmettyrprothraspaspser

117511801185

alaproleuproalaglythrleuaspglnproleuphegluval

119011951200

ileglnglualametglnlyshismetglnglyileglnphearg

120512101215

gluargasnalaglyproglnileaspargasnmetlysaspglu

122012251230

glypheasnilethralaglyvalaspglugluthrglypheval

123512401245

tyrglyglyasnargpheasncysglythrtrpmetasplysmet

125012551260

glygluseraspargalaargasnargglyileproalathrpro

126512701275

argaspglyseralavalgluilevalglyleuserlysserala

128012851290

valargtrpleuleugluleuserlyslysasnilepheprotyr

129513001305

hisgluvalthrvallysarghisglylysalailelysvalser

131013151320

tyraspglutrpasnarglysileglnaspasnpheglulysleu

132513301335

phehisvalsergluaspproseraspleuasnglulyshispro

134013451350

asnleuvalhislysargglyiletyrlysaspsertyrglyala

135513601365

serserprotrpcysasptyrglnleuargproasnphethrile

137013751380

alametvalvalalaprogluleuphethrthrglulysalatrp

138513901395

lysalaleugluilealaglulyslysleuleuglyproleugly

140014051410

metlysthrleuaspproaspaspmetvaltyrcysglyiletyr

141514201425

aspasnalaleuaspasnaspasntyrasnleualalysglyphe

143014351440

asntyrhisglnglyproglutrpleutrpproileglytyrphe

144514501455

leuargalalysleutyrpheserargleumetglyprogluthr

146014651470

thralalysthrilevalleuvallysasnvalleuserarghis

147514801485

tyrvalhisleugluargserprotrplysglyleuprogluleu

149014951500

thrasngluasnalaglntyrcysprophesercysgluthrgln

150515101515

alatrpserilealathrileleugluthrleutyraspleu

152015251530

<210>3

<211>129

<212>rna

<213>烟草蚀纹病毒

<400>3

ucaacacaacauauacaaaacaaacgaaucucaagcaaucaagcauucuacuucuauugc60

agcaauuuaaaucauuucuuuuaaagcaaaagcaauuuucugaaaauuuucaccauuuac120

gaacgauag129

<210>4

<211>6

<212>rna

<213>未知

<220>

<223>kozak序列

<400>4

gccacc6

<210>5

<211>158

<212>rna

<213>非洲爪蟾属

<400>5

cuagugacugacuaggaucugguuaccacuaaaccagccucaagaacacccgaauggagu60

cucuaagcuacauaauaccaacuuacacuuacaaaauguugucccccaaaauguagccau120

ucguaucugcuccuaauaaaaagaaaguuucuucacau158

<210>6

<211>114

<212>rna

<213>未知

<220>

<223>poly(a)114尾

<400>6

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa60

aaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaaa114

<210>7

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>7

augggacacuccaaacagauccggauacugcugcugaacgagauggaaaagcuggaaaag60

acucuauuccggcucgagcagggauacgagcugcaguuccgccugggccccacccuacaa120

gggaaggccgugaccgucuacaccaacuacccuuucccgggcgaaacuuucaaccgggag180

aaguuccggucccuugacugggaaaacccgacugagcgcgaggacgacucggacaaauac240

ugcaagcugaaccuccagcagucgggcucuuuccaauauuacuucuugcaagggaacgag300

aaguccgguggcggcuacaucgugguggacccaauuuugcgcgugggggcugacaaccac360

gugcugccacuggauugugugacccugcaaaccuuccuggccaagugccucggccccuuc420

gacgaaugggagucgcgccugagaguggcgaaagagagcggauacaacaugauucacuuc480

acgccgcuccaaacgcugggucugagccggucaugcuacucacuggcgaaccagcucgaa540

cugaaccccgauuucucccggccaaacaggaaguacaccuggaacgacgugggacagcug600

gucgagaaguugaagaaggaguggaacgugaucuguaucaccgacgucguguacaaccac660

accgcugcaaacucgaaguggauccaggaacauccggaaugugccuacaaccucgugaac720

agcccgcaccugaagccugccuggguguuggauagggcacuguggagguucuccugugac780

guggcagagggaaaguacaaggagaaggguauucccgcacucaucgaaaacgaucaccac840

augaauucgaucagaaagauuaucugggaggauaucuucccuaagcugaagcugugggag900

uucuuucaaguugaugugaacaaggcagucgaacaguuucggcggcuguuaacccaagaa960

aaccgccgcgugaccaaguccgauccgaaucagcaucugaccauaauccaggacccggaa1020

uaccgccgguuuggcugcaccguggacaugaacauugcccugacuaccuuuaucccgcau1080

gauaagggccccgccgcuaucgaagaaugcugcaacugguuccacaagaggauggaggaa1140

cugaacuccgaaaagcauaggcucauuaacuaccaccaggaacaggcagugaacugccug1200

cuggggaacguguucuacgagcgacuggcuggacacggaccgaaguuaggacccgugaca1260

aggaagcacccacuggucacuagauacuucaccuucccauuugaggaaaucgacuucuca1320

auggaggagucgaugauccacuugccuaacaaggccugcuuucucauggcacauaacgga1380

ugggucaugggcgacgauccccuacggaauuuugcagaaccaggcagcgaggucuaccuu1440

cggcgggaacugauuugcuggggcgacuccgucaagcugcgcuacggcaacaagccugag1500

gacugucccuaccuuugggcacacaugaagaaguacacugaaauuacugcgacauacuuc1560

caaggaguccgcuuagauaauugucacuccaccccgcugcauguggcggaguacaugcug1620

gaugccgcaagaaaccuccagccgaaucucuacgugguagcagagcuguucaccgggagc1680

gaggaccuggacaauguguuugucacccggcuggggaucuccucccugauccgggaggcc1740

auguccgccuacaacucacacgaggaggggagacugguguaccgcuacggaggagaaccc1800

gugggcagcuuugugcagccuugccuccggccgcugaugcccgcgauugcgcaugcucug1860

uucauggauaucacucacgauaacgagugccccauugugcacagauccgccuacgacgcc1920

cuuccuuccacaaccaucguguccauggcaugcugcgccuccggcuccacucgggguuac1980

gaugagcuggugccacaccagauuuccgugguguccgaagaacgcuucuacaccaagugg2040

aacccggaagcucugccgucaaacaccggagaagugaacuuccaguccgggaucaucgca2100

gcgcgcugugcuauuagcaagcugcaccaggagcugggagccaagggguucauccagguc2160

uauguggaccaggucgaugaggauaucgucgcugucacgagacacagcccgucuauccau2220

caaagcgucguggccgugucccggacugcguuccggaacccuaaaaccucauucuauucc2280

aaagaggugccccagaugugcaucccuggaaagaucgaagaagucgugcuggaagcccgg2340

accaucgagcggaacaccaagccguacaggaaggacgaaaacuccaucaaugguaccccu2400

gacauuaccguggaaaucagagaacauauccagcugaacgaguccaagaucgugaagcag2460

gccggcguggcgaccaagggucccaacgaguacauucaggaaaucgaguuugaaaaccug2520

ucccccggaagcgugaucauuuuccgggugucccuggacccgcaugcgcaagucgcuguc2580

ggaauucugcggaaucaccucacccaauucucgccgcauuucaagagugguucccuggcg2640

guggauaaugccgauccgauccugaagauucccuucgcgucccuggcaucgagacucacc2700

cuggcggaguugaaccagauucuguaccgcugcgaauccgaggaaaaggaggacggaggc2760

gguugcuacgacauccccaacugguccgcacuuaaguacgcagggcugcagggucuuaug2820

agcgugcuggcagaaauucgcccuaagaacgauuugggacaccccuucugcaacaaccuc2880

cgguccggagacuggaugaucgauuacgugucgaacagacugauuucgagauccggcacc2940

auugccgaggucggaaaguggcuucaggccauguucuucuaccugaagcagaucccgaga3000

uaccugauucccugcuacuucgacgcaauccugaucggggcguauaccacucuucuggac3060

acugccuggaagcagauguccagcuucgugcaaaacggauccaccuucgucaagcaucuu3120

agccugggcucagugcaguugugcggagugggaaaauucccuagccucccuauucuuuca3180

ccggcgcugauggacgugccuuaccgccugaacgaaaucaccaaagagaaggagcagugu3240

ugcgugucgcuggccgcgggucugccgcauuucuccuccggcaucuuccggugcugggga3300

agggacaccuucaucgcucugaggggaauccugcugauuaccgggcgcuacguggaagcu3360

cggaacaucauccuggccuucgcgggaacucugcgccacggccugauuccaaacuugcuu3420

ggcgaaggcaucuacgcgcgcuacaacugccgcgacgcggucuggugguggcuccagugc3480

auucaagacuacugcaagauggugccaaacggccuggacauccugaagugcccggugucg3540

agaauguaccccaccgacgauucugcgccccugccggccgguacucuugaccaaccucug3600

uucgaagugauccaggaagcaaugcagaagcacaugcagggcauucaguuccgggagcgc3660

aacgcagggccgcaaaucgacaggaacaugaaggacgaaggauucaacaucaccgcggga3720

guggacgaagagacuggcuucgucuacgguggaaaucgguucaacugcgggaccuggaug3780

gacaagaugggcgaaucagaccgagcccgcaaccgcggaaucccugccaccccccgggau3840

gggagcgccguggagauugugggacugagcaagagcgcugugcgcuggcugcuggaguug3900

agcaagaagaacauuuuccccuaucacgaagugaccgugaagcggcacggaaaagcuauc3960

aaaguguccuacgacgaguggaacagaaagauccaggacaacuucgagaagcuguuccac4020

guguccgaggacccgucggacuugaaugagaagcacccuaaccucgugcacaagcgggga4080

aucuacaaggacagcuacggagcauccucgccuuggugcgacuaucagcugaggcccaac4140

uucacuaucgcaauggugguggccccagaacuguucacuaccgaaaaggccuggaaggca4200

cuggagaucgcagagaaaaagcugcugggcccucugggcaugaaaacccuggaccccgac4260

gacaugguguacugcgggaucuacgauaacgcucuugacaaugacaacuacaaccuggcu4320

aagggauucaacuaucaccagggccccgaguggcuguggccgaucgguuacuuccugcgc4380

gccaagcuguacuuuucccggcugaugggcccugagacuaccgcaaagacgaucgugcug4440

gucaagaacgugcugucacggcacuacgugcaucuggaacggagcccguggaagggguug4500

cccgaacugaccaacgaaaacgcgcaguacuguccguucucgugcgaaacucaggccugg4560

uccaucgccacuauccucgaaacucucuacgaccuguag4599

<210>8

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>8

augggacauagcaaacaaauuaggauccuccugcugaacgaaauggaaaaacuggaaaag60

acgcuguuucggcuggaacagggcuacgaacuccaguuucgccucgggccaacgcugcaa120

gggaaagcagugaccguguauacaaacuacccauucccuggagagacauucaauagggag180

aaguuuagaagcuuagacugggaaaauccaaccgaacgagaagaugacagcgauaaguau240

ugcaagcugaaucugcaacaguccggaaguuuucaguacuacuuuuugcaagggaacgaa300

aagagcggcggagguuauauugugguggauccaauuuugagaguuggggccgacaaccau360

guacugccucuugacugugugacacugcaaacguuccuggccaagugccugggcccguuu420

gaugagugggaaagccguuugcgcguggccaaggaauccggguacaacaugauccauuuu480

accccacugcaaaccuuaggccugucaaggagcuguuacagucuggccaaccagcuggaa540

cugaaucccgacuucucccggccaaauaggaaguacacguggaacgacguuggccagcua600

guggagaaguugaagaaggaguggaacguuauuugcaucacugacgucguguauaaucac660

acugccgcuaauagcaaauggauccaggaacauccagagugugccuauaaccuggucaac720

agcccgcaucugaagccagcaugggugcuggaccgggcguuguggcgguucucgugugac780

guggccgaaggaaaguauaaggagaaggguauuccggcucugauagagaacgaccaucau840

augaauuccaucaggaagaucauuugggaggacaucuuuccaaaguugaagcugugggag900

uucuuucaaguggaugugaacaaggccguagaacaguuucgccgccuacuaacccaggaa960

aauaggagagucacaaaguccgaucccaaccaacaucugaccauaauucaggaccccgaa1020

uaucgucgauuuggcugcaccguggauaugaacaucgcuuugacaacuuucauaccacac1080

gacaaggguccagccgccauugaagaguguuguaacugguuucacaaacgaauggaggag1140

uugaacagugaaaagcaccgccugaucaauuaucaucaggagcaggccgugaacuguuug1200

cuggggaauguguucuaugagaggcucgcuggucauggcccuaagcuggguccuguaaca1260

agaaagcauccauuagugacgcgcuacuuuacauucccauuugaggagaucgacuuuucg1320

auggaagaguccaugauucaucuccccaacaaggccuguuuucugauggcccacaacggc1380

uggguuaugggggaugauccguugagaaauuuugcggaaccagguucagaaguguaucug1440

cgucgggagcugauuuguuggggcgacuccgugaagcuccgcuaugggaacaagccugag1500

gauuguccuuaucugugggcgcauaugaagaaguauacagagaucacugccacauauuuu1560

cagggcgucaggcuggacaauugucauagcaccccgcuucauguggcugaguauaugcug1620

gacgcagcaaggaaucugcagcccaaucuguaugugguggcggaacuguuuaccgggucc1680

gaggaccuggacaauguauuuguaacccgauugggcaucuccagccugauuagggaagca1740

augagugcauacaacucacacgaggaggggcggcugguuuaucgauaugggggggaaccu1800

gugggcagcuuuguacagccaugucuccggccguugaugccugccauugcucaugcgcuc1860

uuuauggauauaacacaugacaacgaauguccaaucguucauaggagugcuuacgacgcc1920

cugccgagcacaacgaucguguccauggccuguugugcaaguggcagcacacguggcuau1980

gacgaauugguaccccaccaaauuagcgugguuuccgaggagagguucuauacaaagugg2040

aauccagaggcuuugcccucgaacaccggagaggucaacuuucaaucuggcauaauugcc2100

gcucgcugcgccauaucuaaguugcaucaggaacugggcgcgaagggguuuauacaaguc2160

uacguugaccaaguggaugaggacaucguugcugucacgcggcacucaccuaguauucau2220

caauccgugguagcagugucucggacggccuuuagaaacccaaagacaucauuuuacucg2280

aaagaagugccucaaauguguauaccuggcaaaauugaagaggugguccuggaagcccgc2340

acgauagagaggaauacuaagccguauagaaaggaugaaaauucuaucaacggcacuccg2400

gauauuacaguagaaaucagagagcacauucaacuuaaugagucuaagauuguuaagcag2460

gcugguguugcaaccaaagggccaaacgaguacauccaggagauugaauuugaaaaucug2520

ucaccgggcuccgugaucaucuuuagaguaucuuuggauccacaugcucaagucgcuguu2580

ggaauccugagaaaccaucugacacaauuuuccccacauuuuaagagcggcagccuggcc2640

guggacaacgcagacccaauccugaagaucccauuugcaucccuggcuucccgccugacu2700

cuggcugagcugaaccagaucuuguaucgcugugaaucugaagaaaaagaggauggcgga2760

ggcuguuaugacaucccaaauuggagcgcccugaaauaugccggacuccaaggccugaug2820

uccguucuggccgagauuaggccaaagaaugaucugggacacccauuuuguaacaacuug2880

cggucuggagacuggaugaucgacuaugucagcaaccgccugauaagcagauccgguacu2940

aucgcugaagucggaaaauggcugcaggcuauguuuuucuauuugaagcagauuccgaga3000

uauuugauccccuguuauuuugaugccauucugauuggugcuuauacuacccugcuggau3060

accgcuuggaaacagaugaguagcuuuguccaaaauggcuccaccuucguaaagcaucug3120

ucgcugggcuccgugcaauuguguggcgucgggaaguucccuagccugccaauccugucc3180

ccugcucugauggacgugccuuaucgccugaacgagauuacgaaggaaaaggaacagugu3240

ugcgugucacucgcugcugggcugccacacuuuucuucuggaauuuuucgguguuggggg3300

cgggacaccuuuauugcccugaggggcauucugcugauuaccggccgcuaugucgaggcu3360

aggaacauuauccuggcuuucgcggguacccuucggcacggacucauacccaaccuccug3420

ggagaaggaaucuaugcacgguauaacugucgggacgcaguuugguggugguugcagugu3480

auucaagauuauugcaagauggucccgaacggacuggacauacugaagugcccagugucc3540

cggauguauccaacugacgacuccgcaccacugcccgcugggacacuugaccagccauug3600

uuugaaguuauucaggaagcuaugcagaagcauaugcagggaauucaguuuagggagaga3660

aacgcuggaccccagauugaccguaacaugaaggaugagggguuuaacauuaccgcggga3720

guggacgaagagacuggcuucgucuaugguggcaaucgguucaacugcggcaccuggaug3780

gacaaaaugggcgaaagcgauagagcucgaaauaggggcaucccagcaacaccacgggau3840

ggcucugccguggagauugugggccugucuaagagcgcaguucggugguuguuggaacuc3900

agcaagaagaacauuuuuccauaccaugaaguuacagugaagcggcaugggaaggccauc3960

aagguuucuuacgacgaauggaaucggaagauccaggauaacuucgagaaacuguuucau4020

guauccgaggacccuucugaccugaacgaaaagcauccaaauuugguacacaaaagggga4080

aucuauaaggauaguuauggagccagcagcccuuggugcgacuaucagcuacgaccaaac4140

uucacuauugccaugguaguagcaccagaacucuuuacuaccgaaaaggcuuggaaggca4200

cuggagaucgccgagaagaagcuguuagguccacugggcaugaaaacccuggaccccgac4260

gacaugguuuacuguggcaucuaugacaacgcucuggacaaugacaacuauaaucuggcc4320

aagggcuucaacuaccaccagggcccagaguggcuauggccaauuggcuauuuucugcgg4380

gcgaagcuguacuuuucacgauugaugggcccagagacaaccgcuaagaccauaguauug4440

gucaagaacgugcugagucggcacuauguccaccuggaaaggagccccuggaaggggcug4500

cccgagcugaccaacgaaaaugcacaguauuguccguuuucaugcgaaacccaggcuugg4560

uccaucgcgacgauccuggaaacccucuaugaucuguag4599

<210>9

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>9

augggacacucaaaacagauaaggauccugcugcugaacgaaauggagaaacuggaaaag60

acccuguuccggcucgaacagggauaugaacuccaguuuaggcugggcccaacucugcaa120

ggaaaagcugugaccgucuauacuaacuauccauuucccggggaaacguuuaaccgagag180

aaguuccgauccuuggacugggaaaaucccacagagcgggaggaugauucggacaaguau240

ugcaagcugaaucugcaacaaucgggcagcuuucaguacuauuuucuacaaggaaacgaa300

aagagcggcgggggauacauugugguggacccaauccugaggguuggggcagacaaucac360

guacugccuuuggacugugugacauugcaaacauuccuggcaaagugccugggccccuuc420

gaugaaugggagucacggcugcgaguggcuaaggaaucuggcuauaauaugauucacuuu480

acaccauuacaaacgcugggccugagcagaaguugcuacucgcuggcuaaucaguuggag540

uugaacccggacuuuagccgucccaaccggaaguauacauggaaugauguuggccaacuc600

guggagaagcugaagaaggaguggaacgugaucuguauuaccgaugucguguauaaucau660

acagccgcgaacuccaaguggauucaggagcacccagaaugugcauauaacuuggucaau720

agcccccaccugaagccggccuggguacuggaucgggcccuguggcgguuuucuugugac780

guggcagaaggaaaguauaaggaaaaggggaucccagcacugauagagaacgaccaucau840

augaacagcauuaggaagaucauuugggaggacauuuucccaaaguugaagcucugggag900

uuuuuccaaguugacgucaacaaggccguggaacaauuucgaaggcugcugacacaggaa960

aacagacguguaacgaaguccgaccccaaucagcauuugacgaucauacaggauccugag1020

uauaggcgcuuuggcuguacggucgacaugaauauugcucugaccaccuuuaucccucau1080

gacaaggggccagccgccaucgaagaguguuguaauugguuccacaagcgcauggaagag1140

uugaauuccgaaaagcauagguugaucaacuaccaccaggaacaggcagugaacugucug1200

cugggcaacguguuuuaugagcggcuggccggucauggcccuaagcugggaccagugacc1260

aggaagcauccacucguaaccagauauuuuaccuucccguuugaggagauagauuuuagc1320

auggaagaauccaugauucaccuaccgaacaaggcuuguuuucugauggcucacaacggu1380

uggguuaugggcgaugauccccugcgcaacuuugcggaaccgggcucugagguguacuug1440

agaagggagcugauauguuggggggacuccgucaaacugcgcuaugggaauaagccugaa1500

gauugcccuuaucugugggcccauaugaagaaguauaccgagauuaccgcgacauauuuu1560

caaggagugcggcuggacaacugccacagcacgccgcugcauguggcagaguauaugcug1620

gacgcagcccgcaaucugcagccaaaucuguauguuguggcugagcuguuuacgggcucc1680

gaggaccucgacaacguuuucguaacccggcugggcaucagcagccugauccgggaagcu1740

augucagcguauaauagccaugaggagggcagacugguguacagauaugguggcgaacca1800

guuggcagcuuugugcagcccuguuugcgcccucugaugcccgccaucgcacaugcuuug1860

uucauggacaucacgcaugauaacgaaugucccauuguacaucgcuccgccuaugacgcu1920

uugccauccacaacaaucguguccauggcuuguugugcaagcggcagcaccaggggauau1980

gacgaauugguuccgcaucaaaucagcgugguaucagaggaaagguuuuauacaaagugg2040

aauccugaagcccugccauccaacaccggcgaagugaacuuucagucggguaucauugcc2100

gcgcguugcgcuauuagcaaacugcaucaggagcugggugcuaaaggcuuuauccaaguu2160

uauguggaucaaguagacgaagauauuguugccguaaccagacauagccccagcauucau2220

caauccgugguugcugugucccggacggccuucaggaacccuaaaacauccuuuuauucc2280

aaggaagucccacagauguguauuccgggaaagauagaggaagugguuuuggaggcucgc2340

acgauugagcggaacaccaagccauauaggaaggacgagaacucgaucaacggcacgccc2400

gacauuaccguugaaauucgcgagcacauucagcugaacgaaucgaaaauugucaagcag2460

gccggcguagcgaccaaggguccaaacgaguauauccaggaaaucgaguuugagaaucug2520

ucgccuggguccguaaucauuuuuagagucagccuagacccucacgcucaaguggccgua2580

gggauccugaggaaucaucugacgcaguuuucaccccauuuuaaguccggcagccuggca2640

guggauaacgccgaccccauccugaaaauucccuuugcuucccuggccucgcgccugaca2700

cuggcagaauugaaucagauacuguaucguugcgagagcgaggagaaggaggacggaggg2760

ggguguuaugauaucccgaacugguccgcucugaaauaugcgggauugcagggcuugaug2820

aguguacuggccgaaauuagacccaagaacgaucugggccauccguucuguaacaaucug2880

cgauccggcgauuggaugauugauuaugucagcaaccgguugauaagccggagugggaca2940

auugcagaagucggaaagugguugcaagccauguucuuuuaccugaagcagaucccucga3000

uaucugauaccauguuauuucgaugccauucugaucggggccuauacaacucuguuagac3060

acugcuuggaaacagaugucuagcuucgugcaaaacggcucaacauuuguuaagcacuug3120

agccuggggucugugcaguuguguggcguaggaaaguuucccucacugcccauccugucg3180

cccgcccugauggacgugcccuaccgccucaacgaaauuaccaaggagaaagagcagugu3240

uguguuagcuuggcugccgguuugccgcauuuuucaagcggaaucuuccgaugcugggga3300

cgcgauacguucauagcccugagggguauucugcugauuacgggcagauacguagaggcu3360

cggaauauuauccuggccuucgccggcacgcugcggcaugggcugauuccgaacuugcug3420

ggagagggcaucuacgcccgguacaacugcagggacgcuguguggugguggcugcagugc3480

auccaggacuauugcaaaauggugccaaacggccuugacauacugaaguguccugucucu3540

cggauguauccaacggaugacuccgcaccccugcccgcuggaacccuggaucaaccccug3600

uuugaagugauacaggaagcaaugcagaagcacaugcagggaauucaguuuagagagaga3660

aaugcaggcccccaaaucgacagaaacaugaaagaugaaggcuuuaacaucacggcugga3720

guggacgaagaaacuggguuuguguauggcgggaauagguuuaacugugggacguggaug3780

gacaagaugggcgaauccgauagagcgcggaacaggggaaucccggcuacaccccgggac3840

gguagugcuguggagauugucggcuuauccaaauccgccgugcgcuggcugcuggagcug3900

uccaagaagaacaucuuuccuuaccaugaagugaccgugaagcggcauggaaaggccauc3960

aaagucuccuacgacgaauggaauaggaagauucaggacaauuuugagaagcuguuucau4020

guguccgaggaucccagcgaccugaacgagaagcacccuaauuuggugcauaagcggggc4080

aucuauaaggacuccuacggcgcuaguucgccuuggugcgacuaucagcugcggccaaac4140

uuuacgauugcgauggugguagcccccgaauuguuuacgacggaaaaggcuuggaaggcc4200

cuggagaucgcagaaaagaagcugcuggggcccuugggcaugaaaacgcuggaccccgac4260

gauaugguuuauuguggcaucuacgacaacgcccucgacaaugacaauuacaaccuggca4320

aaggguuuuaacuaucaucaggguccugaauggcuguggccaauuggcuacuuuuugcgg4380

gccaagcuguacuuuucacggcugaugggaccugaaaccaccgcuaagaccauuguacug4440

gucaagaacgugcugagcaggcauuacgugcaucuggaaagaagcccguggaagggucug4500

ccagaguugacgaacgagaacgcgcaguauuguccuuucucuugugaaacgcaggcuugg4560

aguauugcaaccauucuggaaacucuuuaugaccuguag4599

<210>10

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>10

augggccacucaaagcagauuagaaucuuacuccugaacgagauggaaaagcuggaaaag60

acccuguuccgccuggaacagggauaugagcugcaguuccggcuuggaccaacccuccaa120

ggaaaggccgugaccguguacacgaacuacccauucccgggcgaaaccuucaacagagag180

aaguuccggagccuggacugggaaaacccgaccgaaagggaagaugauagcgacaaguac240

ugcaagcugaacuugcaacaguccggaucauuccaguacuacuuucugcaagggaacgag300

aagucgggcggcgguuacaucgugguggacccuauucugcgcgugggagccgacaaccac360

guguugccucuggacugugucacccugcaaacuuuccuggccaagugccuggggccauuc420

gaugagugggaaucgcggcugcggguggcaaaagaguccgguuacaacaugauccacuuc480

accccacuccaaacccugggccuguccaggucgugcuacucgcuggccaaccagcuggaa540

cugaacccggauuucucgcggccuaacagaaaguauaccuggaaugacgucggacagcuc600

gucgaaaagcugaagaaggaauggaacguaaucuguaucaccgaugucguguauaaccac660

accgcugccaacuccaaguggauccaggaacaccccgagugcgcuuacaacuuggugaac720

ucgccccaccugaaaccggcuugggugcuggaccgggcccuguggcgguucagcugcgau780

guggcugagggaaaguauaaggagaaggguaucccagcgcucauugaaaacgaccaccau840

augaacucgauccgcaagaucauuugggaggauauuuucccaaaguugaaacugugggag900

uuuuuccaaguggacgugaacaaggcggucgaacaguucagacggcuguugacucaggaa960

aaucggagggucaccaagucggaucccaaccagcaccugaccauaauccaggauccagaa1020

uaccggcgguucggcugcacuguggacaugaacauugcccugaccacuuuuaucccacac1080

gacaagggcccggccgccaucgaagagugcugcaacugguuccacaagcggauggaggaa1140

cugaacucggagaagcaccgccugaucaacuaccaccaggagcaggcgguuaacugucug1200

uugggaaacguguucuacgagcgguuggccggccacggcccuaagcugggcccggucacc1260

cggaagcacccccuggucacccgcuacuucaccuuuccauucgaggagaucgacuucagc1320

auggaagaaucgaugauccaucugccgaacaaggccugcuuccugauggcucacaacgga1380

ugggugaugggcgacgauccucugagaaacuuugccgagccgggcucggagguguaccug1440

aggagggagcugaucuguuggggggacagcgugaagcugagauacggaaacaagccagag1500

gacugcccguaccugugggcccauaugaagaaguacaccgagauuaccgcaacauacuuc1560

caagggguccggcuggacaauugccacucgacuccccugcacguggcggaguacaugcug1620

gacgcggccaggaaccuccagcccaaccucuacgucguggccgagcuguucacugguucc1680

gaggaccuggauaacguguucgugaccagacuggggaucuccucacugauucgcgaagcc1740

auguccgcguauaacucgcaugaagagggccgccugguguaccgcuacggaggcgaaccu1800

gugggcagcuucgugcaaccgugucugcggccucugaugccugccauugcgcacgcccug1860

uucauggacaucacccacgacaacgaaugccccaucgugcaccgguccgccuacgaugcc1920

cucccuucgacuacuaucguguccauggcuugcugcgcguccggcucgacccgcggcuac1980

gaugagcucgugccgcaucagauuagcgugguguccgaggaaagguucuacaccaagugg2040

aauccagaagcgcugccgagcaacaccggggaggucaacuuccagucgggaaucaucgcc2100

gcccgcugugccaucuccaagcugcaccaggaacugggcgcgaaggguuucauccaaguc2160

uacgucgaucaggucgacgaggacaucguggccgugacucggcauuccccgagcauucac2220

caguccgugguggccgugucgcgcaccgccuuccgcaacccuaagaccagcuucuauuca2280

aaagaagugccgcagaugugcaucccuggaaagaucgaggaggugguccuggaagcgcgg2340

acuaucgaaaggaacaccaagccauaccgcaaggacgagaacuccaucaacgguaccccg2400

gacaucacuguggagauccgcgagcauauucaacugaacgaguccaagaucgugaaacag2460

gccggaguggcaaccaagggaccgaacgaguauauccaggaaauugaguucgagaaccuc2520

uccccgggaagcgugauuaucuuccgcgugucccuggacccacacgcccaaguggccguc2580

ggcaucuugcggaaccaccugacucaguucuccccgcauuucaaguccggaagccuggcg2640

guggacaacgcggacccaauccugaagauacccuucgccucacuggccucgcgccugacu2700

uuggccgaguugaaucagauccuguaccgcugcgaauccgaagaaaaggaggacggugga2760

ggcuguuacgacaucccuaacugguccgcacugaaauacgcaggacugcagggacugaug2820

uccguccucgcugaaaucagaccgaagaacgaucucggccacccauucugcaacaaccug2880

agauccggcgauuggaugauugauuacgugucgaaccgacugaucucccgcucggguacu2940

auugcggaagucggaaaauggcugcaggccauguucuucuaccugaagcagaucccacga3000

uaccuuaucccuugcuacuuugacgcgauucugauuggugccuacacgacccugcuggac3060

acggccuggaagcaaauguccagcuuugugcagaacggcagcaccuucgugaaacaccug3120

ucgcugggaucggugcagcucugcggcguggggaaguuuccgucacugccgauccugucc3180

ccggccuugauggaugugcccuaccggcugaacgaaaucaccaaggagaaggagcagugc3240

ugcgugucgcuggccgccgggcugccucacuucuccuccggaauuuuucgaugcuggggu3300

agagacacuuucauugcgcugagggggauucugcuuauuaccggccgcuacguggaagcc3360

aggaacaucauccuggcauucgccggaacccugcggcacgggcugauucccaaccuccuc3420

ggagaaggaaucuacgcucgguacaauugccgggacgcaguguggugguggcuccagugc3480

auccaggacuacugcaagauggucccuaacggacuggacauucugaagugcccagugucc3540

cggauguaccccacugacgauucggcaccgcugccggcugguacccuggaccagccgcug3600

uucgaagugauccaggaagccaugcaaaagcauaugcaggggauucaguuccgcgaaaga3660

aaugccggaccucagaucgaccgcaacaugaaggaugaaggcuuuaacaucacugccgga3720

guggacgaagagacuggauucgucuacgggggaaacagauucaauugcgguacauggaug3780

gauaagaugggagaaagcgacagagcucggaauagaggaauuccggccacaccucgggac3840

ggcucagccguggagaucguggggcuauccaagucugccgugcgcuggcuguuggaacug3900

ucgaagaagaacauuuucccauaccacgaggucaccgugaagcgccacggaaaggccauc3960

aaagugucauacgaugaauggaaccgcaagauucaggacaacuucgagaagcuguuccau4020

gugucggaggacccuuccgaccugaacgaaaagcauccaaaccuggugcacaagcggggg4080

aucuacaaggacuccuacggagcguccuccccuuggugcgacuaccaacuccggccaaau4140

uucacgaucgcgauggugguggccccugaauuguuuaccaccgaaaaggccuggaaggcc4200

cucgagaucgcagagaagaaacugcugggaccccugggcaugaaaacccuggacccggac4260

gauaugguguacugcggaaucuacgacaacgcccucgauaaugacaacuauaacuuggcc4320

aaggguuucaauuaccaccaggggccagaguggcuguggccaaucgguuacuuucugcgg4380

gccaagcuguacuucucgagauugauggggcccgaaaccaccgcuaagacuaucgugcuc4440

gucaagaacgugcugucacggcauuacgugcaccuggaacgcagcccauggaagggccug4500

ccggaacugaccaacgagaacgcacaguacuguccguucucgugugaaacucaggccugg4560

agcauugcgaccauccuggaaacucucuaugaucuguag4599

<210>11

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>11

augggccauucuaagcaaauucggauacugcugcugaacgaaauggagaaacuugaaaag60

acccuguuccggcuggagcagggcuaugagcugcaguuuagauugggcccgacacugcag120

gggaaggcagucaccguuuauaccaauuauccuuuuccuggggaaacguucaaucgugaa180

aaguuucggagccucgacugggaaaacccuaccgagcgagaggaugauagcgacaaguau240

uguaaacucaaucugcagcagucaggcucauuccaauauuauuuucugcaagggaacgag300

aagucuggcggaggcuacauugucguugauccgauacugcggguuggcgccgacaaccac360

guguugccucuggacugcgugacacugcaaacauuucucgcgaaaugcuuaggccccuuu420

gaugagugggaaagccgccugagagucgccaaggagagcggcuauaauaugauccauuuu480

acgccgcugcaaacacugggucugucuaggucauguuacucauuggcuaaccagcuggag540

cugaacccggacuuuaguaggccuaacaggaaguauacauggaaugauguugggcaacug600

guggagaagcugaagaaggaauggaaugucauuuguauuaccgaugucguguacaaccac660

acggcagcaaauucaaaguggauucaggaacauccggaaugcgcuuauaaccucguaaac720

ucaccgcaccugaagccggccuggguacuggacagggcacuguggagauucucuugugau780

guagccgaggggaaguacaaggagaaaggcauucccgcucuuauugaaaaugaccaccau840

augaauagcauuaggaagaucaucugggaagauauuuuuccaaaacugaagcugugggaa900

uucuuucaaguugacgugaacaaggcugucgagcaguucaggcggcuguugacccaggag960

aacagacggguuacuaagagugaccccaaccaacaucugacgaucauccaggacccagag1020

uaucggcgcuuuggcugcacaguggacaugaacaucgcccugaccacguuuaucccccau1080

gauaagggcccggccgcuauugaagaguguuguaacugguuucauaagcgcauggaagaa1140

cucaacagcgaaaagcauagacugaucaacuaucaucaagaacaggcugugaauugucug1200

cugggcaacguguuuuaugagcgguuggcuggccauggccccaaguugggccccgugacg1260

cgaaaacauccccucgugacaagauauuucaccuuuccauuugaagagaucgacuucuca1320

auggaggaaagcaugauucaucugccaaacaaggcuuguuuucugauggcucauaauggc1380

uggguuaugggcgacgacccccugagaaacuuugcggaaccagggucugaaguguaucug1440

cggagggaauugauuugcuggggagacucuguaaagcugcgauaugggaacaagccggag1500

gauuguccguaucugugggcccauaugaagaaguauacagaaauuaccgcaacguauuuu1560

cagggcguacgccuggauaauugucauucaacgccacugcauguggcagaguacaugcua1620

gacgcggcuaggaaucugcagccgaaucuguaugucguggccgagcuguucaccggcucc1680

gaagauuuggacaauguguuugugacccgccucgguauuagcucacugauuagagaagca1740

augucggcuuacaauucgcaugaggaaggucgccugguguaccguuacggcggcgaaccc1800

gugggcaguuuugugcaacccugucugaggccacuaaugcccgcuauugcacaugcccug1860

uuuauggauauaacacaugauaacgaauguccaaucguacaccggagugcuuaugaugcu1920

cugcccucaacgaccaucguaucaauggcaugcugugccuccggcucaacacggggcuau1980

gaugaacugguaccacaccagaucagcgugguuucugaggaacgguuuuacacaaagugg2040

aauccugaggcguugccauccaacacuggcgaagugaacuuucagagcggcauuauugcu2100

gcccgaugugcuauuucaaagcuacaccaggaguugggcgcaaagggguuuauccagguu2160

uauguggaccagguugacgaagauaucguagcugugacgcggcacucuccgucuauccau2220

caauccgugguagccgugucuaggacggcuuuucgcaaccccaagacaaguuucuauucc2280

aaagaaguaccccagauguguaucccggggaagauugaggaagugguccuggaggccagg2340

acgauagaacggaacacgaagccguaucgcaaggacgaaaacagcauaaacgggacgccu2400

gacaucacgguggagauucgcgagcacauccaguugaacgaaucaaagauagugaaacag2460

gcugggguggcuaccaagggcccaaaugaguacauucaggagaucgaguucgaaaaccug2520

uccccgggcagugugaucaucuuuagagucucuuuggauccgcaugcccaggucgcugug2580

ggcaucuugcgaaaucaccugacgcaguuuucuccacauuuuaagaguggcucccuggcu2640

guggacaacgccgacccaaucuugaagauuccguucgcuucccuggcuucacgucugacu2700

cucgcugaauugaaucaaauucuguauagaugcgaaucagaggagaaggaagauggaggc2760

gguuguuacgacaucccgaauuggucggcacugaaauacgccggucugcaaggcuugaug2820

agcguacuggccgagauaagaccaaagaacgaucugggccacccauuuugcaacaacuug2880

cgguccggcgauuggaugauugacuaugucucuaaccgacucaucaguagaagcggaacc2940

auagcugaggucggcaaauggcugcaagccauguucuucuauuugaagcagaucccccga3000

uaucugauccccuguuauuuugacgcaauccucauuggcgccuauaccacacuccucgac3060

accgcuuggaagcagauguccucauuugugcaaaacgguagcaccuuugugaagcaucug3120

ucgcuggguagugugcagcucugcggcguagggaaguuccccaguuugccgauccugagu3180

ccagcucuaauggacgugccauauaggcugaacgagauuaccaaggaaaaggagcagugu3240

ugugucucccuugcugccggucugccccauuuuuccucgggcauuuuuagauguuggggg3300

cgggacaccuucaucgcucugcggggcauccugcugaucaccggcagauauguggaggcu3360

cggaauauuauucuggcuuuugcugggacgcugcgccauggacugauucccaaucuauug3420

ggcgaaggcauauacgcuagguauaacugucgggacgcuguuuggugguggcugcagugu3480

auccaagauuauugcaagaugguccccaacggccuggacauacugaaauguccaguaucu3540

aggauguacccgacugacgacagugcuccccugcccgcuggaacuuuggaucaaccccug3600

uuugagguuauucaagaggcuaugcagaagcacaugcagggcauucaguuucgcgaaagg3660

aacgccggcccccaaauugaccguaacaugaaggacgaaggcuucaauauuacggcuggc3720

guagaugaagaaacaggcuuuguguacggcggcaaccgcuucaacugugggacauggaug3780

gacaagaugggcgaaagcgacagggcucggaacaggggaauuccagccacgccccgcgau3840

ggcagugcuguugaaauugucggcuugucaaaaucagccguacgcugguuauuagagcuc3900

uccaagaagaacaucuuuccguaucaugaagucacgguuaagcggcauggaaaagcaauc3960

aaagugucuuacgacgaauggaauaggaaaauucaggacaacuuugagaagcuguuccau4020

gugucugaggacccguccgaucuuaacgagaagcaucccaauuuggugcacaagaggggc4080

aucuauaaggacucauacggggcuagcucaccuuggugugacuaucagcugcgaccgaau4140

uucacaauagcuauggucguggcuccggagcuuuuuaccaccgagaaggcuuggaaggcc4200

cuggagauugccgagaagaagcuguuaggcccguugggcaugaaaacguuggauccagac4260

gacauggucuauuguggcaucuaugacaacgcucucgacaaugacaacuauaaccuagcu4320

aagggcuucaauuaccaucagggcccggaguggcuguggccaauuggauauuuccugagg4380

gcaaagcuguauuucucccggcugaugggccccgagacaacggcaaaaaccauagucuug4440

guuaagaacgugcugucccgccacuaugugcaccuugaaaggaguccguggaagggccug4500

ccggagcugacaaacgaaaaugcccaguacugcccauuuucuugcgaaacucaggcuugg4560

agcaucgccacaaucuuggaaacccuguaugacuuguag4599

<210>12

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>12

augggacacucgaagcagauccgcauccuccugcugaacgaaauggaaaaacuggaaaag60

acacucuuccggcuggaacagggauaugagcugcaguuuagacuggggcccaccuuacaa120

ggaaaggccgugacugucuauaccaacuacccguuccccggagaaacuuucaaccgggaa180

aaguuccggucacuggacugggaaaacccgaccgagcgggaggacgauagcgacaaguac240

ugcaagcugaaccuucagcaguccggaucguuccaguacuacuuccugcaagggaacgag300

aagucgggcggaggauacauuguggucgauccuauccugcgcgugggagcugacaaucac360

gugcucccucuggacugcgugacgcugcaaaccuuccucgcaaagugccucggaccuuuc420

gacgaaugggaauccagacuccgcguggccaaggagucaggauacaacaugauccacuuc480

acgccgcugcagaccuugggacucucucggagcuguuacucccuggccaaccagcuggaa540

cugaacccagacuucucacgcccgaauagaaaguacaccuggaacgacgugggacagcuu600

guggagaagcucaagaaggaauggaacgucaucugcauaaccgacgucguguacaaccac660

accgcagccaauucuaaguggauucaggaacaccccgaaugcgccuacaaucugguuaac720

ucaccccaccuuaagcccgccuggguccuagacagagcccucuggcgguucucgugugac780

guggccgagggaaaguacaaggagaagggaauccccgcucugauugaaaacgaccaccac840

augaacuccauccgcaagauuaucugggaggacaucuucccgaagcucaagcugugggaa900

uucuuccaaguggacgugaacaaggcggucgagcaguucagacgccugcugacccaggaa960

aaucggagagugaccaagagcgauccuaaccagcaccugaccaucauccaagacccagag1020

uaccggcgguucggaugcacuguggauaugaacaucgcccugaccacuuucaucccucac1080

gacaagggaccggccgcaauugaggaaugcugcaacugguuccauaagcggauggaggaa1140

cugaacagcgagaagcaucgacugaucaauuaucaucaagagcaggcugugaauugccug1200

cugggaaacguguucuacgaacggcuggccggacauggcccuaagcuggggccugugacc1260

cggaagcacccucuugugacccgauacuucaccuucccguuugaagaaauugauuucucc1320

auggaagaauccaugauccaucugccaaacaaggccugcuuccuuauggcccacaauggc1380

ugggucaugggggacgacccucuucggaacuucgccgaaccagggagcgagguguaccuc1440

agaagggagcucaucuguuggggggauuccgugaagcucagauacggaaacaagccagaa1500

gauugccccuaccuuugggcccacaugaagaaguacaccgaaaucaccgccacauacuuc1560

caaggagugcggcuggacaacugccauucaacuccccugcacgucgccgaguacaugcug1620

gacgcugcgagaaacuugcagcccaaccuuuacgugguggccgagcuguucaccgggagc1680

gaggaccuggacaacguguuugugaccaggcucggaaucucgucgcugauucgcgaagcc1740

augagcgccuacaacucccacgaagaggguagacugguguacagauacggaggagagcca1800

gugggauccuucguccaaccgugccugcggccgcucaugccugcgaucgcacacgcgcug1860

uucauggacaucacccacgauaacgaauguccuaucgugcauaggagcgccuaugaugcc1920

cuucccuccaccaccaucguguccauggcgugcugugccucggguagcaccaggggauac1980

gacgagcuggugccgcaccagaucucggugguguccgaagaacgguuuuacacuaagugg2040

aacccugaggcgcugccuuccaacaccggagaagugaacuuccaguccgguaucauugcc2100

gcucgcugcgcaaucagcaaacugcaccaggagcuuggugccaaaggauucauccaaguu2160

uacgucgaucaaguggacgaggauauuguggccgucacuaggcacucuccaagcauucac2220

caguccguaguggcagugucgaggaccgccuuccggaaccccaagacuucauuuuacucg2280

aaagaggucccacagaugugcaucccuggaaagaucgaagaaguggugcuggaagcccgg2340

accaucgagaggaacacaaagcccuaccggaaggacgagaacuccaucaacggaaccccc2400

gacauuaccguggaaauuagagagcacauccaguugaacgagucgaagaucgugaagcag2460

gccggaguggccacuaagggaccaaacgaguacauccaggagaucgaguuugaaaaccug2520

uccccgggcuccgugaucaucuuccgggugucccuugacccccaugcccaaguggccguc2580

ggaauccuuaggaaccaccugacccaguuuucgccccauuucaaguccggauccuuggcu2640

gucgacaaugccgaucccauccugaaaauuccguucgccucccucgcuucccggcucacc2700

cuugccgaacucaaccagauucuguaccgcugcgagucagaagaaaaggaagauggaggg2760

ggaugcuacgacaucccgaacugguccgcccuuaaauacgccgggcugcaaggccugaug2820

uccgugcuggcggagauuagaccgaagaacgacuugggucacccuuuuugcaacaacuug2880

cggagcggagacuggaugaucgacuacgugucgaaccggcugauuagucgguccggaacc2940

aucgccgaagucggaaaguggcuccaagccauguucuucuaccugaagcaaauuccccgc3000

uaccugauaccgugcuacuucgacgccauccucauuggagccuacaccacgcugcuggac3060

accgccuggaagcaaaugagcuccuucgugcaaaacggaucaaccuucgugaagcaccug3120

ucccuggguagcguccagcucuguggcgugggaaaguuuccgucccugccaauucugagc3180

ccggcucugauggaugugccguaucgccugaacgagaucacgaaggagaaggagcagugu3240

ugcgugucgcuggcugcgggacugccucacuucucguccggaaucuuccgcuguugggga3300

cgcgacacguuuaucgcguugagggguauucuccucauuaccggacgcuacguggaagcg3360

cggaacauuauccuggcguucgccggaacccugcgccacggucugauuccuaaucugcug3420

ggagagggaaucuacgcgcgguacaacugccgggaugcugugugguggugguugcagugc3480

auccaggacuauuguaaaauggugccgaacggccuggacauccugaagugcccggugucc3540

cggauguacccgaccgaugauucagcaccacugcccgccgggacccuggaccagccccug3600

uucgaagucauucaggaagcgaugcagaagcauaugcagggaauccaguuccgcgaaaga3660

aacgccggaccucagaucgaccgcaacaugaaggaugagggcuucaacaucaccgcggga3720

guggaugaggaaaccggcuucgucuacggagggaaccgguucaacugcggaaccuggaug3780

gacaagaugggagaguccgaccgcgcaagaaaccgcgguauuccugccaccccgcgggac3840

ggaagcgcgguggagaucgucggacugagcaagagcgcagugcgcuggcugcuggaguug3900

uccaagaagaauaucuuccccuaucacgaggucaccgugaaacgccacgggaaggccauc3960

aaaguguccuacgaugaguggaaccgcaagauucaggauaacuucgaaaagcuguuucau4020

guguccgaggaucccuccgaccucaacgaaaagcacccgaaccucgugcauaagaggggg4080

aucuacaaggacagcuacggugccuccucaccuuggugcgauuaucagcuccgcccgaac4140

uucaccauugccaugguggucgccccugaacuguuuacuaccgagaaggccuggaaggcg4200

cuggagauugccgaaaagaagcuguugggaccccugggcaugaaaacccucgaccccgac4260

gacaugguguacugcggaaucuacgacaacgcccucgacaacgacaacuacaaccucgcg4320

aagggguucaacuaccaccagggccccgaauggcuguggcccaucggauacuuccuccgg4380

gcgaaguuguacuucucccgccugaugggcccugaaaccacggccaaaacgaucgugcuc4440

gugaagaacgugcugucgaggcauuacgugcaccucgagcggagcccguggaaggggcug4500

ccggaacugaccaacgagaaugcacaguacugccccuucuccugcgaaacgcaggcuugg4560

uccauugccacuauuuuggaaacgcuguacgaccuguag4599

<210>13

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>13

augggacacucgaaacagaucagaauccuguugcucaacgaaauggagaagcuggaaaag60

acccucuuucggcucgagcagggcuacgagcugcaguuccgccuggguccgacacuacaa120

ggaaaggcagugacuguguacaccaacuacccauuucccggagaaaccuucaaccgggag180

aaguuccggucccuggacugggaaaacccaaccgaacgagaggaugacuccgacaaguac240

ugcaagcugaaccuccaacaguccgguucauuccaguacuacuuucugcaagggaacgag300

aaguccggaggcggcuacaucguggucgacccgauacuuagagugggagccgacaaucau360

guccugccucuggacugcgugacccugcaaaccuucuuggccaaaugucugggcccguuc420

gaugagugggaaagccgccucagagucgcaaaggaguccggauacaacaugauucacuuc480

acuccgcugcaaacccucggucugucccggucgugcuauucucuggcgaaccagcuggag540

cuuaaccccgacuucucgcgcccaaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcaucacugacgugguguacaaccau660

acggccgccaacucgaaguggauccaagagcaucccgagugcgcguacaaccucgugaac720

agcccgcaucugaagccugcuugggugcuggauagagcccucuggagauucagcugcgac780

guggccgaggggaaguacaaagaaaagggaauuccggccuugauugagaacgaccaucac840

augaacucaauccgcaagaucaucugggaggauaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacguaaacaaggcaguggagcaguucagaagguugcugacucaagaa960

aacagacgcgucacuaaguccgauccuaaccagcaccuuaccaucauucaagacccugag1020

uaccgccgguuuggcugcaccgucgacaugaacaucgcccugaccacuuucaucccgcau1080

gacaagggcccggcggcaaucgaggaaugcuguaacugguuucauaagaggauggaggaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagugaauugccuc1200

cugggcaacguguucuacgaacggcuggcuggacacggaccgaagcugggucccgugacu1260

cgcaagcauccgcucgugacucgcuacuucaccuucccguuugaggagauugacuucucc1320

auggaagaauccaugauccaccucccgaacaaggcuugcuuccugauggcgcacaacgga1380

ugggucaugggcgacgacccacugcgcaacuucgcugagccuggcucggaggucuaccug1440

agaagggaauugauuugcuggggagacuccgucaagcugcgcuauggaaacaagcccgaa1500

gauugccccuaccugugggcucacaugaagaaguacacggaaaucacugccacguacuuc1560

cagggaguccggcuggacaauugccacuccaccccccuccauguggccgaguacaugcuc1620

gaugcagcgaggaaucugcagcccaaucuguacgugguugcagaacuguucacuggcucc1680

gaggaccucgacaacguguucgugaccagacuggggaucuccucccugauccgggaagcc1740

augucggccuacaacucccaugaagagggccgccugguguaccgcuacggcggagaaccc1800

gugggaagcuucgugcagccuugccuccggccgcugaugccugcgaucgcccacgcccug1860

uucauggauaucacucacgacaacgaaugccccauugugcaucgcucggccuacgacgca1920

cugccuucgaccacuaucguguccauggccugcugcgccuccgggagcacccgcggauac1980

gaugaacucgugccgcaccagaucagcgugguguccgaagaaagauucuauaccaagugg2040

aaccccgaagcccugccgagcaauaccggggaagugaacuuccaguccgguauuaucgcc2100

gcucgcugugccaucagcaaacuccaccaagagcucggugccaagggauucauucaaguc2160

uacguggaucaggucgacgaagauauuguggccgugaccaggcacucaccuuccauccac2220

caauccgucgucgccgugucccggacugcguuucggaaccccaagacuucguucuacucg2280

aaagaagugccacagauguguaucccgggaaaaaucgaagaggucgugcucgaagcccgg2340

accauugagaggaacaccaagccuuaccggaaagacgagaacucuaucaacgguaccccu2400

gauauuacuguggagauccgcgaacacauccagcugaacgaaucaaagaucgucaagcag2460

gcuggaguggccaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccuggcuccgugauuaucuuccgggugucccuggacccucacgcccaaguggccgug2580

ggaauucucagaaaccaccugacccaguucucaccccacuuuaaguccgguucccuggcg2640

guggacaacgccgauccgaucuugaagauccccuucgcaucgcuggccucccgccugacu2700

cucgcggaacugaaccagauccuguaccgcugugaaucagaggaaaaggaggacggcggc2760

ggcuguuacgauauccccaauuggucggcuuugaaauacgcgggacuucaggggcugaug2820

ucugugcuggcggaaauccggccgaagaacgaccugggacacccauucugcaacaacuug2880

cggagcggagacuggaugaucgauuacgucagcaacagauugaucagccggagcggcacu2940

aucgccgaggucggaaaguggcuccaggccauguucuucuaccugaagcagaucccccga3000

uaccucauccccuguuacuucgacgccauucugaucggggccuacaccacccugcuggac3060

accgccuggaagcagaugagcaguuuugugcaaaacggguccaccuucgugaagcaccuu3120

ucacugggcucagugcagcucugcggcgugggaaaguuccccucgcugcccauucugagc3180

ccggcccugauggacgucccuuaccggcugaacgagaucaccaaggagaaggagcagugc3240

uguguuucccuggcugccgggcugccacacuucucguccggcaucuuccggugcuggggc3300

cgggauaccuucauugcccugcggggaauccugcuuaucaccggucgcuacguggaggcu3360

cggaacauuauucuggcguucgccggcacccuuagacacggucugauuccgaaucuuuug3420

ggcgaaggaaucuacgccagauacaacugucgggacgccguguggugguggcuccagugc3480

auucaggacuauugcaagauggugccgaacggccuggacauccugaagugcccagugucg3540

aggauguauccaaccgacgacagcgcaccucugccggccgggacccucgaccaaccccug3600

uucgaagucauucaagaggcuaugcagaagcacaugcaggguauucaguuccgggagcgg3660

aacgcggggccccagauugauaggaacaugaaagacgagggcuucaacaucacugccggc3720

guggacgaagaaaccgguuuuguguacggaggaaacagauucaacugcgguaccuggaug3780

gacaagaugggagaguccgaucgcgcgcgcaacagagggaucccggcaaccccgcgggac3840

ggauccgcgguggaaauugugggacugagcaagagcgccgugcgguggcuccuggaacug3900

agcaaaaagaacaucuuccccuaccacgaagugaccgugaagcggcacggaaaggccauc3960

aaagucucauacgaugaauggaauaggaagauccaggauaacuucgagaagcuguuucac4020

guguccgaggaucccuccgaucugaacgaaaagcauccgaaucucgugcacaagcgcggg4080

aucuacaaggacucguacggagcguccuccccuuggugcgacuaucagcugcggccuaac4140

uucaccauugccauggucguggccccggagcuguucacaacugagaaggccuggaaggcc4200

cuugaaauugccgagaagaagcugcuggggccuuuggggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuggacaacgauaacuacaaucuggcg4320

aagggcuucaauuaccaccagggcccggaauggcucuggccuauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugaugggaccagagacuaccgccaagacuaucguccuc4440

gugaagaacgugcugucccggcacuacgugcaucuggagaggagcccuuggaagggacuu4500

ccugagcugacgaacgaaaacgcgcaguacugccccuucuccugcgaaacccaggcuugg4560

uccauugccacuauacuggaaaccuuauaugaccuguag4599

<210>14

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>14

augggucacuccaagcaaaucagaaucuuacuccuuaacgaaauggaaaagcuugaaaag60

acacucuuccgcuuggagcagggcuacgagcugcaguuccggcuggguccgacacuucag120

gggaaagccgugaccguguauaccaacuaccccuuuccgggagaaacauucaaucgcgag180

aaguuccggucgcuggacugggagaacccuaccgagagggaggacgacucugauaaguac240

ugcaagcugaaucuccagcaaucagguucuuuccaauauuacuuccuucaaggaaacgaa300

aaguccgggggcggcuacauuguaguggaccccauccuucgggucggcgcggauaaccau360

gugcuuccccucgacugcgugacucuccaaacuuuccucgccaagugccugggaccauuc420

gaugaaugggaaucccgccugcgcguggccaaggagagcggcuacaacaugauucacuuc480

acuccgcuucaaacccuugggcugucccgcuccugcuauucccuugcgaaccagcuggaa540

cuuaacccggacuucucucggccgaacagaaaguacacuuggaacgacgugggccagcuu600

gucgagaagcugaagaaggaauggaacgugaucugcaucaccgacgugguguacaaccac660

accgcggcaaacuccaaguggauccaggaacauccugagugcgcauacaaccucgugaac720

aguccgcaucugaagccugccugggugcuggauagagcccuguggcgcuucuccugcgac780

guggcugagggaaaguacaaggaaaagggcaucccugcgcucauugaaaacgaucaccac840

augaacagcauccgcaagauuauuugggaggacaucuucccuaagcucaagcucugggag900

uuuuuccaaguugacgugaacaaggccguggagcaguucagacggcuccugacucaagaa960

aacagacgcgucaccaaguccgacccuaaccaacaccucaccaucauccaggaucccgaa1020

uaccgccgguuuggcugcacuguggacaugaacauugcccugaccaccuucauuccgcac1080

gacaaaggcccggccgcgauugaagagugcuguaacugguuccacaagagaauggaggag1140

cugaacuccgaaaagcauagacuuaucaacuaccaccaggaacaggccgugaacugccug1200

cugggaaacguguuuuacgagagacucgccggacacgguccaaaguuggguccugugacc1260

cgcaaacacccgcucgucacccgcuacuuuaccuucccguucgaggagaucgacuucagu1320

auggaggagagcaugauccaucuccccaacaaggccuguuuccucauggcccacaacggc1380

ugggucaugggcgacgacccccugcgcaacuucgcugaacccggcucggaaguguaccuu1440

cggagggagcuuaucuguuggggcgacagcgugaagcuuagauacggcaacaagccagaa1500

gauuguccguaccugugggcgcacaugaagaaguacaccgagaucaccgcgacguacuuu1560

caaggagugcggcucgauaacugccacuccaccccucugcacguggcagaguacaugcua1620

gacgcggcccggaaccuccagcccaaccuuuacgugguggccgaacucuucacugguucu1680

gaggaucuugauaacguguucgugacuaggcucggcauuuccucccucauccgggaagcc1740

augucggccuauaacucccacgaggaggggcggcugguguaccgcuacggaggcgaaccg1800

gucggcagcuucgugcagccgugccuccgcccucugaugcccgcuauugcucacgcccuu1860

uucauggauaucacucacgauaaugagugcccuaucgugcaucggagcgccuacgacgcu1920

cucccuuccaccaccaucguguccauggcgugcugcgccuccgguucaaccaggggcuac1980

gaugaacuugugccgcaccagaucucagucgucagcgaggaaagguucuacacuaagugg2040

aacccugaagcccugcccucuaacacgggcgaagugaacuuucagagcgguaucauugcc2100

gcuagaugcgcaaucuccaaguugcaccaggaacugggagccaagggguucauccagguc2160

uacguggaccaggucgacgaggacaucgucgccgugacccggcauuccccgagcauccau2220

caguccguggucgccgugucacggaccgccuuccgcaaccccaagaccuccuucuacucc2280

aaggaagugccgcaaauguguaucccuggcaaaaucgaggaaguggugcucgaagcgcgg2340

acgauugagaggaauacuaagccguacagaaaggacgaaaacuccaucaacggcaccccg2400

gacaucacuguggagauccgggagcacauccagcucaacgagagcaaaauugugaagcag2460

gccggcgucgcuacuaagggcccaaacgaguacauccaggagauugaguucgaaaaccuu2520

agcccugggucugugaucaucuuucgcgugucccucgacccgcacgcacaggucgcaguc2580

gggauucuccggaaccaucugacucaguucagcccccacuucaagagcggcagccuugcc2640

gucgacaacgccgaucccauccucaaaaucccuuucgcaucccuugcgucgaggcuuacc2700

cuggcggaauugaaccagauucuguaccgcugcgagucggaagaaaaagaggauggcggc2760

ggcugcuacgacauuccgaacugguccgcccugaaauacgcgggccuucagggccuuaug2820

agcgucuuggccgagauccgccccaagaacgaccuggggcaccccuuuugcaacaaccuc2880

agaagcggcgauuggaugaucgacuacgugucgaacaggcucaucagccgauccggcacu2940

auagccgaggucggaaaguggcugcaggccauguucuuuuaccucaaacagaucccgcgg3000

uaccugaucccgugcuacuucgacgcuauucucauuggcgccuacacuacccugcucgau3060

accgcuuggaagcagaugagcucauucgugcaaaacggaagcaccuucgugaagcaccuc3120

ucccugggaucagugcagcugugcggcgugggaaaguucccauccuuaccaauucucucg3180

ccugcccugauggacgucccuuaucgccugaacgaaaucacgaaggagaaggaacagugu3240

ugugucucacuggcugccggccucccgcacuucucauccggcaucuuccggugcuggggu3300

agagacacuuucauugcgcuccggggaauucugcuuaucacuggccgcuacguggaagcc3360

cgcaacaucauccuugccuuugccgggacccugcggcacggccugaucccuaaccuucuc3420

ggggagggcaucuaugcgcgauacaauugccgggacgccgucuggugguggcugcagugc3480

auucaggacuauugcaagauggugccaaauggucuggacauucugaaguguccagugucc3540

cggauguacccuaccgacgauagcgccccacugcccgccggaacccucgaucagccccug3600

uucgaagucauucaggaagcgaugcagaagcauaugcaggguauccaauuccgcgaaagg3660

aaugccggcccacaaaucgacagaaauaugaaggaugagggcuuuaacaucaccgccggc3720

guggacgaggagacugguuucgucuacggcggcaaucgguucaauugcgggaccuggaug3780

gacaagaugggcgaaagcgaccgggccagaaaccggggcauuccggcuaccccccgcgau3840

ggcucggccguggaaaucgugggccucuccaagucugccgugcgguggcuuuuggagcuc3900

uccaagaaaaacaucuucccguaccacgaagugaccgugaagagacacgggaaggccauc3960

aaaguguccuacgacgaauggaaccggaagauccaggacaacuucgaaaagcuguuccac4020

guguccgaggaucccuccgacuugaacgaaaagcaccccaaccucgugcacaagcgcggc4080

aucuacaaggauuccuacggagcguccucaccuuggugcgacuaucagcugaggcccaac4140

uucaccaucgcaauggugguggccccugaguuguucaccacugagaaggcuuggaaggcc4200

cuugagaucgccgaaaagaagcugcucggcccgcuggggaugaaaacccucgaccccgau4260

gacaugguguacugcgggauauacgacaaugcacuagacaacgacaacuacaaccuggcc4320

aagggcuucaauuaccaucagggcccggaguggcuuuggccuaucggcuacuuccugcgg4380

gccaagcuguacuucucacggcuuaugggaccggagacuacugcaaagaccauugugcuu4440

gugaagaacgugcuuucgcgccacuacgugcaucuggaacggagccccuggaaggggcuc4500

cccgagcugaccaacgagaacgcccaguacugucccuucuccugugaaacccaggcuugg4560

uccauugccaccauucuggaaacccuguacgaccucuag4599

<210>15

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>15

augggacacucaaagcaaauucggauccuccugcucaacgagauggaaaagcucgagaaa60

acccucuuucgccuggagcaggguuaugagcuccaguuccgccuggguccgacccuccaa120

gggaaggccgucacuguguacacuaacuauccauuccccggagagacuuucaaccgggaa180

aaguuccgcagccucgauugggagaacccuacugaacgggaggacgauucggacaaguac240

uguaaacugaaccuccagcagagcggcucauuucaauacuacuuucugcaagggaacgag300

aaguccggagggggguacaucgucguggauccuauccuucgcgugggcgccgacaaccau360

gugcugccguuggacugcgugacccugcaaaccuuccucgccaaaugccucggaccuuuc420

gaugagugggaauccaggcugagaguggccaaggaaucgggguacaacaugauucacuuc480

accccucuccaaacccugggccugucucggagcugcuacucccuggccaaccagcuggag540

cugaaucccgacuucucccggcccaaccggaaguacacuuggaaugacgugggccaacug600

guggagaagcucaagaaggaguggaacgugaucugcauuaccgacgugguguacaaccau660

accgccgccaacuccaaguggauccaggaacacccagaaugugccuacaaccucgucaac720

ucaccccaccugaaaccagcaugggugcuggaucgcgcccucuggcgguucucgugugac780

guggccgaaggaaaguacaaagagaagggcaucccugcccugaucgaaaaugaccaccac840

augaauuccauuagaaagaucauuugggaggacauuuucccuaaguugaagcucugggag900

uucuuccaaguggacgucaacaaggccguggaacaguuucgccggcuccugacccaagaa960

aaccgccgcgugaccaaguccgacccuaaccagcaccugaccauaauccaggacccugag1020

uacagacgguucgguugcacugucgacaugaacaucgccuugacuacuuucaucccgcac1080

gacaaggguccugccgccauugaggagugcugcaacugguuccacaagcggauggaagaa1140

cugaacuccgaaaagcaccgccucaucaacuaccaccaggagcaggccgugaacugccug1200

cuggggaacguauucuacgagaggcuggccggacacggacccaagcugggacccgugacc1260

agaaagcauccucucgucacccgcuacuuuacuuucccguuugaagagaucgacuucuca1320

auggaagagucgaugauccaucucccuaacaaggccugcuuccugauggcccacaacggc1380

ugggugaugggcgacgauccucugagaaacuucgcugagcccgguucggaaguguaccuu1440

agacgggaacuuauuugcuggggcgauuccgugaaguuacgcuacggaaacaagccugag1500

gacugcccuuaccugugggcccauaugaagaaguacaccgagauuaccgccaccuacuuc1560

caagggguccggcuggacaacugccacucaacuccucugcacguggcugaguacaugcug1620

gaugcggcccggaauuugcagccuaaccuuuacguggucgccgaacucuuuaccgggucc1680

gaggaccuggacaacguguucgugacucggcucggaaucuccucacugauuagagaggcc1740

auguccgcauacaacucgcacgaagaaggccggcuggucuaucgauacggcggcgaaccu1800

gucggaagcuucguccagcccugccugcggccgcugaugccagcgaucgcccacgcccuc1860

uucauggacaucacccaugacaacgaaugucccaucgugcaccgcuccgccuacgaugcc1920

uugccaagcaccaccaucguguccauggcgugcugcgccagcgguagcacuaggggcuac1980

gaugaacuugugccgcaccagaucagcgugguguccgaggaaagguuuuacacgaagugg2040

aaccccgaagcccugcccuccaacacuggggaagugaacuuccaguccgggaucauugcg2100

gcccgcugcgcgaucucgaagcuccaccaggaacucggcgcgaaaggauucauucaaguu2160

uacguggaccaggucgacgaggacaucgucgccgugacucgccacuccccuucaauccau2220

caauccgugguggcggugucgcggaccgcuuuccggaacccuaagacuucguucuacucg2280

aaagaagugccucagauguguauccccggaaagaucgaggaaguggugcucgaggccagg2340

acuauugagaggaauaccaagccuuaccggaaggaugagaacuccauuaacgguacuccu2400

gacaucaccgucgagauccgggaacacauccagcucaacgaaagcaaaaucgugaagcag2460

gccggcguggccacuaaggguccgaacgaguacauccaggaaaucgaauuugagaaccug2520

ucgcccggaagcgugauuauuuuucgggugucccuggacccgcacgcccaagucgccgug2580

gguauccugcgcaaucaucugacucaguucagcccucacuucaaguccggcagccuugcc2640

guggacaacgccgauccgauccugaagaucccauucgccucacucgccucacggcucaca2700

cuggccgaacucaaucagauccucuaucgcugugaauccgaagagaaggaggacggcgga2760

gguugcuacgauauuccgaauugguccgcacugaaauacgccggacugcagggccucaug2820

uccguguuggccgaaauccgcccuaagaacgaccucggccacccguucugcaacaaccuc2880

agaucuggagacuggaugaucgauuacgugucaaaccgccugaucucgagguccggcacu2940

aucgccgaagucggaaaguggcuccaagcaauguucuucuaccugaagcagaucccucgc3000

uaccugauaccuuguuacuucgacgccauccucauuggcgccuacacuacucugcuggau3060

acugccuggaagcaaaugagcagcuucgugcagaacggaagcacuuucgucaagcaucug3120

ucgcucgggagcgugcagcugugcggcgucggaaaguuuccuucccugcccauucugucc3180

ccugcccucauggaugugccguaccgccuuaacgagaucacuaaggagaaggagcagugu3240

ugcgugagccuggcugccgggcucccucacuucucguccggaaucuucagaugcuggggc3300

cgcgacaccuucauugcccugcgagggauccuguugauuacuggccgcuacguggaggcc3360

aggaauaucauucucgccuucgcgggaacccugcggcacggccugaucccuaaccuccug3420

ggagaaggaaucuaugcgagauauaacugcagggacgccguguggugguggcuccagugc3480

auccaggacuacugcaagauggugcccaacgggcuggacauccucaagugccccguguca3540

cggauguacccaacugaugacagugcuccucugccggccgguacucucgaccagccacuc3600

uuugaagucauccaggaggccaugcagaagcacaugcagggcauucaauuccgggagagg3660

aacgccggaccucagauugaccggaacaugaaggacgaggguuucaauaucacugccggc3720

guggacgaagaaaccggcuucgucuacggaggaaacagauucaacugcggaaccuggaug3780

gauaagaugggagaaagcgacagagcgcggaacagggguaucccugccacuccccgggac3840

ggaucggccguggaaauugugggacuuuccaaguccgccgugcgguggcuccuggagcuu3900

uccaagaagaacaucuucccuuaccaugaagugaccgugaagcggcacgggaaggccauc3960

aaagucuccuacgaugaauggaaccgcaagauucaggacaauuucgagaagcuguuccau4020

gucuccgaggacccuucugaccugaaugagaagcaucccaaccuggugcacaagagaggc4080

aucuacaaggacagcuacggagcuuccuccccuuggugcgauuaccagcuccggccaaac4140

uucacuaucgccauggugguggcgccugaacuguucaccacugaaaaggccuggaaggcg4200

cucgaaaucgcggagaagaagcugcucgggccucucgggaugaaaacccucgacccugau4260

gauaugguguacugcggaaucuacgauaacgcccuagacaacgacaacuacaaccuggcc4320

aagggauucaacuaccaucaggggcccgagugguuguggccuauuggcuacuuccugaga4380

gccaagcucuacuucucccgccucaugggccccgaaaccacugccaagaccaucgugcuc4440

gugaagaacgugcucucccggcacuaugugcaccuugagcgcucgccauggaagggacug4500

cccgaacugacuaacgagaacgcccaguacugccccuucuccugugaaacucaggccugg4560

uccaucgccacaauuuuggaaacccucuacgaucuguag4599

<210>16

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>16

augggacauucaaagcaaauccggauucuguuacuuaaugagauggagaaguuggagaaa60

acauuguuuagacucgagcagggcuacgaacugcaguuucgccugggcccuacacuacaa120

gggaaagccgucaccgucuauacaaacuaucccuuccccggcgaaacguuuaaucgggag180

aaguucagaucucuggauugggagaaccccaccgaacgggaggaugauagcgacaaguau240

ugcaaacugaacuugcagcagucuggcaguuuucaguauuauuuucugcaagggaacgag300

aaguccggcggcggcuauauaguggucgaccccauccuucgugugggagcugacaaccau360

guguugccccuggacuguguuacacugcaaaccuuucuggcuaagugucucgguccuuuu420

gaugaaugggaaucgcggcucaggguggcaaaagaauccggcuauaacaugauucauuuu480

acaccccugcaaacccugggccucucaaggaguuguuacagccuugccaaucagcuggag540

cugaaccccgacuuuucccgucccaaccggaaguauacuuggaacgacgugggccagcuc600

guagaaaagcugaaaaaggaguggaacgugaucuguauaaccgauguggucuauaaccac660

accgccgccaauucgaaguggauccaggagcaucccgagugugcuuacaaccucgugaac720

agcccccaucuuaagcccgcuuggguacuugaccgcgcacuuuggagguuuuccugugac780

guggcugaggggaaguauaaggaaaagggcauccccgcccugaucgaaaacgaccaucac840

augaacaguauacggaagaucauuugggaggauauuuuucccaaacugaagcugugggag900

uuuuuucaaguggaugugaacaaggcugucgaacaguuuaggaggcugcugacccaagaa960

aauagacgcgugacuaagagcgacccaaaucagcauuugacaauuauacaggaccccgaa1020

uaucgccgauucggcuguaccguggauaugaauaucgcauugacuacuuucaucccccac1080

gacaagggccccgccgcuauugaggaaugcuguaauugguuucauaagcgaauggaggag1140

cugaacucugagaagcacaggcugauuaacuaucaucaggaacaggccguuaacuguuug1200

cugggcaacguguuuuaugaacggcuugccggccauggcccgaaguugggcccgguuaca1260

agaaagcauccacuugugacccgcuacuucaccuuuccguucgaagaaauugacuuuagc1320

auggaggagucaaugauccaccuccccaacaaggcuugcuuucuuauggcucacaacggc1380

ugggugaugggcgacgacccccugcggaacuuugcggaaccgggcucagaggucuaucua1440

agaagggaacugauuugcuggggcgacuccgugaagcugagauacgggaacaagccugag1500

gauugccccuaccucugggcucacaugaaaaaguauacagaaauuacugcuacguauuuc1560

caaggcguacggcuugacaacugucacuccaccccacugcaugucgccgaguauauguua1620

gaugcugcucgaaacuugcagcccaauuuguauguggucgcugaacuguuuacggggagu1680

gaagaucucgacaacgucuuuguaacccgacugggcaucagcucgcuaauucgggaggcc1740

auguccgcuuacaacucccaugaggaaggccgccuuguauaucguuauggcggcgaaccc1800

guggggagcuuuguucaaccgugucuacgcccccugaugcccgccaucgcucaugcccua1860

uucauggauaucacucaugacaaugaguguccuauugugcauaggagugcuuaugacgcc1920

cucccaagcacaacgaucguguccauggcuuguugugcuaguggcuccacaagaggcuau1980

gacgaacuggugccccaucaaaucuccguagugucugaagagagauuuuacaccaagugg2040

aaccccgaggcucucccuucaaacacuggagagguuaacuuucaauccgggauuauugcu2100

gcuagaugugcuaucagcaagcuccaucaggaacugggcgcaaagggcuucauucaaguu2160

uauguagaccagguugacgaggacauaguugcaguaacucggcauuccccuucgauacau2220

cagucugucguggccguguccaggacagcauuucgcaaucccaagacuagcuuuuacucc2280

aaagaaguaccacaaauguguauccccgggaagaucgaggaagugguacuggaagcccgg2340

acuauugagagaaacaccaagccguaucggaaggacgagaauucuaucaacggcacaccu2400

gauauaacaguggaaauacgcgaacacauucaguugaaugaguccaagaucgugaagcag2460

gccggcgucgccaccaagggccccaacgaguauauccaggagaucgaauuugaaaaccug2520

agccccggcucuguuauuauauuucggguuucauuagauccucaugcucaaguggcugua2580

ggcauccuccggaaucaucugacucaguucucuccccacuucaagagcggcagccuggcu2640

gucgauaaugccgaccccauacuuaagauucccuuugcuucccuggcuucaaggcugacc2700

cuggcugaacuuaaucaaauccuauaccgaugcgaaagcgaagagaaggaagauggcggc2760

ggcuguuacgauaucccgaacuggagcgcacugaaauaugcuggcuuacaaggccucaug2820

aguguguuggcugagauuagacccaagaaugacuugggccauccauuuuguaacaaccug2880

agaagcggcgacuggaugaucgauuacgugucuaaccgacucaucucccgaagcggcacc2940

auugcugagguuggcaaauggcugcaggcuauguucuuuuaucugaaacagauuccucgg3000

uaccugauucccuguuauuucgacgcuauucugauuggcgcauauaccacgcucuuggac3060

acugcauggaagcaaaugagcucuuuuguccaaaauggcuccacuuuuguuaaacaucug3120

aguuugggcagcgugcaguuauguggcguuggcaaauuuccaagccugcccauacugucc3180

cccgcucugauggacguccccuaccgacugaacgagaucaccaaggaaaaggaacagugc3240

ugugugucuuuagcugccggcuugccgcauuuuucaagcggcauuuuccgguguuggggu3300

cgggacaccuucaucgcacugagaggcauucugcugaucacuggccgcuauguggaagcu3360

aggaauaucauuuuagccuuugcggguacccuucggcacgggcugauccccaaucuuuug3420

ggcgaaggcaucuacgcacguuacaauugccgggaugccguauggugguggcuccaaugu3480

auccaggacuauugcaagaugguucccaacggccucgauauccugaagugccccguguca3540

aggauguauccuaccgaugacagugcuccccuuccugcuggcacccuggaucagccgcuc3600

uuugaaguuauucaggaagcaaugcaaaagcauaugcagggcauccaguuucgggaaaga3660

aacgcuggcccgcaaauagacaggaacaugaaggaugaaggcuucaauauuacugcuggc3720

guagacgaagagacaggguucgucuacggcggcaauagguuuaacuguggcacuuggaug3780

gacaagaugggcgaaucugaccgcgcgaggaacagaggcaucccagcaacaccgagggac3840

ggcagcgcuguggagauugugggccugucuaagucugccgugcgcuggcuacucgaacug3900

uccaagaagaauaucuuucccuaucaugaagucaccguaaagcggcauggcaaagcuauu3960

aagguuuccuaugacgaguggaacaggaagauucaggacaauuuugagaagcuguuccau4020

gugucggaggacccuagcgaucucaacgagaagcaccccaacuuaguacauaagaggggc4080

aucuauaaggauagcuauggcgcuagcagcccuuggugugacuaucagcuccgucccaac4140

uuuaccauugcuaugguaguggcgcccgaguuguuuaccacugagaaggcuuggaaggcu4200

cuugaaauagccgagaagaaauugcugggcccccugggcaugaaaacucuggaucccgau4260

gacaugguauacuguggcaucuaugacaaugcccuggacaaugacaauuacaaucuggcc4320

aaggguuuuaacuaucaccagggcccugaauggcuguggccuauuggcuauuuucuucgc4380

gccaagcuauauuuuaguaggcugauggguccagaaacaacugcaaagacaauugugcuc4440

gugaagaacgugcuuucccggcacuaugugcaucuggaaaggaguccauggaagggcuug4500

ccggaauugacuaacgagaacgcccaguauugucccuuuucuugugaaacucaggccugg4560

uccauugcuacuauucuggagacucuauaugacuuguag4599

<210>17

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>17

augggccauuccaagcaaauucgaauucugcugcugaacgaaauggaaaaguuggaaaag60

acauuguuccgucuggagcagggcuaugagcugcaguuuaggcuuggcccgacguugcag120

ggcaaagccgugaccguauauacuaacuaucccuucccuggcgaaacguuuaaccgggag180

aaguuucgcucacuggacugggagaaucccacggaaagggaggacgauagcgauaaguac240

uguaaacugaaucugcaacagucuggcucuuuccaauauuauuuucugcaagggaacgag300

aaguccgggggcggcuauauuguaguggaccccaucuugagagugggcgcugacaaccau360

guauuaccccuugauugcgugacgcugcagaccuuucuggcuaaguguuugggcccuuuc420

gaugagugggaaagccggcugaggguggccaaggagagcggcuauaauaugauucauuuu480

accccuuugcaaacucuggggcucucuaggagcuguuauuccuuggcuaaucagcuggaa540

cugaaccccgauuuuagccggcccaaccgaaaguauacauggaaugacguugggcaauug600

guugagaagcugaagaaggaauggaauguuauauguauaacagacgugguguauaaccau660

accgcugcuaauucgaaauggauucaggaacauccugagugcgccuacaaccucguaaau720

aguccucaucugaagccggcuugggugcuggacagggcucucuggagguuuagcugugau780

guggccgaagggaaguauaaggagaaggguaucccggcucugauugagaacgaccaccau840

augaacaguauaaggaagauaaucugggaggacauuuuucccaaacugaagcugugggaa900

uucuuucaaguggacgugaacaaggccguugagcaguuuagacgcuugcugacacaagag960

aaccgaagggucaccaagagugacccuaaccagcaucuuacaauuauccaagaccccgag1020

uaucgucgguuuggcuguacuguggacaugaacauugcucugaccaccuuuauaccccac1080

gauaagggccccgcugcuaucgaagaguguuguaacugguuccacaagaggauggaagag1140

uugaacucugaaaagcaucggcugauuaacuaucaucaggaacaggcugugaacugccug1200

cucggcaacguauucuacgagagauuggcuggccauggaccuaagcugggcccgguuacg1260

agaaagcauccccugguuacgcgguauuucaccuucccguuugaggagauugauuuuagc1320

auggaagaauccaugauccaccuccccaacaaggcuugcuuccugauggcacauaacgga1380

uggguuaugggcgacgacccccugaggaauuuugcugaacccggcuccgaagucuaucug1440

agaagggaacugaucuguuggggcgacuccgucaaguugcgcuauggcaauaagccugag1500

gacuguccauaucugugggcucacaugaagaaguacacagagaucaccgcuacauacuuu1560

cagggcgucaggcucgacaauugucacuccacaccccugcacguggcugaguauaugcug1620

gaugccgcuaggaaucuccagccuaaccuauauguggucgcugaacuguucaccggcucu1680

gaggaucuggauaauguguuugugacacgccugggcaucagcucccugauccgcgaggcu1740

augagugccuacaauagucacgaggaaggccggcuuguguaccgcuauggcggcgaaccc1800

gugggcagcuuuguacaaccuugucugcggccucugaugcccgcuauugcucacgcuuug1860

uuuauggacaucacccaugacaacgaaugucccauuguacaccggucugcuuacgacgcu1920

cugcccuccacaacuauugucaguauggcuuguugugcaucuggcucaacucggggcuac1980

gacgaauuaguuccgcaucaaaucucuguaguguccgaagaacgguuuuauacaaaaugg2040

aaccccgaagcgcugcccuccaauaccggcgaagugaacuuucagucugggaucaucgcc2100

gcuagaugugcuauuucuaaacugcaucaggaacugggcgcuaagggcuuuauucaagua2160

uauguggaccaggucgacgaggacaucguagcuguaacccggcacagccccagcauacau2220

cagagugucguggcugugucuagaacagcuuuuaggaacccaaagaccucuuuuuacucc2280

aaagagguuccacagauguguaucccgggcaaaauugaggaaguggucuuggaggccagg2340

acaauugagcguaauacgaagcccuauagaaaggaugagaauagcaucaacggcacuccu2400

gauaucacuguggaaauccgggagcauauacaguugaacgagucuaagaucguuaagcag2460

gcugguguagcuaccaagggucccaaugaguauauucaggaaauugaguuugaaaaccug2520

uccccgggcagcguaauuaucuuuagagucagucucgacccccaugcucaaguggcagug2580

gggauccugcggaaccauuugacucaguucuccccccauuuuaagucuggcagucuggcc2640

guugacaacgcugaccccauauugaagauucccuuugcuucccuggcuucacgguugacc2700

cuggccgaacugaaccagauuuuauaucgcugcgaguccgaggaaaaggaggauggcggc2760

ggcuguuaugacauucccaacuggucugcucuaaaauacgcugggcugcagggucugaug2820

agugugcuggcugaaauucgccccaagaacgaccugggccauccauuuugcaacaaucug2880

cgcaguggcgacuggaugauugauuauguguccaaccggcugauuagucggagcggcacg2940

aucgcagaagucggcaaauggcuccaggcuauguuuuuuuaccuaaagcagauacccaga3000

uaccugaucccuuguuauuuugacgcuauacugauuggcgcuuacacaaccuugcuggac3060

accgccuggaagcagaugagcagcuuuguccaaaauggcagcacauucgugaagcauuug3120

ucucugggcagugugcagcuguguggcgugggcaaauuuccaaguuugccgauccugucu3180

cccgcuuugauggaugugccauaucgacugaacgagauaaccaaggaaaaggaacagugu3240

uguguuucacucgcugcuggcuugccccauuuuuccucuggcauuuuccgauguuggggg3300

agggacacauucauugcccugcgugggauccugcugauuaccggccgcuacguugaggcu3360

agaaacauuauuuuggcuuucgccggcacauugagacauggucugauacccaaucugcug3420

ggcgaaggcauauaugcuagguauaacugucgcgacgcaguguggugguggcugcaaugc3480

auccaggauuauugcaagaugguuccuaacggccuagacauccugaagugcccagugucc3540

cggauguauccaaccgaugauucagcuccccugcccgccgguacacuggaccaaccccug3600

uucgaaguuauucaagaagccaugcagaagcacaugcaggguauccaguuucgagagagg3660

aaugcaggcccccaaauugaccggaacaugaaggaugaaggcuucaacauuacugcuggc3720

gucgacgaagaaacaggguuuguguacggcggcaaccgguuuaacugcggcacauggaug3780

gacaagaugggcgaaagcgaucgcgcacggaaccggggcauccccgccacgccgcgugau3840

ggcucugcuguggagaucgucggccucagcaaauccgcuguccgauggcuguuagagcug3900

ucgaagaagaacaucuuucccuaccaugagguuaccguuaagagacacggcaaagcuauc3960

aaagugucuuaugacgaauggaauagaaagauucaagacaacuucgagaaacuguuucau4020

guguccgaggaucccagcgaccucaacgaaaagcaucccaaucucguacauaagaggggc4080

aucuauaaggacucauauggcgcaucaaguccuuggugcgacuaucagcuucggcccaau4140

uucacgaucgcaauggucguggcacccgagcuguuuacuacggagaaggcuuggaaggcu4200

cuggaaaucgcugagaagaagcugcugggccccuugggcaugaaaacccuggaucccgac4260

gacaugguauacuguggcauauaugacaacgcucuggauaacgauaacuauaauuuggcu4320

aaaggcuuuaauuaucaccagggcccagaauggcuauggcccauuggcuacuuucugcga4380

gcuaagcuauauuuuucucgccugaugggcccugaaaccaccgcuaagacuaucgugcuc4440

gucaagaacguacugaguaggcauuacgugcacuuggagcgcagcccauggaagggcuug4500

ccggaacugacgaacgaaaacgcucaguauuguccguuuucuugugaaacacaggcuugg4560

aguauugcuacuauccuggaaacucuguacgaucuguag4599

<210>18

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>18

augggucauuccaaacaaauuaggauccugcuguugaacgaaauggaaaagcucgaaaag60

accuuauuucgccuggagcagggcuaugaguugcaguuucggcugggaccaacucugcaa120

ggaaaggcuguaaccguguacacaaauuauccuuuucccggcgaaacguuuaacagggag180

aaguuucgaucucuggauugggagaaccccacugaaagggaggacgauagcgacaaguau240

ugcaaacugaaucugcaacaguccggcagcuuucaauauuauuuucugcaagggaacgaa300

aagagcggcgggggcuauauuguaguagacccuauacugagagucggagcugacaaccau360

guucugcccuuggacugcgugacacugcagaccuuuuuggcuaagugucugggccccuuu420

gaugaaugggagagucggcuccguguggcuaaggagagcggguacaauaugauucacuuu480

accccccugcaaacuuugggacuuucccggagcuguuauagccuggcaaaccagcuggag540

uugaauccugacuuuucccgcccaaauaggaaguauaccuggaacgacgugggccaacug600

guggagaagcugaagaaggaguggaacgugaucugcauuaccgacgucguguauaaucau660

accgccgccaacuccaaguggauacaggaacauccugagugugcuuacaaccucguaaac720

uccccgcaucugaagccagcuuggguucuggauagagcuuuguggcgguucagcugugac780

gucgcugagggaaaguacaaggaaaaagggauuccugcucucaucgagaaugaccaccac840

augaacaguauuaggaagauuaucugggaggacaucuucccgaagcuaaagcugugggaa900

uucuuccaaguggacgugaacaaggccguggagcaguuccgacggcuguuaacucaagag960

aaccguagggucacaaaaucggauccuaaccagcaccugaccauuauccaagacccggaa1020

uaucggcgguucggcuguacuguggacaugaacauugcuuugacaacuuucauuccccac1080

gacaaggguccagcagcuaucgaggaauguuguaauugguuucauaagcggauggaggaa1140

cucaacuccgagaagcauaggcugauuaauuaucaucaggaacaggcugugaauugucug1200

uugggcaauguuuucuacgaacggcuggcuggccauggccccaaacucggaccuguuaca1260

aggaagcauccacugguuacccgauacuuuaccuuuccauuugaagaaauugauuuuagc1320

auggaagaauccaugauccaucuaccuaacaaggccuguuuucugauggcccauaacggc1380

uggguuaugggagaugaucccuugcggaacuuugcugaacccggaucugaaguauaucug1440

cggagagaguugauuuguuggggcgacuccguaaagcugcgcuauggcaacaagccagag1500

gacugucccuauuugugggcucauaugaagaaguauaccgagaucaccgcuacguauuuu1560

caaggcgucaggcucgauaauugucauuccacuccgcugcauguugcugaguauauguug1620

gacgcugcucgaaaucugcagcccaauuuguauguuguggccgagcuguuuaccggcucc1680

gaggaccucgauaacguguucgucacgcgacuaggcaucagcagcuugauccgggaagcc1740

auguccgcuuauaacucccacgaggagggccgacuggucuaccgcuauggcggcgaacca1800

gugggcaguuuuguacagccuugucugaggccccucaugcccgcuauugcucaugcucug1860

uucauggacauuacucaugauaacgagugcccuauagugcaucgguccgccuacgacgcc1920

cugccgagcacuacaauaguguccauggcuuguugugcaagcgggagcacccgcggcuau1980

gacgagcuggugccgcaucaaauaucuguagucagcgaagaaagguuuuauaccaagugg2040

aacccggaagcuuuaccuuccaauacuggggaagugaacuuucagagcggcauuaucgcu2100

gcgagaugugcuauauccaaguugcaucaggaacugggggcaaagggguuuauucaagua2160

uauguagaccagguugacgaagauauaguggcugugacacgccacagcccaagcauccac2220

caguccgugguggcugucagccggacugcuuuucgcaacccaaagacaagcuuuuauagc2280

aaagaagugccgcagaugugcauucccggcaaaauugaggaggucgugcuggaggcuagg2340

acuaucgaaaggaacaccaagccguacaggaaggacgagaauuccaucaacgggacucca2400

gauauuacaguugagauccgggaacauauucaguugaaugagucgaagauuguuaagcag2460

gcuggcguagcuacaaaggggccaaacgaguauauucaagagauagaauucgaaaaccug2520

agccccgguuccgugaucauuuuucgagugucccuggauccucaugcucaaguggccguu2580

ggcauucugagaaaccaucucacacaauuuuccccucacuuuaaaaguggcagccuggcu2640

guggacaacgccgauccgauccugaagauuccauucgcuucccuggcuagucgccugaca2700

cuggcugaacuaaaccagauucuuuaccgcugugaaucugaagagaaggaggacggcggc2760

gguugcuaugacaucccaaauuggagcgcucugaaauacgcugggcugcagggccucaug2820

agcguacuggcagaaaucagacccaagaacgaccugggccaccccuucuguaacaaccug2880

agguccggcgauuggaugaucgacuaugugucgaacagacucaucucaagaagcggcacu2940

auagcugaggucggcaaaugguugcaggcuauguucuuuuaucugaagcaaauuccgcgg3000

uaucugaucccgugcuauuuugacgcuauauugaucggcgcuuauacgacuuugcuggac3060

acagccuggaagcagauguccagcuucgugcagaacggcagcacuuuugugaagcaccug3120

agucugggcucaguacagcuguguggcgugggcaaauuccccagccuaccaauucugucc3180

cccgcucugauggauguucccuaucggcugaacgagauuaccaaggaaaaggagcaaugu3240

ugcgugagccuggcagccggccugccccacuuuucuuccggcauuuuucgcuguuggggu3300

cgggacaccuucauugcacugcggggcauccuguuaaucaccggccgcuauguggaagcu3360

agaaauauuaucuuggcuuuugcuggcacucugcgacacggccugauccccaaccuucug3420

ggcgaaggcaucuaugcucgcuacaauugucgcgacgccgucuggugguggcugcagugu3480

auacaggacuauugcaagauggugccaaauggccuggacauccuuaaauguccaguuucc3540

cggauguacccaacugacgacagcgcuccuuugccugccggcacacuggaucagccgcug3600

uuugaagugauccaggaagcuaugcagaagcauaugcagggcauucaguuucgggaacga3660

aaugcuggcccacaaauugacagaaacaugaaggaugaggguuuuaacauuacugcuggc3720

gucgaugaagagacaggguuuguguacggcggcaacagguucaacugcggcacauggaug3780

gacaagaugggcgaaucugaccgugcuaggaacaggggaauccccgcuaccccccgggac3840

ggcagcgcuguggaaaucguaggccuguccaaguccgccguucgcuggcuucuggagcug3900

agcaagaaaaacaucuuucccuaucacgaggucacagugaagagacauggcaaagcuauc3960

aaagucucuuacgaugaguggaauagaaagauucaagauaacuuugaaaaguuguuccac4020

guuucggaggaccccagcgaucugaaugagaagcaucccaacuuggugcacaagaggggc4080

auauacaaggacucuuauggugcuagcagcccuuggugcgacuaucagcugaggcccaac4140

uuuacuaucgccauggugguggcaccggaacuguuuacaacggagaaggcuuggaaggcu4200

cuggaaauugcugagaagaaguugcuggggccccuggggaugaaaacgcuggauccagac4260

gacauggucuacuguggcauauaugauaaugcucuggauaacgauaauuacaaucuggcu4320

aaggguuucaacuaucaucaggggccagaguggcucuggccuauuggcuauuuccuccgu4380

gcuaagcuguacuuuucucgccugauggggccagaaacuaccgcaaagaccauuguauug4440

gucaagaacgugcugagccggcauuauguacauuuggaacgguccccuuggaaaggccug4500

cccgaacucacuaacgagaacgcucaguauuguccguuuuccugcgaaacccaggcuugg4560

uccaucgcaacuauuuuggaaacccuguacgaccuguag4599

<210>19

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>19

augggccacagcaagcaaaucagaauccuccugcucaacgagauggaaaagcucgaaaag60

acccuguucagacuggagcagggauacgagcugcaguuccgccucggaccaacccuccaa120

gggaaggccgugaccguguacaccaacuacccauucccgggagaaaccuucaaccgggaa180

aaguucaggagccuggacugggaaaaccccaccgagagagaggacgacagcgacaaauac240

ugcaagcugaaccuccaacagagcggcagcuuccaguacuacuuccuccaaggaaacgaa300

aagagcgggggcggcuacaucgugguggacccaauccugcgggucggggcagacaaccac360

gugcugccacuggacugcgugacacugcagaccuuccuggccaagugccugggaccguuc420

gacgaaugggagagccggcugcggguggccaaggagagcggcuacaacaugauccacuuc480

acaccgcuccaaacccucggccugagcagaagcugcuacagccuagccaaccagcuggag540

cucaacccggacuucagcaggcccaacagaaaguacaccuggaacgacgugggacagcuc600

guggaaaagcugaaaaaggaauggaacgugaucugcaucaccgacgugguguacaaccac660

accgccgccaacagcaaauggauccaggaacacccggaaugcgcguacaaccucgugaac720

agcccccaccugaagccggccuggguacuggacagggcacuguggcgcuucagcugcgac780

guggccgaaggaaaguacaaggagaagggcauccccgcccugaucgagaacgaccaccac840

augaacagcauccggaagaucaucugggaggacaucuucccaaagcugaagcugugggag900

uucuuccaagucgacgugaacaaggccguggaacaguucagacgccugcugacgcaggag960

aaccggagggucaccaagagcgaccccaaccagcaccugaccaucauccaagacccggaa1020

uaccggagauucggaugcaccguggacaugaacaucgcccugaccaccuucaucccacac1080

gacaaggggcccgcagccaucgaggagugcugcaacugguuccacaagagaauggaggaa1140

cugaacagcgaaaagcaccgccucaucaacuaccaccaggaacaggccgugaacugccuc1200

cucggaaacguguucuacgagcggcuggccggccacgggcccaagcugggccccgugacc1260

cgcaagcacccgcucgugacgcgguacuucaccuucccguucgaagaaaucgacuucagc1320

auggaggagagcaugauccaccucccgaacaaggccugcuuccucauggcccacaacggc1380

ugggucaugggcgacgacccgcugcggaacuucgcagagcccggaagcgaaguguaccuc1440

agaagggagcugaucugcuggggagacagcgugaagcugcgcuacggaaacaagcccgag1500

gacugcccguaccugugggcgcacaugaagaaguacaccgagaucaccgccaccuacuuc1560

caaggagugcggcuggacaacugccacagcaccccgcugcacguggccgaguacaugcug1620

gacgccgccagaaaccuccagcccaaccucuacgugguggcagagcuguucaccgggagc1680

gaggaccucgacaacguguucgugacccgacucggcaucagcagccugauccgggaagca1740

augagcgccuacaacagccacgaggaagggaggcugguguacagauacggaggagaaccc1800

gugggcagcuucgugcagccgugccugaggccccugaugccagccaucgcgcacgcgcug1860

uucauggacaucacccacgacaacgaaugcccgaucgugcaccggagcgcauacgacgcc1920

cugccgagcaccacgaucgucagcauggccugcugcgccagcggcagcacccgaggauac1980

gacgagcuggugccccaccaaaucagcgucgucagcgaagaacgcuucuacaccaagugg2040

aacccggaagcacugccgagcaacaccggagaagugaacuuccagagcggaaucaucgcc2100

gcgcgcugcgcgaucagcaaacugcaccaggaacugggagccaagggguucauccagguc2160

uacgucgaccaaguggacgaggacaucguggcagugacccgccacagccccagcauccac2220

caaagcgugguggccgugagccggacagcguuccggaaccccaagacgagcuucuacagc2280

aaagaggugccccagaugugcaucccgggaaagaucgaggaaguggugcucgaagcgcgc2340

accaucgaacgcaacaccaaaccguaccgcaaggacgaaaacagcauaaacgggaccccc2400

gacaucaccguggagaucagggaacacauccagcugaacgagagcaagaucgugaagcag2460

gccggggucgccaccaagggcccgaacgaguacauccaggagaucgaguucgagaaccuc2520

agccccgggagcgugaucaucuucagagucagccuggacccacacgcccaaguggccgug2580

ggcauccuccggaaccaccugacccaguucagcccgcacuucaagagcgggagccucgcc2640

guggacaacgccgacccgauccugaagaucccguucgcgagccuggccagccggcucacc2700

cuggccgaacugaaccagauccuguaccgcugcgagagcgaagaaaaggaggacggagga2760

gggugcuacgacaucccaaacuggagcgcgcugaaauacgcgggccugcagggccugaug2820

agcgugcuggccgaaauccgccccaagaacgaccugggacacccauucugcaacaaccug2880

aggagcggagacuggaugaucgacuacgucagcaacagacugaucagccgcagcggcacc2940

aucgccgaagucggaaaauggcuccaggccauguucuucuaccugaagcagaucccgcgg3000

uaccugaucccgugcuacuucgacgccauccugaucggcgccuacaccacccugcucgac3060

accgccuggaagcagaugagcagcuucguccaaaacgggagcaccuucgugaagcaccuc3120

agccugggcagcgugcagcugugcggggucggaaaauucccgagccugcccauccugagc3180

ccggcgcugauggacgugccguacagacugaacgagaucaccaaggaaaaggaacagugc3240

ugcgugagccuggccgccggacugccgcacuucagcagcggcaucuuccggugcuggggg3300

cgcgacaccuucaucgcccugcggggaauccugcugaucacgggccgcuacguggaggcc3360

cggaacaucauccuggccuucgccggcacccugcggcacggacugaucccgaaccuccug3420

ggagaggggaucuacgcccgguacaacugccgggacgccguguggugguggcugcagugc3480

auccaggacuacugcaagauggugcccaacggccuggacauccugaagugccccgucagc3540

cggauguacccgaccgacgacagcgccccgcuccccgccggaacccucgaccagccacug3600

uucgaagugauccaggaggccaugcaaaagcacaugcagggaauccaguucagagaacgg3660

aacgccggaccccagaucgaccggaacaugaaggacgagggauucaacaucaccgccgga3720

gucgacgaggaaaccggcuucgucuacggagggaaccgguucaacugcggaacauggaug3780

gacaagaugggagagagcgaccgcgccaggaaccgcggaaucccagcaaccccgcgggac3840

gggagcgcaguggaaaucguggggcugagcaaaagcgccgugcgguggcugcucgaacuc3900

agcaagaagaacaucuuccccuaccacgaagucaccgugaagagacacggaaaggccauc3960

aaagucagcuacgacgaauggaacaggaagauacaggacaacuucgagaagcuguuccac4020

gucagcgaggacccgagcgaccugaacgagaagcaccccaaccuggugcacaagcgcggg4080

aucuacaaggacagcuacggcgcgagcagcccguggugcgacuaccaacugcgccccaac4140

uucaccaucgccauggucguggcccccgaacucuucacgaccgagaaagcguggaaggcg4200

cuggagaucgcggaaaagaagcuccucggaccccuggggaugaaaacccuggaccccgac4260

gacaugguguacugcggcaucuacgacaacgcgcuggacaacgacaacuacaaccuggcc4320

aagggcuucaacuaccaccagggccccgaauggcuauggccgaucggcuacuuccugcgg4380

gccaagcuguacuucagccgccucaugggcccagaaaccaccgcaaagaccaucgugcug4440

gucaagaacguccugagccgccacuacgugcaccucgagagaagcccauggaagggacug4500

cccgagcugaccaacgaaaacgcgcaguacugcccguucagcugcgaaacccaggccugg4560

agcaucgccaccauccuggaaacacuguacgaccucuag4599

<210>20

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>20

augggccacagcaaacagauccggauccuccuacucaacgaaauggaaaagcucgaaaag60

acucuguuccggcuggagcaaggauacgagcuucaguuccgguugggcccgacgcugcag120

gggaaggccgugacagucuacacuaacuacccauuccccggcgaaaccuucaacagagag180

aaguucaggucccuggacugggagaaccccacugaacgggaagaugauuccgacaaguac240

ugcaagcugaaccuccagcaauccgguucauuccaguacuauuuccugcaaggaaacgaa300

aagagcggaggaggcuacauugugguugauccaauccuucgcgugggagccgauaaucau360

gugcugccgcuggauugcgucacccugcaaaccuuccuggcgaagugccugggcccguuc420

gacgaaugggaaucccgccugcgggucgccaaagaguccggguauaacaugauccacuuc480

accccacuccaaacucuuggccuguccagauccugcuacucguuggccaaccaguuggag540

cugaacccggacuucucacggccuaaccggaaguacacuuggaacgacgucggacaacuc600

guggagaagcugaagaaggaauggaaugucaucugcauuacugaugucguguacaaccac660

acggcggcgaauucaaaguggauccaggagcacccagaaugcgccuacaaccuggucaau720

uccccucaccugaagccggccugggugcucgaccgggcccuguggcgguuuucgugcgau780

guggcggagggaaaguacaaggagaaggggauuccggcucucaucgaaaacgaccaccac840

augaacuccauccggaaaauuaucugggaggacaucuucccgaaacuuaagcugugggaa900

uucuuccaaguggacgucaacaaggcuguggagcaguuccggagauugcugacacaagaa960

aaccgccgcgugaccaaauccgauccgaaccagcaccugacuaucauucaagacccggaa1020

uaccggagguuuggcugcacuguggacaugaauaucgcgcugaccaccuucaucccgcac1080

gacaagggaccggcagccaucgaagagugcuguaacugguuccauaagaggauggaagaa1140

uugaacucugaaaagcaccggcugauuaacuaccaucaggaacaggccgugaacugucuc1200

cugggaaacguguucuacgagcggcuggcgggacacggacccaagcucggccccgugacc1260

cgcaagcauccucucgugacuagauacuuuacuuucccauucgaggagaucgacuucucc1320

auggaagaaucaaugauccaccucccuaacaaggcuugcuuucugauggcacacaacggc1380

ugggugaugggcgaugacccccugaggaacuuugccgagcccggcuccgaaguguaccug1440

aggagagagcugauuugcuggggggacagcgucaagcugcgcuauggaaacaagccggaa1500

gauugcccuuaccucugggcccacaugaagaaguacacugagauuacugccaccuacuuu1560

caaggagugcgccuggauaacugccacucaaccccgcugcaugucgcugaguacauguug1620

gacgcagcccggaaucugcaaccgaaccucuacgugguggcggagcuguucaccggcucg1680

gaggaucucgacaacguguucgugacucgccugggcaucucaucgcugauccgggaagca1740

auguccgccuacaacucccaugaggagggucggcugguguaccgcuacggcggagaaccc1800

gugggguccuucgugcaaccgugccugcgaccccugaugcccgccaucgcccaugcccuc1860

uuuauggauauuacccacgauaacgaaugcccuaucgugcaccgcucagccuaugaugcc1920

cuccccuccaccaccaucguguccauggccugcugcgccucggggagcacccgggguuau1980

gacgagcuggugccgcaccagauuucggugguguccgaggagagauucuacaccaagugg2040

aacccagaagcucugccgucaaacacuggagagguuaacuuucaguccgguauuaucgcc2100

gcuagaugugcuauuagcaaacugcaccaagagcugggcgccaaggguuucauccaaguc2160

uacgucgaucaggucgacgaggacaucguggcugucacuaggcacucaccuagcauccac2220

cagagcgugguggccgugagccgcacugccuuccgcaacccaaagaccagcuuuuacucc2280

aaggaggucccucagaugugcauuccuggaaagaucgaagaagugguccuggaagcccgg2340

accaucgaacgcaacaccaagccuuaccggaaggacgaaaacucgaucaacgguaccccg2400

gauauuacuguggagauucgcgaacacauccagcucaaugaguccaagaucgugaagcag2460

gccggaguggcaaccaaggggccgaacgaguacauccaggagaucgaauucgagaaucuc2520

agcccuggcagcgugaucaucuuccgagugucguuggacccacaugcucaggucgccgug2580

ggcauccugaggaaccaccugacccaguuuuccccgcauuucaaguccgguucgcuggcc2640

guggacaacgcagauccgauccugaagauccccuucgccuccuuggcuucgcgccucacg2700

cuggccgagcugaaccagauccuguauagaugcgaauccgaagaaaaggaagauggaggc2760

gguuguuacgacaucccgaacugguccgccuugaaauacgccggacugcagggauugaug2820

uccgugcuggccgaaauuagaccgaagaacgaccuggggcacccguucugcaacaaccuc2880

cggucgggggacuggaugauugauuacgugucgaaccgccucaucucccgguccgguacu2940

auugcggaggucggcaaauggcuccaggccauguucuucuacuugaagcaaaucccccgc3000

uaccugauccccugcuacuucgacgccauccugaucggagccuacaccacccugcuggac3060

accgcguggaagcagaugucuagcuucguccagaacggcuccaccuucgugaagcaccug3120

ucacugggcucagugcagcugugcggaguuggaaaguuccccagccugccuauccugucc3180

ccggccuugauggacgugccguacagacugaacgaaaucacuaaggagaaggagcagugu3240

ugcgugucguuggcggccgggcugccccacuuuucaagcgggauuuuccggugcugggga3300

agggacaccuucaucgcgcugcggggaauccugcugauuaccggacgcuacguggaggcu3360

cggaacaucauucucgcguucgccggcacccugcgccauggacugaucccuaaucugcuu3420

ggagagggcaucuacgcucgguacaacugcagagaugccguguggugguggcuccaaugc3480

auccaggauuacugcaagauggugccuaacggucuggacauucugaagugcccugugucc3540

cgcauguaccccaccgacgacuccgccccccugccugccggaacccucgaccagccucug3600

uucgaagucauccaagaggccaugcagaagcauaugcagggcauucaguuccgcgaacgg3660

aacgcagggccccagaucgaccggaacaugaaggaugaaggguucaacaucaccgccgga3720

guggaugaagagacuggauuugucuacggaggaaaccgcuuuaacugcgggaccuggaug3780

gacaagaugggagagucagacagggccagaaauagaggaauccccgcgaccccgcgcgac3840

ggauccgccguggagauugugggccugucaaagagcgccguccgcuggcugcuggaacuu3900

agcaagaagaacaucuucccuuaccacgaagugaccgugaaaagacauggcaaagccauc3960

aaagucuccuacgacgaguggaaccgcaagauucaggacaacuucgaaaagcuguuccac4020

guguccgaagaucccuccgaucugaacgagaagcauccgaaccugguccauaagcgggga4080

aucuacaaggauagcuacggugccagcucgccguggugugacuaccagcugcggccaaau4140

uucacgauugcgauggucgucgccccugaguuguucaccacugagaaggccuggaaagcc4200

cuggaaauagccgagaagaaauuacuggggccacugggcaugaaaacucucgacccugac4260

gacaugguguacuguggaaucuacgacaacgcacuggacaacgauaacuacaauuuggcc4320

aagggauucaacuaccaccaggggcccgaauggcuguggccuaucggauacuuccuucgg4380

gcaaagcuuuacuucucccgccugaugggaccugaaacuacugccaagaccauugugcuu4440

gugaagaacgugcucucacggcacuacgugcaccuggagagauccccguggaaggggcuc4500

ccggagcugaccaacgagaacgcccaguacugcccuuucuccugcgaaacccaagccugg4560

uccaucgccaccauacuugaaacucuguacgaccuguag4599

<210>21

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>21

augggacacuccaagcagauccgcauucuccuccugaacgaaauggaaaagcuggaaaag60

accuuauuucgccuugaacaaggauacgagcugcaguuccggcuuggaccgacccuccaa120

gggaaagcugucaccgucuacaccaacuaccccuucccgggggagacuuucaacagagag180

aaguucagauccuuggacugggaaaaucccacggaacgggaggacgacuccgauaaguac240

uguaaacugaaccuccagcagucgggaucguuccaguacuacuuccuacaagggaacgaa300

aaguccgguggugguuacaucgugguggacccgauccugcgcgugggggccgacaaccac360

gugcugccgcuggacugcgugacucugcaaaccuuccuggccaagugccucggcccguuc420

gaugaaugggagucgagacugcggguggccaaggaaagcggauacaauaugauucacuuu480

acuccgcugcaaacccuggggcugucgcgcuccugcuacucgcucgcuaaccagcuggaa540

cugaauccggauuuuagccggccgaaccggaaguauacguggaacgacgucggucagcug600

gucgagaagcucaagaaggaguggaacgucauuugcaucaccgacguggucuacaaccac660

accgcggccaauuccaaguggauccaggaacacccggagugcgccuauaacuuggugaac720

uccccucauuugaaacccgcaugggugcucgaccgggcccuguggcgcuuuucaugcgac780

guggcggaagggaaguacaaggaaaaggggauucccgcccugaucgagaacgaucaccac840

augaacucaauucgcaaaaucaucugggaggauaucuucccuaagcucaagcugugggaa900

uucuuccaagucgacgucaacaaggccguggaacaauucagaaggcugcugacccaagag960

aaccgcagagugaccaagucggacccgaaccagcaccugacuauaauccaggacccggaa1020

uaccggagguucgguugcaccguggacaugaacauugcacucaccaccuucaucccgcac1080

gauaaggguccggcggcgauugaggagugcugcaacugguuccacaagcggauggaggaa1140

cugaacuccgagaagcaccggcugauuaacuaccaccaggaacaggcugugaauugccug1200

cuggggaacguguucuacgaacggcucgccggccacggccccaagcuggggcccgucacc1260

cgcaagcacccgcucgugacucgauauuucaccuucccguucgaggaaauugauuucucc1320

auggaggaaucaaugauccaucugccgaacaaggccuguuucuugauggcccacaacggc1380

ugggugaugggagaugacccgcugagaaauuucgccgagccgggguccgagguguaccug1440

aggagagaacucaucugcuggggggauuccgugaaacugcgcuacgggaacaagcccgag1500

gacugccccuaccugugggcacauaugaagaaguacaccgaaaucaccgccaccuacuuc1560

caagggguccggcuggauaacugccauucaacuccgcuccauguggccgaauacaugcug1620

gacgccgcacggaacuugcagcccaaccucuacgugguggccgaacucuucacugggagc1680

gaagaucucgauaacguguucgugacccggcucggaauuucgagccugauccgggaagcg1740

augucugcuuacaacucgcacgaagagggaaggcugguguacagauacgggggggagccc1800

gugggauccuucgugcaaccgugccugaggccgcuuaugcccgcgaucgcccacgcucug1860

uucauggacaucacccacgacaacgaauguccgauuguccaccggagugccuacgaugcc1920

cuuccgagcacuaccaucgugucgauggcgugcugugcguccgggucuacccgcggcuac1980

gacgaacucgucccgcaccaaaucagcgugguguccgaagaacgguuuuacacuaagugg2040

aacccggaggccuugcccucgaacaccggggaggucaacuuccagucgggaaucauugcc2100

gcccgaugugccaucucaaaguugcaccaagaacucggggcaaagggguucauccaagug2160

uacguggaccaaguggacgaggauauuguggccgugaccaggcacuccccgucgauccac2220

caguccgugguggcagucucaagaacugccuuccggaaccccaagaccuccuuuuacucg2280

aaggaagugccccagaugugcaucccgggcaaaaucgaagaagucgugcuggaagccaga2340

acuaucgagcggaacaccaagcccuaccggaaggaugagaacagcaucaacggcacgccc2400

gacaucaccgucgagaucagagagcacauccagcugaacgaauccaagauugucaagcag2460

gccggcguagcgacuaagggacccaacgaauacauccaggagaucgaauucgaaaaccug2520

ucgccgggauccgugauuaucuuccgggugucccuggacccgcacgcccaaguggccgug2580

ggaauccugcggaaccaccugacccaguucuccccgcauuucaaguccggcucccuggcg2640

guggacaaugcagacccgauucucaagaucccguucgccuccuuggccucccgccugacc2700

cucgccgaacucaaccagauccuguaccgcugcgagucugaggaaaaggaggacggggga2760

ggaugcuacgauauuccgaacuggucugcccuuaaauacgcgggacugcagggucugaug2820

ucggugcucgccgagaucagaccgaagaacgaccuggggcacccguuuugcaacaaccug2880

agaucgggggauuggaugaucgacuacgugucgaaccggcuuaucucucgcuccggcacc2940

aucgccgaggucgggaaguggcugcaggccauguucuucuaccugaagcaaauuccgcgc3000

uaccugaucccgugcuacuuugaugccauccugaucggcgccuacacgaccuugcuggac3060

accgccuggaagcagaugagcagcuucgugcagaacggcuccacguucgugaagcaucug3120

ucccugggauccgugcagcuuugcggugucggaaaguucccuucgcugccuauucugucc3180

ccggcgcugauggacgugccguaccggcugaacgagaucacuaaggagaaggaacaaugc3240

ugcgugucacuggcggcgggacucccccacuucuccuccgggauuuuccgguguugggga3300

agagauaccuucauugcccugagggggauacugcugaucaccggaagauacguggaggcu3360

agaaacaucauccucgccuucgccggcacucuccgccacgggcugauccccaaccucuug3420

ggcgaaggaaucuacgcccgguauaacugccgcgacgcggucuggugguggcuucagugc3480

auccaggauuacugcaaaauggugccgaauggacuggauauucugaagugccccguuagc3540

cgcauguaccccaccgaugacuccgcacccuugccggcgggcaccuuggaccagccgcuc3600

uuugaagugauccaggaggccaugcagaagcacaugcaggguauccaguucagagagcgg3660

aacgcugggccgcagauugaccggaacaugaaggacgaagguuucaacauuacugccggg3720

guggacgaagagacuggguuuguguacggggggaaccgcuucaacugugggaccuggaug3780

gauaagaugggggagucggaucgggcucggaacagggggauccccgcuaccccccgggac3840

gggucggcuguggagauugucgggcugagcaagagcgcagugcgcuggcugcuggagcuc3900

agcaaaaagaacaucuuccccuaccacgaagucacugugaagagacacggaaaggccauc3960

aagguguccuacgaugaguggaacagaaagauccaagacaacuucgagaagcuguuccau4020

guguccgaggauccgagcgaucugaacgaaaagcauccgaaccucgugcacaagcgcggg4080

aucuacaaggacucguacggcgcauccucgccguggugcgacuaccagcugcgccccaau4140

uucaccauugccauggugguggcgcccgagcuguucacuaccgagaaggccuggaaggcc4200

cuggagauugcugagaagaagcugcugggaccgcucgggaugaaaacuuuggacccugac4260

gacaugguguacuguggaaucuacgacaaugcgcucgacaacgacaacuacaaucuugcg4320

aagggauucaacuaccaucaggggcccgaauggcuguggccgaucggguacuuccugcgc4380

gccaagcuguacuucucccggcugauggggcccgagacaaccgccaagaccauugugcuc4440

gucaagaacguucucucccggcacuacgugcaccucgaaagauccccguggaaggggcug4500

cccgagcucaccaacgagaacgcacaguacugcccguucuccugugaaacccaggccugg4560

agcaucgccaccauauuggaaacucuguaugaccucuag4599

<210>22

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>22

augggacacucgaaacagaucagaauccuguugcugaacgaaauggagaagcuggaaaag60

acccucuuucggcucgaacagggcuacgagcugcaguuccgccuggguccgacucuacaa120

ggaaaggcagugacuguguacaccaacuacccauuucccggagaaaccuucaaccgggag180

aaguuccggucccuggacugggaaaacccaaccgaacgagaggaugauuccgacaaguac240

ugcaagcugaaccuccaacaguccggaucauuccaguacuacuuuuugcaaggaaacgag300

aaguccggaggaggcuacaucguggucgacccgauucugagagugggagcugacaaucau360

guccugccucuggacugcguaacccugcaaaccuucuuggccaaaugccugggcccguuc420

gaugagugggaaagccgccuccgggucgcaaaggaaagcggcuacaauaugauucacuuc480

acuccucugcaaacccucggucugucccgguccuguuauucccuggcgaaccagcuggag540

cuuaaccccgacuucucgcgcccaaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcaucacugacgugguguacaaccac660

accgcggccaacuccaaguggauccaagaacaucccgaaugcgcguacaaccucgugaac720

agcccgcaucugaagccugccugggugcuggauagggcccucuggagauucagcugcgac780

guggccgaggggaaguacaaagaaaagggaauucccgcccugauugagaacgaccaucac840

augaacucaauccgcaagaucaucugggaggauaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacgugaacaaggcaguggagcaguucagaaggcugcugacucaagaa960

aacagacgggucacuaaguccgacccuaaccagcaccuuaccaucauucaagacccggag1020

uaccgccgguuuggcugcacugucgacaugaacaucgcccugaccacuuucaucccgcau1080

gacaagggcccggcggcaaucgaggaaugcuguaacugguuucauaagaggauggaggaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagugaauugccuc1200

cugggaaacguguucuacgaacggcuggcuggacacggaccgaagcugggucccgugacu1260

cgcaagcauccgcucgugacucgcuacuucaccuucccguuugaggagauugacuuuucc1320

auggaagaauccaugauccaccucccgaacaaggcuugcuuccugauggcgcacaacgga1380

ugggucaugggcgacgacccacugcgcaacuucgcugagccuggcagcgaggucuaccug1440

agaagggaacugauuugcuggggagacuccgucaagcugcgcuauggaaacaagcccgaa1500

gauugccccuaccugugggcucacaugaagaaguacacugaaaucacugccacguacuuc1560

cagggaguccggcuggacaauugccacuccaccccccuccauguggccgaguacaugcuc1620

gaugcagcgaggaaucugcagcccaaucuguacgugguugccgaacuguucaccggcucc1680

gaggaccucgacaacguguucgugaccagacuugggauuuccagccugauccgggaagcc1740

augucggccuacaacucccaugaagagggccgccugguguaccgcuacggcggagaaccc1800

gugggaagcuucgugcagccuugccuccggccgcugaugccugcgaucgcccacgcccug1860

uucauggauauuacccacgacaacgaaugccccaucgugcaucgcucggccuacgacgca1920

cugccuucgaccaccaucguguccauggccugcugcgccuccgguagcacccgcggauac1980

gaugaacucgugccgcaccagaucagcgugguguccgaagaaagauucuacaccaagugg2040

aacccugaggcacugccgagcaacaccggagaagugaacuuccagucggguauuaucgcc2100

gcucgcugugccaucuccaaacuccaccaagagcucggugccaagggauucauucaaguc2160

uacguggaucaggucgacgaagauauuguggccgugaccaggcacucaccuuccauccac2220

caauccgucgucgccgugucacggacugccuuccggaaccccaagacuucguucuacucg2280

aaagaggugccacagauguguauccccggaaagaucgaagaggucguccuggaagcccgg2340

accauugagaggaacaccaagccuuaccggaaggacgagaacagcaucaacgguaccccu2400

gauauuacuguggagauccgcgaacacauccagcucaacgaaucaaagauugucaagcag2460

gccggaguggccaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccuggcuccgugauuaucuuccgggugucccuggacccucacgcccaaguggccguc2580

ggcauccucagaaaccaccugacccaguucucaccccauuucaaguccgguucccuggcg2640

guggacaacgccgauccgaucuugaagauccccuuugcaucccuggccucccgccugacu2700

cucgcggaacugaaccagauccuguaccgcugcgaaucagaggaaaaggaggacggcggc2760

ggcuguuacgauaucccgaauugguccgcucugaaauaugcgggacuucaggggcugaug2820

agcgugcuggcggagauccggccgaagaaugaccugggacacccauucugcaacaacuug2880

cggagcggagacuggaugaucgauuacgucagcaacagauugaucucccggagcggcacu2940

aucgcggaggucggaaaguggcuccaggccauguucuucuaccugaagcagaucccccga3000

uaccucaucccguguuacuucgacgccauucugaucggggccuacaccacccugcuggac3060

accgccuggaagcagaugagcuccuuugugcaaaacggguccaccuucgugaagcaccuu3120

ucacugggaucagugcagcucugcggcgugggaaaauuccccucgcugcccauucugagc3180

ccggcccucauggacgucccuuaccggcugaacgagaucaccaaggagaaggagcagugc3240

uguguuucccuggcugccggacuuccacacuucucguccggcaucuuccggugcuggggc3300

cgggauaccuucauugcccugcggggcaucuuguugaucaccggucgcuacguggaggcu3360

cggaacauuauucuggcauucgccggcacucugagacacggucugauuccgaaucuuuug3420

ggcgaaggaaucuacgcccgcuacaacugucgggacgccguguggugguggcuccagugc3480

auucaggacuauugcaagauggugccgaacggccuggacauccugaagugcccagugucg3540

aggauguauccaaccgacgacagcgcgccucugccggccgggacccucgaccaaccccug3600

uucgaagucauucaagaggcuaugcagaagcacaugcaggguauucaguuccgggagaga3660

aacgcggggccccagauugauaggaacaugaaagacgagggcuucaacaucacugccggc3720

guggacgaagaaaccgguuuuguguacggaggaaaccgguucaacugcgguaccuggaug3780

gacaagaugggagaguccgaucgcgcgcgcaacagagggaucccggcaaccccgcgggac3840

ggaucagcgguggaaauugugggacugagcaagagcgccgugcgcuggcuccuggaacug3900

agcaaaaagaacaucuuccccuaccacgaagugaccgugaagcggcacggaaaggccauc3960

aaagucucauacgaugaauggaauaggaagauccaggauaacuucgagaagcuguuucac4020

guguccgaggaucccuccgaucugaacgaaaagcauccgaaucucgugcacaagcgcggc4080

aucuacaaggacucguacggagccuccuccccuuggugcgauuaucagcugcggccuaac4140

uucaccauugccauggucguggcuccggagcuguucacuacugagaaggccuggaaggca4200

cuugaaauugccgagaagaagcugcuugggccuuuggggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuggacaacgacaacuacaaucuggcg4320

aagggcuucaauuaccaccagggcccggaauggcuguggccuauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugaugggaccagagacuaccgccaagacuaucguccuc4440

gugaagaacgugcugucccggcacuacgugcaucuggagaggagcccuuggaagggccuu4500

ccugagcugaccaacgaaaacgcccaguacugccccuucuccugcgaaacccaggcuugg4560

uccauugccacuauacuggaaaccuuauaugaccuguag4599

<210>23

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>23

augggacacucaaagcagauccggauccuccugcugaacgaaauggaaaagcucgaaaag60

acucuguuccggcuggaacagggcuaugagcugcaguuccggcucggaccgacgcugcaa120

ggaaaggccgugacuguguacaccaacuaccccuucccgggagaaacuuuuaacagagaa180

aaguuuaggucccuggacugggagaacccgaccgagcgggaagaugacuccgauaaguac240

ugcaagcugaaccuccagcagucgggaucguuccaguacuacuuccuucaaggaaaugag300

aagucugguggaggauacaucgugguggaccccauccugagagugggagccgacaaucac360

guccugccgcuugacugcgugacucugcaaaccuuccuggcuaagugucucgggccguuc420

gacgaaugggaguccaggcugcgcguggcuaaggagagcggcuacaauaugauccacuuc480

accccgcuccaaacucucggacucucgcgcuccuguuacucccucgccaaccaacuggag540

cugaacccggacuucucccgcccgaaccggaaguacaccuggaacgacgucggucagcuc600

guggagaaauugaagaaggaguggaacgugaucugcauuacggacgucguguacaaccau660

acugcggccaacuccaaguggauucaagagcacccggaaugcgcuuacaaccuugucaac720

uccccgcaccugaagccggccugggugcuggacagagcccuguggcgguucucgugcgac780

guggcagagggaaaguacaaggagaagggcauccccgcccuuauugagaaugaccaucac840

augaacuccauccggaagaucaucugggaggauaucuucccgaagcucaagcugugggaa900

uucuuccaaguggacgugaacaaggccguggaacaguuccggagacuccugacccaagaa960

aaccggagagugaccaagagcgacccgaaccagcaucugacuaucauucaggauccggag1020

uaucggcgguuuggcugcacuguggacaugaacaucgcccucaccaccuucaucccgcac1080

gacaagggccccgccgcgaucgaggaaugcugcaacugguuccacaagcgcauggaggag1140

cugaauuccgaaaagcaccgccugaucaacuaccaucaggagcaggcagugaacugucuc1200

cugggaaacguguuuuacgaacggcuggccggacacggcccgaagcugggucccgugacc1260

cgcaagcauccccucgugacgcgguacuucaccuucccguucgaggagaucgacuucagc1320

auggaagaguccaugauccaucugccgaacaaggccugcuuccucauggcgcauaauggu1380

ugggucaugggagaugauccccuccgaaacuuugcggagccggguucggaaguguaucug1440

aggagggagcucaucugcuggggagauagcgugaaacugagauacgggaacaagccggaa1500

gauuguccguaccugugggcacacaugaagaaguacaccgaaaucacugccacuuacuuc1560

caaggaguucgccuggauaacugccauucaaccccucugcaugucgccgaguacaugcug1620

gacgccgcucgcaaccuucagccgaaucucuacguggucgccgagcuguucaccgguucc1680

gaagaucuggacaacguguucgugacuagacugggaaucagcagccugauccgggaagcg1740

augagcgccuacaacucccacgaagagggccggcucguguauagauacggcggagagccg1800

gucgggagcuucgugcaacccugccugcggccgcugaugcccgccauugcccacgccuug1860

uucauggauaucacccacgacaacgaguguccgaucgugcaccggagcgcguacgacgcg1920

uuaccguccaccacgauugugucgauggccugcugcgccuccggaucgacccgcggcuac1980

gaugagcuggucccgcaucaaaucagcgucgucagcgaagaacgguucuacacuaagugg2040

aaccccgaggcgcuccccuccaacaccggagaagugaacuuccaauccggcauuaucgcu2100

gcacgcugcgcgauuagcaagcugcaucaggagcuuggcgcuaagggguucauacagguc2160

uacguggaucaggucgacgaggacauuguggccgugacucgccacucaccguccauucac2220

caaagcgugguggcugugucccggaccgcuuuccggaaucccaagaccucauucuacucc2280

aaggagguuccgcagauguguaucccgggaaagauugaggaagugguccuagaggcucgc2340

acuauugaacgcaacaccaagccguacagaaaggacgagaauuccauuaacgggaccccg2400

gauauuaccguagaaauuagagaacauauucagcugaacgagucgaagaucgugaagcag2460

gccgggguggcuaccaagggcccgaacgaauacauccaggagauugaguucgaaaaccuc2520

ucccccggcucggugaucaucuuccgggugucccucgauccccacgcccaaguggccgug2580

ggaaucuugagaaaccaccugacucaguucagcccgcauuucaaguccggaucacucgcc2640

guggacaacgccgacccgauccuuaagauccccuucgcaucacuggccagccgccugacc2700

cuugccgaacugaaccaaauccucuaucggugcgaauccgaggagaaggaagaugggggu2760

ggaugcuaugacauuccuaacuggucugcccugaaauacgcaggccugcagggacugaug2820

uccguccuggccgaaauccgcccgaagaaugaccuggggcaccccuuuugcaacaaucug2880

agguccggagauuggaugauugauuacguguccaaccgccugauuucgcggagcggcacc2940

aucgcggaagugggaaaguggcugcaagccauguuuuucuaccugaaacagaucccccgg3000

uaccucaucccgugcuauuucgaugcgauuuugauuggcgcguacaccacccuccucgac3060

acugccuggaagcaaaugagcuccuucgugcaaaacgguucaaccuucgucaagcacuug3120

ucgcuggggucgguccaacuguguggagucggaaaguucccgagccugcccauccugucg3180

ccugcccugauggacgugcccuaccggcugaacgagaucaccaaagaaaaggagcagugc3240

ugcgugucccuggcggccggacucccccauuucucguccgggaucuuuagauguugggga3300

cgggauacuuucauugcgcugcgcggcaucuuguugauuaccggacgcuacguggaagcg3360

cggaacaucauacucgccuucgccggcacccucagacacggccugaucccgaaccuccug3420

ggagaaggcaucuacgcacgauacaacugucgggacgccgucuggugguggcugcagugc3480

auucaggacuacugcaagauggugccgaacggucuggacauccugaagugccccguguca3540

aggauguacccgaccgacgauagcgcaccgcugcccgcggggacccuggaucagccgcug3600

uucgaagugauccaagaagccaugcaaaagcacaugcagggaauucaguucagagaaagg3660

aacgcaggcccccagauugaccggaacaugaaggacgaggguuucaacaucaccgccggc3720

gucgacgaagaaacgggguuuguguacgggggcaaccgcuucaacugcgguacuuggaug3780

gacaagaugggggaaucagaccgcgcccgcaaccgcggaauuccggcgaccccgcgcgau3840

ggauccgcaguggaaaucgugggacuguccaagucggcugugcgguggcugcuggagcug3900

uccaagaagaacaucuucccguaccacgaggucaccgugaagagacacgggaaggccauc3960

aagguguccuacgacgaauggaaccggaaaauccaggauaacuucgaaaaacuguuucac4020

guguccgaggacccgucugaccugaacgaaaaacacccgaacuuggugcauaagcgggga4080

aucuacaaggacaguuacggagccucaagcccguggugcgacuaccagcugcggcccaac4140

uucacaaucgcgauggugguggcgcccgagcuuuucaccacggagaaagccuggaaggca4200

cuggagaucgcugaaaagaagcugcucgguccccucggcaugaaaacccuggacccggac4260

gauaugguguacugcggaaucuacgacaacgcccuggacaaugauaacuacaaccuggcc4320

aagggauucaauuaccaccaggggccggaauggcuguggccgaucggcuacuuucugcgg4380

gcuaagcucuacuucucgcggcugaugggaccggaaaccacagccaagaccauuguccuc4440

gucaagaacgugcugucccgccacuacgugcaucuggagcggucaccuuggaagggccug4500

cccgagcugaccaacgaaaacgcccaguacugccccuucuccugugaaacucaagccugg4560

ucaaucgccacuauucucgaaacucuguacgaucuguag4599

<210>24

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>24

augggucacagcaaacaaauccggauccugcugcucaacgaaauggaaaagcuggaaaag60

acucuguuucgccuggagcagggcuacgaacuccaauuccggcugggaccaacgcugcaa120

gggaaggccgucaccguguacaccaacuaccccuuucccggagagacuuuuaaccgcgaa180

aaguucagaagccuggacugggaaaaccccaccgaacgggaagaugauucggacaaguac240

ugcaagcugaaccuccagcaguccggcagcuuccaguacuacuuccuccaagggaacgaa300

aagagcggaggaggcuacaucgugguggauccgauccuucggguuggagcggacaaccau360

gugcugccucuggacugcgugacucugcaaaccuuccuagccaagugccucggcccguuc420

gaugagugggaaucccggcugcgaguggcgaaggagucagguuacaacaugauccacuuc480

acaccgcugcagacccugggacucucccgguccugcuacucauuggccaaccagcucgaa540

cugaacccggacuucucaaggccgaaccgcaaguacacuuggaaugacgugggacaguug600

guggagaagcugaagaaagaguggaacgugaucugcauuaccgacgugguguacaaccac660

acugcggcgaauucgaaguggauucaggaacauccggaaugcgccuacaacuuggugaac720

ucaccucaccugaagccugccugggugcuggacagagcccuguggcgcuuuagcugugac780

gucgcggaggggaaguacaaggaaaagggaauccccgcccugaucgagaacgaccaccau840

augaauagcauucgcaagaucaucugggaggacauuuucccgaagcugaagcugugggag900

uucuuccaagucgacgucaacaaggccgucgaacaguuccggcgguugcugacccaagaa960

aaccggagagugacgaaaagcgacccuaaccagcaccugacaaucauucaggacccugaa1020

uaccggagauucggcuguaccgucgauaugaacaucgcccugaccaccuuuauuccccac1080

gauaagggcccggcggccaucgaggaguguugcaacugguuccacaagagaauggaggaa1140

cucaacuccgaaaaacaccgguugauuaauuaccaccaggagcaggcggucaacugccug1200

cugggcaacguguucuacgaaaggcucgcugggcacggcccuaagcugggaccugucacu1260

cggaaacacccccuggugacccgguacuuuacuuucccguucgaagagaucgacuucucc1320

auggaggaaagcaugauccaccucccuaacaaggccugcuuccugauggcccacaacgga1380

ugggucaugggcgacgacccuuugcggaacuuugccgagccgggcucagagguguaccuu1440

agacgcgaacugaucugcuggggagacuccgugaagcugcgcuacgggaacaagcccgaa1500

gauuguccuuaccugugggcacacaugaagaaguacaccgaaaucacugccaccuacuuc1560

caaggagugcgcuuggauaacugucauagcacuccucugcacgucgccgaguacaugcug1620

gacgcagccaggaaucuccagccuaaucuguacgugguggccgaacuguucaccgggagc1680

gaggaccuggacaacguguucgugacccggcugggcaucagcucccuuauccgggaggcc1740

auguccgcauacaacucgcacgaggagggucgccugguguaccgcuacggaggagagccg1800

gucggaucauuuguccaaccaugccuccggccccugaugccagcgaucgcgcacgcucuc1860

uucauggacaucacccacgauaacgaaugcccuaucgugcaccggagcgcuuacgacgcc1920

cucccuucgaccaccauuguguccauggccugcugcgccuccgguuccacucggggcuac1980

gaugaacuggugccacaccagauuuccguggugucagaggagcgguucuacaccaagugg2040

aacccagaggcgcugccgagcaacacuggggaagugaacuuccaguccggaaucauagcg2100

gcuagaugugcaauuuccaagcuucaucaggagcugggcgccaaaggauucauccagguc2160

uacguggaccaaguggaugaggacauuguggccgugacuagacauucaccgucaauccac2220

caaucggucguggcuguguccagaaccgcauuccgcaaccccaagacuuccuucuacucc2280

aaggaggucccucagaugugcaucccgggaaagaucgaggagguggugcuggaggccagg2340

accaucgaaagaaacacuaagccuuaccggaaagacgaaaacuccaucaaugggacuccc2400

gauauuaccguggagauuagggagcacauucagcugaacgaaucaaagauugugaaacag2460

gccggggucgcaacuaaagggccuaaugaguacauccaagagaucgaguucgaaaaccug2520

ucgccggguuccgugaucauuuuccgcguguccuuggacccucacgcccaaguggccgug2580

ggcauccugaggaaccaccugacccaguucagcccacacuucaaguccggauccuuggcu2640

guggacaacgccgauccaauccucaagaucccuuuugcgucgcuggccucacggcuuacc2700

cuggccgagcugaaccagauccuguaccgcugcgagagcgaagaaaaggaggacggugga2760

gguugcuacgacauuccaaacugguccgcgcuuaaguacgccggacuccagggucugaug2820

uccgugcuugccgagaucagaccgaaaaacgaccuggggcaccccuuuugcaacaaccug2880

agaagcggagacuggaugaucgacuauguguccaaccggcugauuucgagaagcgguacu2940

auugccgaggucggaaaguggcuccaagcaauguuuuucuaccugaagcaaauuccccgc3000

uaccugaucccgugcuacuuugacgccauucugaucggugcauacacuacccugcuggac3060

accgcguggaagcagauguccagcuucgugcagaauggcuccaccuucgucaagcaucug3120

ucccucggaagcgugcagcugugcggagugggaaaguuuccgucgcugccaauccugucc3180

cccgcgcugauggaugucccguaccggcugaacgaaaucacgaaggaaaaagaacagugc3240

ugcgugucccuugccgccggacugccgcacuucuccuccggcauuuuccggugcugggga3300

cgggauaccuucaucgcgcugagagguauucugcugauuaccggcagauauguggaagcc3360

cgcaacaucauccuggccuuugccggcacucugcggcacgggcucaucccuaaccucuug3420

ggagaaggcaucuacgcgcgcuacaacugccgggaugcuguguggugguggcugcagugc3480

auccaggacuacuguaaaauggugcccaauggccuugacauccucaagugcccagugucc3540

cggauguacccgaccgaugacuccgcgccccugcccgccggcacccuugaucaaccucug3600

uucgaagucauccaagaggccaugcagaagcacaugcagggaauccaguucagggaaaga3660

aacgccgggccucagaucgaccggaacaugaaggacgagggauucaacauuaccgccgga3720

guggacgaggaaacuggcuucguguacgguggaaaccgcuucaacugcggcaccuggaug3780

gauaagaugggcgaauccgaucgcgcccgcaaccggggaaucccagcaacuccuagggac3840

ggaagcgcagucgagaucguggggcuguccaaguccgccgugcgguggcucuuagaacug3900

uccaagaagaauauuuuccccuaccacgaggucaccgugaagcgccauggaaaggccauc3960

aaaguguccuaugacgaauggaaccgcaagauccaggacaacuucgaaaaguuguuccac4020

guguccgaggaccccagcgaucugaacgaaaagcaccccaaccucgugcacaagaggggc4080

aucuacaaggacuccuacggagcuagcuccccuuggugcgauuaccaacugcggccuaau4140

uucaccaucgccauggucgucgcacccgaacucuucaccaccgagaaggccuggaaggcu4200

cuggaaaucgccgaaaagaagcuucugggcccgcugggcaugaaaacucucgauccugac4260

gauauggucuacuguggcaucuacgacaacgcccuugacaacgacaacuacaaccuggcc4320

aagggcuuuaacuaccaccagggcccagaguggcucuggcccaucggauauuuccugcgg4380

gccaaacuguacuucucgcgguugauggguccggaaaccacagcuaagaccaucgugcuc4440

gugaagaaugugcugucgcggcacuauguccaucuggagcgcucccccuggaagggacuc4500

ccugagcugacuaaugagaacgcccaguacugcccuuucuccugcgaaacccaggccugg4560

agcaucgcuaccauucucgaaacgcucuacgaucuguag4599

<210>25

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>25

augggacauucuaaacagauucggauccuccugcucaacgaaauggagaagcucgaaaag60

acccuguuccggcucgaacagggauacgaacugcaauuccggcugggucccaccuuacaa120

ggaaaggccgugacugucuacaccaacuacccguuccccggcgaaaccuucaauagggag180

aaguuccggucccucgauugggagaacccuacagagcgcgaagaugauucagacaaguau240

ugcaagcugaauuugcagcagagcggcucauuccaauacuacuuccugcaaggaaacgaa300

aagucgggcggcggcuacaucgugguggacccuauucugagagugggcgccgacaaccau360

guccugccgcuggacugcgucacccugcaaacuuuccuggccaagugccuggguccuuuc420

gaugagugggaaucgagacuucgcguggcaaaggaaucggguuauaauaugauucacuuc480

accccgcugcaaacccugggccugucgcggucuugcuacucacuggccaaccagcuggaa540

cugaacccagauuucucacgccccaaccggaaguacaccuggaacgaugugggccagcuu600

guggaaaagcucaaaaaggaguggaacgugaucugcauuacugacgugguguacaaccau660

acugcugcuaauuccaaguggauccaggaacauccugagugugcuuacaaccuggucaac720

uccccacaccugaagcccgccugggugcuggaucgggcucucuggcgguucuccugcgau780

gucgccgaaggaaaguacaaggagaaggggaucccugcgcugaucgaaaacgaccaucac840

augaauuccaucaggaaaaucaucugggaggacaucuucccuaagcucaagcugugggag900

uucuuucaagucgacgugaacaaggccguggagcaguucagacggcugcugacacaagag960

aaccgccgcgucaccaagagcgacccgaaucagcaccugacgauuauccaggacccugag1020

uacagaagauucggcugcaccguggauaugaacauugcucugaccaccuucaucccccac1080

gauaagggucccgcagccauugaggagugcugcaacugguuccacaagaggauggaagaa1140

cugaauuccgagaagcaccggcugaucaauuaucaccaagaacaagccgugaacugccuu1200

cugggaaacgucuuuuacgagcgccuggcgggacaugggccaaagcucgggcccgugacc1260

agaaagcacccacuggucacccgcuacuucaccuucccguucgaggaaaucgacuucagc1320

auggaagagucgaugauccacuugccgaacaaggccugcuuccucauggcccauaacggu1380

ugggucaugggcgaugacccucuucgcaacuucgcggagcccgguucugaagucuaucuu1440

cggcgggaacugauuugcuggggagacuccgucaagcugcgcuacggaaacaagcccgag1500

gauugcccguacuugugggcccauaugaagaaguacacugagaucacugccacuuacuuc1560

caaggagugcgccucgacaauugucacagcacuccgcugcacguggcggaguacaugcug1620

gacgccgcucgcaacuugcagccuaaucuguaugucguggccgaguuguucaccggcucg1680

gaagaucuggacaacguguucgucacucgccugggaaucuccucccugauccgggaagcg1740

augagcgccuacaacucccacgaagaggggcgguugguguaccgcuacggcggagagccu1800

gucggaaguuucgugcagcccugucugaggccccugaugcccgcuaucgcccaugcgcug1860

uuuauggacaucacccacgacaacgaaugcccuauugugcaccgcuccgccuaugaugcc1920

cugcccuccaccacuauugucagcauggccugcugcgccucgggguccacccggggauac1980

gacgaacuggugccccaccaaauuuccgugguguccgaggaacgguucuacaccaagugg2040

aacccugaagcgcugccaucgaacacuggagaagugaacuuucagucgggaauuaucgca2100

gcccgaugcgccaucagcaagcugcaccaggaacucggcgcaaaggguuuuauccaaguc2160

uacguggaccaggucgacgaggacauugucgccgugacccggcacuccccauccauccac2220

cagucugugguggcugugucaaggacggcuuuccggaacccaaagaccagcuucuacagc2280

aaggaagugccucagaugugcaucccggggaagaucgaagaaguggugcuggaggccaga2340

accaucgaaagaaacaccaagcccuaucggaaggacgagaacucgaucaacgguacuccg2400

gacauuaccgucgagauacgcgagcacauucagcugaacgaguccaaaaucgugaagcag2460

gccgggguggccacgaagggucccaacgaguacauucaggagaucgaguucgagaaccug2520

agccccggguccgugaucaucuuccgcgugucccuggacccccacgcccaaguggccgug2580

ggcauccugcggaaccaucugacccaguucuccccgcacuucaagagcggcucgcucgcc2640

guggacaacgcggacccgauccucaagaucccuuucgcaucgcuggccucccgccugacc2700

cuggccgaacugaaucagaucuuguaccgaugcgaaucagaagagaaggaggacgggggg2760

ggcugcuacgauauccccaacuggagcgcguugaaguacgcaggauugcagggauugaug2820

uccguccucgcugaaauccgcccgaagaacgaccugggacacccguuuugcaacaaccug2880

agaucaggggauuggaugaucgauuacgugucgaacagacugaucucgcgcagcggcacu2940

auugccgaaguggggaaguggcuccaggccauguucuucuaccugaagcagaucccucgg3000

uacuugaucccuuguuacuucgacgccauccugaucggagccuacaccacccugcuugac3060

acugcauggaagcagauguccagcuucgugcaaaacggaagcaccuucgugaagcaccug3120

ucccugggauccgugcagcucugcggcgugggaaaguuuccgucccuccccauccugagc3180

ccugcccuuauggacgugccguacaggcugaacgaaauuaccaaagagaaggagcaaugc3240

uguguguccuuggcggccggauugccgcauuucuccuccgggauuuuccggugcugggga3300

cgggacaccuuuaucgcacugagggguauucuccugaucaccggucgcuacguggaggcu3360

cgcaacauuauucuggccuucgcgggcacgcuuagacauggauugaucccuaaccuucug3420

ggagaagggaucuacgcgcgguacaacugccgcgaugccguguggugguggcugcagugc3480

auccaggacuacugcaaaauggugccgaauggucuggauauccugaaguguccgguuucg3540

cggauguacccuaccgacgacagcgccccucucccggccggcacucucgaccagccccua3600

uuugaaguaauccaggaggccaugcaaaagcacaugcagggcauacaguucagagagagg3660

aacgccggaccgcagauugaccggaacaugaaggacgagggauucaacauuaccgcggga3720

guggaugaggaaacugguuucguguacggcggaaaccgguuuaacugcggcacuuggaug3780

gacaagaugggagaauccgaccgcgcccgaaaccgcggaauucccgccacuccccgcgac3840

ggcuccgccguggaaauugugggacugucaaaguccgcaguccgcuggcugcuggaacuc3900

ucaaagaagaacaucuucccguaccacgaggucaccgugaagcggcacggcaaagcgauc3960

aaagugucguacgacgaguggaaccggaagauucaggauaacuucgagaagcuguuucac4020

guguccgaagauccaagcgaccugaacgagaagcaucccaacuuggugcacaagcgcggc4080

aucuacaaggauuccuacggagccagcagcccguggugcgacuaccaacuccgccccaac4140

uucaccaucgccauggugguggcgccggagcuguucacgacggagaaagcuuggaaggcu4200

cucgaaaucgcggagaagaagcugcuggguccucuggggaugaaaacccuggacccggac4260

gauaugguguacugugggaucuacgacaacgcccuggacaacgacaacuacaaccucgcc4320

aagggguucaacuaccaccagggacccgaauggcucuggccaaucggauacuuccugaga4380

gcgaagcuuuacuucucgcggcugauggguccugaaaccacggccaagaccaucgugcuc4440

gugaaaaaugugcugucaaggcacuacgugcaucuggagaggucgccauggaagggucug4500

ccggaacugaccaacgaaaacgcacaguacugccccuuuucgugcgagacucaggccugg4560

uccaucgccaccauucucgaaacucucuacgaccuguag4599

<210>26

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>26

augggacacucgaaacagaucagaauccuguugcucaacgaaauggagaagcuggaaaag60

acccucuuucggcucgaacagggcuacgagcugcaguuccgccuggguccgacacuacaa120

ggaaaggcagucacuguguacaccaacuacccauuucccggagaaaccuucaaccgggag180

aaguuccggucccuggacugggaaaacccaaccgaacgagaggaugacuccgacaaguac240

ugcaagcugaaccuccaacaguccggaucauuccaguacuacuuucugcaagggaacgag300

aaguccggaggcggcuacaucguggucgacccaauacuuagagugggagccgacaaucau360

guccugccucuggacugcgugacccugcaaaccuucuuggcgaaaugucugggcccguuc420

gaugagugggaaagccgccucagagucgcaaaggaguccggauacaacaugauucacuuc480

acuccgcugcaaacccucggucugucccggucgugcuauucucuggcgaaccagcuggag540

cuuaaccccgacuucucgcgcccaaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcaucacugacgugguguacaaccau660

acggccgccaacucgaaguggauccaagagcaucccgagugcgcguacaaccucgugaau720

agcccgcaucugaagccugcuugggugcuggauagagcccucuggagauucagcugcgac780

guggccgaggggaaguacaaagaaaagggaauuccggccuugauugagaacgaccaucac840

augaacucaauccgcaagaucaucugggaggauaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacguaaacaaggcaguggagcaguucagaagguugcugacucaagaa960

aacagacgggucacuaaguccgauccuaaccagcaccuuaccaucauucaagacccugag1020

uaccgccgguuuggcugcaccgucgacaugaacaucgcccugaccacuuucaucccgcau1080

gacaagggcccggcggcaaucgaggaaugcuguaacugguuucauaagaggauggaggaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagucaacugccuc1200

cugggcaacguguucuacgaacggcuggcuggacacggaccgaagcugggucccgugacu1260

cgcaagcauccgcucgugacucgcuacuucaccuucccguuugaggagauugacuucucc1320

auggaagaauccaugauccaccucccgaacaaggcuugcuuccugauggcgcacaacgga1380

ugggucaugggcgacgacccacugcgcaauuucgcugagccuggcucggaggucuaccug1440

agaagggaauugauuugcuggggagacuccgugaagcugcgcuauggcaacaagccugaa1500

gauugccccuaccugugggcucacaugaagaaguacacggaaaucacugccacguacuuc1560

cagggaguccggcuggacaauugccacucgaccccgcuccauguggccgaguacaugcug1620

gaugcagcgaggaaucugcagcccaaucuguacgugguugcagaacuguucacuggcucc1680

gaggaccucgacaacguguucgugaccagacuggggauuuccucacugauccgggaagcc1740

augucggccuacaacucccaugaagagggccgccugguguaccgcuaugggggagaaccc1800

gugggaagcuucgugcagccuugccuccggccgcugaugccugcgaucgcccacgcccug1860

uucauggauaucacucacgacaacgaaugccccauugugcaucgcucggccuacgacgca1920

cugccuucgaccacuaucguguccauggccugcugcgccuccgggagcacccgcggauac1980

gaugaacucgugccgcaccagaucagcgugguguccgaagaacgguucuacaccaagugg2040

aaccccgaagcccugccuagcaauaccggggaagugaacuuccaguccgguauuaucgcc2100

gcucgcugcgccaucuccaaacuccaccaagagcucggugccaagggauucauucaaguc2160

uacguggaucaggucgacgaagauauuguggccgugaccaggcacucaccuuccauccac2220

caauccgucgucgccgugucccggacugcguuucggaaccccaagacuucguucuacucg2280

aaagaagugccacagauguguaucccgggaaaaaucgaggaggucgugcucgaagcccgg2340

accauugagaggaacaccaagccuuaccggaaagacgagaacucuaucaacgguaccccu2400

gauauuacuguggagauccgcgaacacauccagcugaacgaaucaaagaucgucaagcag2460

gcuggaguggccaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccuggcuccgugauuaucuuccgggugucccuggacccucacgcccaaguggccgug2580

ggaauucucagaaaccaccugacccaguucucaccacacuuuaaguccgguucccuggcg2640

guggacaacgccgauccgaucuugaagauccccuucgcaucgcucgccucccgccugacu2700

cucgcggaacugaaccagauccuguaccgcugugaauccgaggaaaaggaggacggcggc2760

ggcuguuacgauauccccaauuggucggcuuugaaauacgcgggacuucaggggcugaug2820

ucugugcuggcggaaauccggccgaagaacgaccugggacacccauucugcaacaacuug2880

cggagcggagacuggaugaucgauuacgucagcaacagauugaucagccggagcggcacu2940

aucgccgaggucggaaaguggcuccaggccauguucuucuaccugaagcagaucccccga3000

uaccucauccccuguuacuucgacgccauucugaucggggccuacaccacccugcuggac3060

accgccuggaagcagaugagcaguuuugugcaaaacggguccaccuucgugaagcaccuu3120

ucacugggcucagugcagcucugcggcgugggaaaguuccccucgcugcccauucugagc3180

cccgcccugauggacgucccuuaccggcugaacgagaucaccaaggagaaggagcagugc3240

uguguuucccuggcugccgggcugccacacuucucguccggcaucuuccgguguuggggc3300

cgggauaccuucauugcccugcggggaauccugcuuaucaccggucgcuacguggaggcu3360

cggaacauuauucucgcguucgccggcacccugagacacggucugauuccgaaucuguug3420

ggcgaaggaaucuacgccagauacaacugucgggacgccguguggugguggcuccagugc3480

auucaggacuauugcaagauggugccgaacggccuggacauccugaagugcccagugucg3540

aggauguauccaacugacgacagcgcaccucugccggccgggacccucgaccaaccccug3600

uucgaagucauucaagaggcuaugcagaagcacaugcaggguauucaguuccgggagcgg3660

aacgcggggccccagauugauaggaacaugaaagacgagggcuucaacaucacugccggc3720

guggacgaagaaaccgguuuuguguacggaggaaaccgcuucaacugcgguaccuggaug3780

gacaagaugggagaauccgaucgcgcgcgcaacagagggaucccggcaaccccucgggac3840

ggauccgcgguggaaauugugggacugagcaagagcgccgugcgguggcuccuggaacug3900

uccaaaaagaacaucuuccccuaccacgaagugaccgugaagagacacggaaaggccauc3960

aaagucucauacgaugaauggaacaggaagauccaggauaacuucgagaagcuguuucac4020

guguccgaggaucccuccgaucugaacgagaagcauccgaaucuggugcacaagcgcggg4080

aucuacaaggacucguacggagcguccuccccuuggugcgacuaucagcugcggccuaac4140

uucaccauugccauggucguggccccggagcuguucacaacugagaaggccuggaaggcc4200

cuugaaauugccgagaagaagcugcuggggccuuuggggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuggacaacgauaacuacaaucucgcg4320

aagggcuucaauuaccaccaaggccccgaauggcucuggccuauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugaugggaccagagacuaccgccaagacuaucguccuc4440

gugaagaacgugcugucccggcacuacgugcaucuggagaggagcccuuggaagggacuu4500

ccugagcugacgaacgaaaacgcgcaguacugccccuucuccugcgaaacccaggcuugg4560

uccauugccacuauacuggaaaccuuauaugaccuguag4599

<210>27

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>27

augggacacucgaaacagauccggauccuguugcugaacgaaauggagaagcuugaaaag60

acccuguuucggcuggagcagggcuacgagcugcaguuccgccuggguccgacacuacaa120

ggaaaggccgugacuguguacaccaacuacccauuucccggagaaacuuucaaccgggag180

aaguuccggucccuggacugggaaaacccaaccgaacgagaggacgacucggacaaguac240

ugcaagcugaaccuccaacaguccggaucauuccaguacuacuuucugcaagggaacgag300

aaguccggaggcggcuacaucguggucgacccgauacuuagagugggcgccgacaaucau360

guccugccucuggauugcgugacccugcaaaccuucuuggccaaaugucugggcccguuc420

gaugagugggaaagccgccucagagucgcaaaggaguccggauacaacaugauucauuuc480

accccgcugcaaacccugggucugucccggucgugcuauucucuggcgaaccagcuggag540

cuuaaccccgacuucucgcgcccaaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcaucacugacgugguguacaaccau660

acggccgccaacucgaaguggauccaggagcaucccgagugcgcauacaaccucgugaac720

agcccgcaccuuaagccugcuugggugcuggacagagcccucuggagauucaguugcgac780

guggccgaggggaaguacaaggaaaagggaauuccggccuugaucgagaacgaccaucac840

augaacucaaucaggaagaucaucugggaggacaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacguaaacaaggcaguggagcaguucagaagguugcugacccaagaa960

aacagacgcgucacuaaguccgauccuaaccaacaccuuaccaucauucaagacccugaa1020

uaccgccgguuuggcugcaccgucgauaugaacaucgcccugaccacuuucaucccgcau1080

gacaagggcccggcggcaaucgaggaaugcuguaacugguuucauaagagaauggaagaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagugaacugccug1200

cugggcaauguguucuacgaacggcuggcuggacacggaccgaagcugggucccgugacu1260

aggaagcauccgcucgugacucgcuacuucaccuucccguuugaggagauugacuucucg1320

auggaagaauccaugauccaucugccuaacaaggcuugcuuccugauggcgcacaacgga1380

ugggucaugggcgacgacccccugcgcaacuucgccgagccuggcucggaggucuaccug1440

agaagggaacuuaucuguuggggagacuccgucaagcugcgcuacggaaacaagcccgaa1500

gauugccccuaccugugggcucacaugaagaaguacacggaaaucacugcaacguacuuc1560

cagggaguccggcuggacaauugccacuccaccccccuucauguggccgaguacaugcuc1620

gaugcagcgaggaaucugcagccgaaucuguacgugguugccgaacuguucacuggcucc1680

gaggacuuggacaacguguucgugaccagacuggggaucuccucccugauccgggaagcc1740

augucggccuacaacucccaugaagagggccgccugguguaccgcuacgggggagaaccc1800

gugggaagcuucgugcaaccuugccugcggccgcugaugccugcgaucgcccacgcccug1860

uucauggacaucacucacgauaacgaaugcccgauugugcaucgcucggccuacgacgca1920

cugccgagcaccacuaucguguccauggccugcugcgccuccgggagcacucgcggauac1980

gaugaacucgugccgcaccagaucagcgugguguccgaagaacgcuucuauaccaagugg2040

aaccccgaagcgcugccaucgaauacuggcgaagugaacuuccaguccgguauuaucgcc2100

gcucgcugugccaucagcaaacugcaccaagagcuuggugccaagggauucauucaaguc2160

uacguggaucaggucgacgaagauauuguggccgugaccaggcacucaccuuccauccac2220

caaucagucguggccgugucccggaccgcguuccggaaccccaagaccagcuucuacucg2280

aaagaagugccucagauguguaucccgggaaaaaucgaagaggucgugcuggaagcccgg2340

accauugagaggaacaccaagccuuaccggaaagacgagaacucuaucaacgguaccccu2400

gauauuacuguggagauccgcgaacacauccagcugaacgaaucaaagaucgucaagcag2460

gcuggaguggccaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccuggcuccgugauuaucuuucgggugucccuggacccucacgcccaaguggccgug2580

ggaauucucagaaaccaccugacccaguucucaccccacuucaaguccgguucccuggcg2640

guggauaacgccgacccgauuuugaagauccccuucgccucgcuggccucccgccugacu2700

cucgcggaacugaaccagauccuguaccgcugugaaucagaggaaaaagaggacggcggc2760

ggcuguuacgauauucccaauuggucggcuuugaaauacgcgggacuucaggggcugaug2820

ucugugcuggcggaaauccggccgaagaacgaccugggacacccauucugcaacaacuug2880

cgguccggagacuggaugaucgauuacgucagcaacagauugaucagccggagcggcacu2940

aucgcugaggucggaaaguggcugcaggccauguucuucuaucugaagcagaucccccga3000

uaccucauccccuguuacuucgacgccauucugaucggggccuacaccacccugcuggac3060

accgccuggaagcagaugagcaguuuugugcaaaacggguccaccuucgugaagcaccuu3120

ucacugggcucagugcagcucugcggcgugggaaaguuccccucucugcccauucugagc3180

ccggcccugauggacgucccuuaccggcugaacgagaucaccaaggagaaggagcagugc3240

ugcguuucccuggcugccgggcugccacacuucucguccggcaucuuccggugcuggggc3300

cgggauaccuucaucgcccugcgggguauccugcuuaucaccggucgcuacguggaggcu3360

cggaacauuauucuggcguucgccggcacccuuagacacggacugauuccgaaccuuuug3420

ggcgaaggaaucuacgccagauacaacugucgggacgccguguggugguggcuucagugc3480

auucaggacuauugcaagauggugccgaacggccuggacauccugaagugcccagugucg3540

aggauguauccaaccgacgacagcgcaccucugccggccgggacccucgaccaaccccug3600

uucgaagucauucaggaggcuaugcagaagcacaugcaggguauucaguuccgggagcgg3660

aacgcggggccgcagauugauaggaacaugaaagacgagggcuucaacaucacugccggc3720

guggacgaagaaaccgguuuuguguacggaggaaacagauucaacugcgguaccuggaug3780

gacaagaugggagaguccgaucgcgcgcgcaacagagggaucccggcaaccccgcgggac3840

ggauccgcgguggaaauugugggacugagcaagagcgccgugcgguggcugcuggaacug3900

agcaaaaagaacaucuuccccuaccacgaagugaccgugaagcggcacggaaaggccauc3960

aaagucucauacgaugaauggaauaggaagauccaggauaacuucgagaagcuguuucac4020

guguccgaggaucccuccgaucugaacgaaaagcacccgaaucucgugcacaagcgcggg4080

aucuauaaggacucguacggagcguccuccccuuggugcgacuaucagcugcggccuaac4140

uucaccauugccauggucguggccccggagcuguucacaacugagaaggccuggaaggcc4200

cuugaaauugccgagaagaagcugcuggggccuuuggggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuggacaacgauaacuacaaucuggcc4320

aagggcuucaauuaccaccagggcccggaauggcuguggcccauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugaugggaccagagacuaccgccaagacuaucguccuc4440

gugaagaacgugcugucccggcacuacgugcaucuggagaggagcccuuggaagggacuu4500

ccugaacugacuaacgagaacgcgcaguacugccccuucuccugcgaaacccaggcuugg4560

uccauugccaccauacuggaaacccuuuaugaccuguag4599

<210>28

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>28

augggacacucgaaacagauuagaauccuguugcucaacgaaauggagaagcuggaaaag60

acccucuuucggcuggagcagggcuacgagcuccaguuccgccuggguccgacacuacaa120

gggaaggcagugaccguguacaccaacuacccauuucccggagaaaccuucaaccgggag180

aaguuccggucccuggacugggaaaacccaaccgaacgagaggaugacagcgacaaguac240

ugcaagcugaaccuccaacagucgggaucguuccaguacuacuuucugcaagggaacgag300

aaguccggaggaggcuacaucguggucgacccgauacuuagagugggagccgacaaccau360

guccugccucuggacugcgugacccugcaaaccuucuuggccaaaugucugggcccguuc420

gaugagugggaaagccgccucagaguggccaaggaguccggguacaacaugauucacuuc480

acuccgcugcaaacccucggucugucccggucgugcuauucucuggcgaaccagcuggag540

cugaaccccgacuucucccgcccaaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcauuacugacgugguguacaaccac660

accgccgccaacucgaaguggauccaagaacaucccgagugcgcguacaaccucgugaac720

agcccgcaucugaagccggcuugggugcucgauagagcccucuggagauucuccugugac780

gucgccgaggggaaguacaaagagaaggguauuccggcccucauugagaacgaccaucac840

augaacucaauccggaagaucaucugggaggauaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacguaaacaaggccguggaacaguucagaaggcugcugacucaagaa960

aaccgccgcgucacuaaguccgauccuaaccagcaucuuaccaucauccaagacccugag1020

uaucgccgguuugggugcaccgucgacaugaacaucgcacugaccacuuucaucccgcau1080

gacaaggggccggcggccaucgaggaaugcuguaacugguuucauaagaggauggaggaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagugaauugccuc1200

cuggggaacguguucuacgaaaggcuggcuggacacggaccgaagcuggggcccgugacu1260

cgcaagcauccgcucgugacucgcuacuucaccuucccguuugaggagauugacuucuca1320

auggaagaauccaugauccaccucccgaacaaggcuugcuucuugauggcgcacaaugga1380

ugggucaugggcgacgacccacugcgcaacuucgcugagccuggcucggaggucuaccug1440

agaagggaauugauuugcuggggggacuccgucaagcugcgcuauggaaacaagccggaa1500

gauugccccuaccugugggcucacaugaagaaguacacggaaauuacugccacguacuuc1560

cagggcguccggcuggacaacugccacuccacuccccuccauguggccgaguacaugcuc1620

gacgcagcgaggaaucugcagcccaaucuguacgugguugcagaacuguucacugggucc1680

gaggaccucgacaauguguucgugaccagacuggggaucuccucccugauccgggaagcc1740

augucggccuacaacucccaugaagagggccgccugguguaccgcuacgggggagaaccc1800

guggggagcuucgugcagccuugccuccgcccgcugaugccugccaucgcccacgcccug1860

uucauggauaucacucaugacaacgaaugucccauugugcaucgcucggccuacgacgca1920

cugccuucgaccacuaucguguccauggccugcugcgccuccgggagcaccaggggauac1980

gacgaacucgugccgcaccagaucagcgugguguccgaagagagauucuauaccaagugg2040

aaccccgaagcgcugcccagcaauaccggggaagugaacuuccaguccgguauuaucgcc2100

gcucgcugugcgaucagcaagcuccaccaggagcucggugccaagggauucauucaaguc2160

uacguggaccaggucgacgaagauaucguggccgugaccaggcacucaccuuccauucac2220

caauccguggucgccgugucccggacugcuuuucggaaccccaagacuucguucuacucg2280

aaagaagugccacagauguguaucccggggaaaaucgaagaggucguccucgaagcccgg2340

accauugagaggaacaccaagccuuaccggaaagacgagaacucuaucaacgggaccccu2400

gauauuacuguggagauccgcgaacacauccagcugaacgaaucaaagaucgucaagcag2460

gcuggaguggcgaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccuggcuccgugauuaucuuccgggugucccuggacccucacgcccaaguggccgug2580

ggaauucucagaaaccaccugacucaguucucaccccacuuuaagucugggucccuggcg2640

guggacaacgccgauccgaucuugaaaaucccuuucgcaagccuggccucccgccugacu2700

uuggccgagcugaaccagauccuguaccgcugugaaucagaggaaaaggaggacgggggu2760

ggcuguuacgauauccccaacugguccgcuuugaaauacgcgggacugcaggggcugaug2820

uccgugcuggcggaaaucagaccgaagaacgaucuggggcaccccuucugcaacaacuug2880

cgguccggagacuggaugaucgauuacgucagcaaccgguugaucagcagaagcgguacu2940

aucgccgaggucggaaaguggcugcaggccauguucuucuaccugaagcagaucccucga3000

uaccucauccccuguuacuucgacgccauuuugaucggggccuacaccacccugcuggac3060

acugccuggaagcagaugagcaguuuugugcaaaaugggucgaccuucgugaagcaccuu3120

uccuugggcucagugcagcucugcggcguggggaaguuccccucgcugcccauucugucc3180

ccggcccugauggacgucccuuaccggcugaacgagauuaccaaggagaaggagcagugc3240

uguguuucccuggcugccgggcugccacacuucucguccgggaucuuccggugcuggggc3300

cgcgauaccuucauugcgcugcgggguauccugcuuaucaccggucgcuacguggaggcu3360

cggaacauuauccuugcauucgccgguacccugagacacggucugaucccgaaucuucuc3420

ggggaaggaaucuacgcaagauacaacugccgggacgccguguggugguggcuccagugc3480

auucaggacuauugcaagauggugccgaacggacuugacauccugaagugcccagugucg3540

aggauguacccuaccgacgacagcgcuccucugccggccgggacccuggaccaaccccug3600

uucgaagucauccaagaggcuaugcagaagcacaugcaggguauucaguuccgggaacgg3660

aacgcggggccccagauugauaggaacaugaaggacgaggguuucaacaucacugccggc3720

guggacgaagaaacuggguuuguguacggaggaaacagauucaacugcgguaccuggaug3780

gacaagaugggagaauccgaucgcgcgcgcaacagagggaucccggcaaccccgcgggac3840

ggauccgcgguggaaauugugggacugagcaagagcgccgugcgguggcuccuggaacug3900

uccaaaaagaacaucuuccccuaccacgaagugaccgugaagcggcacggaaaggccauc3960

aaagucucauacgaugaauggaaucggaagauccaggauaacuucgagaagcuguuucac4020

guguccgaggaucccuccgaucucaacgaaaagcauccgaaucucgugcacaagcgcggg4080

aucuacaaggacucguacggggcguccucaccuuggugcgacuaucagcugcggccuaac4140

uucacuauugcgauggucguggccccggaguuauucacaacggagaaggccuggaaggcc4200

cuugaaauugcggagaagaagcugcuggggccucucgggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuugacaacgauaacuacaaucuggcc4320

aagggguucaauuaccaccaggggccggaauggcucuggcccauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugauggggccagagacuaccgccaagacuaucguccuc4440

gugaaaaacgugcugucccggcacuacgugcaucuggagaggagcccuuggaagggacug4500

ccagagcugacgaacgagaacgcgcaguacugccccuucuccugcgaaacccaggcuugg4560

ucgauugccacuauacuggaaaccuuauaugaccuguag4599

<210>29

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>29

augggacacucaaagcaaauccgcauucugcugcugaacgagauggaaaagcuggaaaag60

acucuguuccggcuggaacaggguuacgagcugcaguuucggcucggcccaaccuugcaa120

gggaaggccgucacugucuacaccaacuacccuuuuccgggggagacuuucaaccgcgaa180

aaguuccgcucccuggauugggaaaaccccacugaacgggaggaugacagcgacaaguac240

ugcaaacugaaccuucagcaguccggcagcuuccaauacuacuuccugcaaggaaacgaa300

aaguccggcggcgguuacaucguggucgaccccauucugagagugggagccgauaaucau360

gugcugccccuggacugcgucacccugcaaacuuuccuggcuaagugccugggaccguuc420

gaugagugggaauccaggcuccgcguggcgaaggagucgggcuacaacaugauucauuuc480

acuccccuucaaacucuggggcugagucgcagcuguuacucccuggccaaccagcuugaa540

cugaacccagacuuuucccggccaaacagaaaguacaccuggaacgacgugggacaauug600

guggagaagcuuaagaaggaauggaacgugaucugcaucaccgaugugguguauaaccac660

acugccgcgaauuccaaguggauccaggaacaccccgagugugcuuacaaccuugugaac720

agcccucaccuuaagccggccugggugcuggaucgggcgcuguggagauucuccugcgac780

guggccgaagggaaguacaaagaaaagggaauccccgcccugauugaaaaugaccaccau840

augaacuccauucggaaaaucauuugggaagauaucuuucccaagcugaagcucugggag900

uucuuucaaguggaugugaacaaggcuguggagcaguuccggcggcugcugacccaggag960

aaccgccgcgugaccaaguccgacccuaaccagcacuugaccaucauacaggacccggaa1020

uaccggagauucggcugcacugucgacaugaacauugcccucacuaccuucaucccgcau1080

gacaagggacccgcugccaucgaagagugcugcaacugguuccacaagcggauggaagaa1140

cugaacucugaaaagcacaggcugaucaacuaccaccaggaacaggcugugaacugccug1200

cugggcaacguguucuacgagagacucgcaggacacggaccgaagcugggcccugugacc1260

cggaagcauccucuggucacccgcuacuucaccuucccguucgaagagaucgacuuuucg1320

auggaagaaucgaugauccaccucccuaacaaggccugcuuccucauggcgcacaacggc1380

ugggucaugggcgacgacccgcugagaaacuucgccgagcccgggagcgaaguguaccuc1440

cggcgggaacuuauuugcuggggagauagcgugaagcuuagauauggcaacaagccugag1500

gacugcccauaccugugggcgcacaugaagaaguacacugaaauuaccgcgaccuacuuc1560

caaggaguccgacucgacaacugccacagcaccccacuucacgucgcggaguacauguug1620

gaugccgcacggaaucuccagcccaaucuguaugucguggcugaacuguucacuggaucc1680

gaggaccuugacaauguguucgugacuagacuggggaucuccagccugauccgggaagcu1740

auguccgcguacaacucccacgaagagggacggcugguguaccgcuacggcggagagccc1800

gugggaagcuucgugcagcccugccugcggccucugaugccggccaucgcucacgcccug1860

uucauggauaucacucacgacaaugaguguccuaucgugcacaggagcgcguacgacgcc1920

cugcccuccacuacuaucgugucgauggccugcugcgcaagcgguucuacccgcgguuac1980

gacgagcuugucccgcaccaaauauccguggugucagaggaacgguucuacaccaagugg2040

aacccggaggcccugccuucaaacaccggcgaagugaacuuccaguccggaaucauugcc2100

gcccgcugugccauuucaaaguugcaccaggagcugggcgccaagggauucauucagguc2160

uacguugaccaggucgacgaagauaucguggccguuacuagacauucaccgagcauccau2220

cagagcguggucgcagucagcaggacugccuuccgcaacccgaaaaccucguucuacucc2280

aaggaagugccccagauguguaucccgggaaaaauugaggaaguggugcuggaggcccgg2340

accaucgagcggaacacuaagcccuaccggaaggacgagaauucaaucaacggaaccccu2400

gacaucaccguggagauccgcgagcauauccaacugaacgagucgaagaucgucaagcag2460

gcugggguggcaacuaagggcccuaacgaguacauucaggagauugaauucgagaaccug2520

ucccccggguccgugaucauuuuccgcgugucccuggacccacaugcucaaguagcagug2580

gggauccugagaaaccaccugacccaguuuagcccgcacuucaaguccggaucccuggcc2640

guggauaacgccgacccgauccugaagauccccuuugcaucccuggcuucccggcugacc2700

uuggccgaacugaaccagauucuguaccgcugcgaaucagaggaaaaggaggacggaggc2760

ggaugcuacgauauccccaauuggucggcgcugaaguacgccggccuucaaggacugaug2820

uccgugcuggccgagaucaggccgaagaaugaccugggacacccguucugcaacaacuug2880

agaagcggggacuggaugauugauuacgugucgaaccggcugaucucccggagcggcacc2940

aucgcggaagucggaaaguggcuccaggccauguucuucuaccugaagcagaucccccgc3000

uaccugauccccugcuacuucgacgcgaucuugauuggggcauacaccacucugcuugac3060

accgcuuggaagcagauguccuccuucgugcaaaacggauccaccuucgugaagcaccug3120

ucccuuggaucagugcagcugugcggcgugggaaaguucccuucccuucccauccugucc3180

ccugcgcugauggacgugccguaccggcucaacgagaucaccaaggaaaaggaacagugc3240

ugcgugucacuggcagccggccuuccgcauuuuucgagcggaauuuucagauguuggggc3300

agagacaccuucauugcgcugcgcgguauccugcugauuaccggcagauacguggaagcc3360

agaaacauuauccuggcguuugcugguacucugcggcacggacugauuccuaaccuguug3420

ggagaggggaucuacgcccgguacaauugcagagaugccguguggugguggcugcagugc3480

auccaggacuacugcaagauggugcccaacggacuugacauucugaagugcccggugucg3540

cgcauguaccccaccgacgacucugcgccccugccggccgguacccuggaucagccgcug3600

uucgaagugauccaggaagccaugcaaaagcacaugcagggaauucaguucagggaacgg3660

aacgcaggcccgcaaaucgaccggaacaugaaggacgaaggcuucaacauuaccgccggc3720

guggacgaggaaaccggcuucguguacggcggcaaccgguucaauugcgguacuuggaug3780

gacaagaugggagaaagcgaccgcgccaggaaucggggcauuccugccaccccgcgggac3840

gguagcgcgguggagaucgugggccuuucgaaguccgcgguccgcuggcuucuggagcug3900

ucuaagaaaaacaucuucccuuaccacgaggucaccgugaaacgccacggaaaggccauc3960

aagguguccuacgacgaauggaacaggaagauccaggacaacuuugagaagcuguuucac4020

gugucggaagauccguccgaccugaacgaaaagcaccccaaccuuguccauaagcgcggu4080

aucuacaaagauucguauggugcauccuccccuuggugcgacuaccaacuccggccgaac4140

uucaccaucgcaauggugguggccccggagcuguucaccacugaaaaggccuggaaggcc4200

cuggaaaucgccgaaaagaagcugcugggaccgcuggggaugaaaacccuggaccccgau4260

gauaugguguacugcgggaucuacgacaacgcccuggauaacgacaacuacaaccuggcc4320

aagggcuucaacuaccaucaggguccggaguggcuguggccaaucggauacuuccugagg4380

gccaagcuguacuucucccgcuugaugggccccgaaacuaccgcaaagacuaucgugcuc4440

gugaagaacguccugucccggcacuacgugcaucuggaacggucgccguggaaaggccug4500

ccagaguugaccaacgagaaugcccaguauugcccguucucaugcgaaacccaagccugg4560

agcauugccacuauucuggaaacccucuacgaccuguag4599

<210>30

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>30

augggacacucgaaacagaucagaauccuguugcucaacgaaauggagaagcucgaaaag60

acccuguuccggcuggagcaggguuacgagcugcaguuccgccuggguccgacucuacaa120

gggaaagcagugacggucuacaccaacuacccguuucccggagaaaccuucaaccgggag180

aaguuccggucccuggacugggagaacccgaccgaacgagaggaugacucagauaaguac240

ugcaagcugaacuugcaacaguccgggucauuccaguacuacuuucugcaagggaacgag300

aagucaggagggggcuacaucguggucgacccgauacugcgcgugggagccgacaaucac360

guccugccgcuggacugcgugacccugcaaaccuuccucgccaaaugucuggggccguuc420

gaugagugggaaagccgccucagagucgcaaaggaguccggauacaacaugauucacuuc480

acuccgcugcaaacacucggucugucccggucgugcuauucucuggcgaaccagcuggag540

cuuaaucccgacuuuucccgcccgaaccggaaguacaccuggaacgacgucgggcagcuu600

guggaaaagcugaagaaggaguggaacgugaucugcaucacugaugugguguacaaccac660

acggcugccaacucgaaguggauccaagagcaucccgagugcgcguacaacuuggugaac720

agcccgcaucugaagccugcuugggugcuggacagagcccucuggagauucagcugcgac780

guggccgaggggaaguacaaagaaaaggggauuccggccuugauugagaacgaccaucac840

augaacucaauccgcaagaucauuugggaggauaucuucccuaagcuuaaguugugggag900

uucuuccaaguggacguaaacaaggcaguggagcaguucagaaggcugcugacucaagaa960

aacagacgcgucacuaaguccgacccgaaccagcaccuuaccaucauccaagacccggag1020

uaccgccgguucggcugcaccgucgauaugaacauagcccugaccacuuucaucccccau1080

gacaaggggccggcggcaaucgaggaaugcuguaacugguuucauaagcggauggaggaa1140

cugaauuccgagaagcaccggcugauuaacuaccaccaggaacaggcagugaacugccug1200

cugggcaacguguucuacgaacggcuggcuggacacggaccgaagcugggucccgugacu1260

agaaagcauccgcucgucacucgcuacuucaccuucccguuugaggagauugacuucucc1320

auggaagaauccaugauccacuugccgaacaaggcuugcuuccugauggcgcacaacgga1380

ugggucaugggcgacgacccgcugaggaauuucgcggagccggguucggaaguguaccug1440

agaagggaacucauuugcuggggagacuccgucaagcugcgcuaugggaacaagcccgag1500

gauugccccuaccugugggcucacaugaagaaguacacggaaaucaccgccacguacuuc1560

cagggaguccggcuggacaauugccacuccaccccccuccauguggccgaguacaugcug1620

gaugcagcgcgcaaucugcagccgaaucuguacgugguugcagagcuguucacugggucc1680

gaggaccucgacaacguguucgugacuagauuggggaucuccucccucauccgggaagcc1740

augucggccuacaacucccaugaggaggggaggcugguguacagauacggcggcgaaccc1800

gugggaagcuucgugcagccgugccuccggccgcugaugccggccaucgcccacgcccug1860

uucauggauaucacucacgacaacgaaugcccgaucgugcaucgcucggccuacgacgca1920

cugccguccaccacuaucguguccauggcaugcugcgccuccgggagcacccgcggauac1980

gaugagcucgugccgcaccagauuagcgugguguccgaagaacgcuucuauaccaagugg2040

aaccccgaagcccugccguccaauaccggggaagugaacuuccaguccgguauuaucgcc2100

gcucgcugugcgaucucgaaacuccaccaagagcucggugccaagggguucauucagguc2160

uacguggaucaggucgacgaggauauuguggcagugaccaggcacucaccuagcauccac2220

caauccguggucgccgugucacgcacugcguuucggaaccccaagaccucguucuacucg2280

aaagaagugccgcagauguguaucccgggaaagaucgaagaggucgugcuggaagcacgg2340

accauugagaggaacaccaagccuuaccggaaagacgagaacucuaucaacgggaccccg2400

gauaucacuguggagauucgcgaacacauccagcugaacgaaucaaagaucgucaagcag2460

gcuggaguggccaccaagggacccaacgaguacauccaggagaucgaauuugaaaaccuc2520

uccccgggguccgugaucaucuuccgggugucccuggacccccacgcccaaguggccgug2580

ggaauucucagaaaccaccugacccaguucucaccccacuuuaagucggguucccuggcc2640

guggacaacgccgauccgauccucaagaucccguucgcgucgcuggccucccgccucacu2700

cucgcggaacugaaccagauccuguaccgcugugaaucagaggaaaaggaggacggcggc2760

ggcuguuacgauauuccgaauuggucggcuuugaaauacgcgggacuucaggggcugaug2820

ucuguccuggcggaaauccggccgaagaacgaccuggggcacccguucugcaacaacuug2880

cggagcggagauuggaugaucgacuacgucagcaacagacugaucagccggagcggcacu2940

aucgccgaggucggaaagugguugcaggccauguucuucuaccugaagcagaucccccga3000

uaccucaucccguguuacuucgacgccauccugaucggggccuacaccacccuccuggac3060

accgccuggaagcagaugagcaguuuugugcaaaacggguccaccuucgugaagcaccuu3120

ucccugggcucagugcagcugugcggcgugggaaaguuccccucgcugcccauucugagc3180

ccggcccugauggacguccccuaccggcugaacgagaucaccaaggagaaggagcagugc3240

ugugugucccuggcugccgggcugccgcacuuuucguccggcaucuuccggugcuggggg3300

cgggauaccuucauugcccugcggggaauccuucuuaucaccggucgcuauguggaggcu3360

cggaacauuauucuggcguucgccggaacccugagacacgggcugauuccgaaccucuug3420

ggggaagggaucuacgcccgcuacaacugucgggacgccguguggugguggcuccagugc3480

auucaggacuauugcaagauggugcccaacgggcuggacauccugaagugcccggugucg3540

aggauguauccgaccgacgacagcgcaccccugccggccgggacccucgaccaaccccug3600

uucgaagucauucaagaggcuaugcagaagcacaugcaggguauucaguuccgggaacgg3660

aacgcggggccccagauugauaggaacaugaaagacgaggguuucaacaucacugccggc3720

guggacgaagaaaccgguuuuguguacggaggaaaccgguucaacugcgguaccuggaug3780

gauaagaugggagaaucagaucgcgcgcgcaacagagggaucccggcaaccccgcgggac3840

ggaucggcuguggaaauugugggacugagcaagagcgccgugcgguggcugcuggaacug3900

agcaaaaagaacaucuuccccuaccacgaagugaccgugaagcggcacggaaaggccauc3960

aaagucuccuacgaugaauggaauaggaagauccaggauaacuucgagaagcuuuuucac4020

guguccgaggaucccuccgaucugaacgagaagcauccgaaucucgugcauaagaggggg4080

aucuacaaggacuccuacggagcguccuccccuuggugcgacuaucagcugcggccuaac4140

uucaccauugccauggucguggccccggagcucuuuacaaccgagaaggccuggaaggcc4200

cucgaaauugccgaaaagaagcugcuggggcccuuggggaugaaaacccuggauccggac4260

gacaugguguacugcggaaucuacgacaacgcccuggacaacgacaacuacaaucuggcg4320

aagggcuucaauuaccaccaggggccggaauggcucuggccgauuggguacuuccugcgc4380

gccaagcuguacuucucacggcugaugggaccggagacuaccgccaagaccaucguccuc4440

gugaagaacgugcugucgcggcacuacgugcaccuggagaggagccccuggaaggggcuu4500

cccgagcugacgaacgagaacgcgcaguacugucccuucuccugcgaaacccaagccugg4560

uccauugccacuauacuggaaaccuuauaugaccuguag4599

<210>31

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>31

augggccacagcaagcagauccggaucuugcugcugaacgagauggagaagcuggagaag60

acccuguucaggcuggagcagggcuacgagcugcaguuccgguugggccccaccuugcag120

ggcaaggccgugaccguguacaccaacuaccccuuccccggcgaaaccuucaacagggag180

aaguuccggucccuggacugggagaaccccaccgagagggaggacgacuccgacaaguac240

ugcaagcugaaccugcagcaguccggcuccuuccaguacuacuuccugcagggcaacgag300

aaaagcggcggcggcuacaucgugguggaccccaucuugcgggugggcgccgacaaccac360

gugcugcccuuggacugcgugacccugcagaccuucuuggccaagugcuugggccccuuc420

gacgagugggagagcaggcugaggguggccaaggaguccggcuacaacaugauccacuuc480

acccccuugcagacccugggccuguccagguccugcuacucccuggccaaccaguuggag540

uugaaccccgacuucuccaggcccaacaggaaguacaccuggaacgacgugggccagcug600

guggagaaguugaagaaggaguggaacgugaucugcaucaccgacgugguguacaaccac660

accgccgccaacagcaaguggauccaggagcaccccgagugcgccuacaaccuggugaac720

uccccccacuugaagcccgccuggguguuggacagggcccuguggcgguucuccugcgac780

guggccgagggcaaguacaaggagaagggcauccccgccuugaucgagaacgaccaccac840

augaacuccauccggaagaucaucugggaggacaucuuccccaagcugaagcugugggag900

uucuuccagguggacgugaacaaggccguggagcaguucaggaggcugcugacccaggag960

aacaggcgggugaccaaguccgaccccaaccagcaccugaccaucauccaggaccccgag1020

uacaggcgguucggcugcaccguggacaugaacaucgcccugaccaccuucaucccccac1080

gacaagggccccgccgccaucgaggagugcugcaacugguuccacaagaggauggaggag1140

uugaacuccgagaagcaccggcugaucaacuaccaccaggagcaggccgugaacugccug1200

uugggcaacguguucuacgagcggcuggccggccacggccccaagcugggccccgugacc1260

aggaagcaccccuuggugaccagguacuucaccuuccccuucgaggagaucgacuucucc1320

auggaggaguccaugauccaccugcccaacaaggccugcuuccugauggcccacaacggc1380

ugggugaugggcgacgacccccugcggaacuucgccgagcccggcuccgagguguaccug1440

aggagggagcugaucugcuggggcgacagcgugaaguugcgguacggcaacaagcccgag1500

gacugccccuaccugugggcccacaugaagaaguacaccgagaucaccgccaccuacuuc1560

cagggcgugcggcuggacaacugccacuccaccccccugcacguggccgaguacauguug1620

gacgccgccaggaacuugcagcccaacuuguacgugguggccgagcuguucaccggcagc1680

gaggaccuggacaacguguucgugaccaggcugggcaucagcuccuugaucagggaggcc1740

augagcgccuacaacagccacgaggagggcagguugguguaccgguacggcggcgagccc1800

gugggcuccuucgugcagcccugcuugaggcccuugaugcccgccaucgcccacgcccug1860

uucauggacaucacccacgacaacgagugccccaucgugcacagguccgccuacgacgcc1920

cugcccagcaccaccaucguguccauggccugcugcgccagcggcagcaccaggggcuac1980

gacgaguuggugccccaccagaucuccgugguguccgaggagcgguucuacaccaagugg2040

aaccccgaggccuugcccuccaacaccggcgaggugaacuuccagagcggcaucaucgcc2100

gccaggugcgccaucagcaagcugcaccaggagcugggcgccaagggcuucauccaggug2160

uacguggaccagguggacgaggacaucguggccgugaccaggcacucccccagcauccac2220

caguccgugguggccguguccaggaccgccuucaggaaccccaagaccuccuucuacagc2280

aaggaggugccccagaugugcauccccggcaagaucgaggagguggugcuggaggccagg2340

accaucgagaggaacaccaagcccuacaggaaggacgagaacuccaucaacggcaccccc2400

gacaucaccguggagaucagggagcacauccagcugaacgagagcaagaucgugaagcag2460

gccggcguggccaccaagggccccaacgaguacauccaggagaucgaguucgagaacuug2520

ucccccggcagcgugaucaucuucagggugagccuggacccccacgcccagguggccgug2580

ggcauccugcggaaccaccugacccaguucagcccccacuucaaguccggcagccuggcc2640

guggacaacgccgaccccaucuugaagauccccuucgccucccuggccuccagguugacc2700

uuggccgagcugaaccagauccuguaccggugcgaguccgaggagaaggaggacggcggc2760

ggcugcuacgacauccccaacugguccgcccugaaguacgccggccugcagggcuugaug2820

uccguguuggccgagaucaggcccaagaacgacuugggccaccccuucugcaacaacuug2880

agguccggcgacuggaugaucgacuacgugagcaaccggcugaucucccgguccggcacc2940

aucgccgaggugggcaagugguugcaggccauguucuucuaccugaagcagaucccccgg3000

uaccugauccccugcuacuucgacgccaucuugaucggcgccuacaccacccugcuggac3060

accgccuggaagcagauguccagcuucgugcagaacggcuccaccuucgugaagcaccug3120

uccuugggcuccgugcagcugugcggcgugggcaaguuccccucccugcccauccugucc3180

cccgcccugauggacgugcccuacagguugaacgagaucaccaaggagaaggagcagugc3240

ugcgugucccuggccgccggcuugccccacuucuccuccggcaucuuccggugcuggggc3300

agggacaccuucaucgcccugaggggcauccugcugaucaccggccgguacguggaggcc3360

aggaacaucaucuuggccuucgccggcacccugaggcacggccugauccccaaccugcug3420

ggcgagggcaucuacgccagguacaacugccgggacgccguguggugguggcugcagugc3480

auccaggacuacugcaagauggugcccaacggccuggacauccugaagugccccgugucc3540

aggauguaccccaccgacgacuccgcccccuugcccgccggcacccuggaccagcccuug3600

uucgaggugauccaggaggccaugcagaagcacaugcagggcauccaguuccgggagagg3660

aacgccggcccccagaucgaccggaacaugaaggacgagggcuucaacaucaccgccggc3720

guggacgaggaaaccggcuucguguacggcggcaaccgguucaacugcggcaccuggaug3780

gacaagaugggcgagagcgacagggccaggaacaggggcauccccgccacccccagggac3840

ggcuccgccguggagaucgugggccugagcaaguccgccgugcggugguugcuggaguug3900

uccaagaagaacaucuuccccuaccacgaggugaccgugaagaggcacggcaaggccauc3960

aagguguccuacgacgaguggaacaggaagauccaggacaacuucgagaagcuguuccac4020

guguccgaggaccccuccgacuugaacgagaagcaccccaaccuggugcacaagcggggc4080

aucuacaaggacagcuacggcgccuccagccccuggugcgacuaccagcugaggcccaac4140

uucaccaucgccauggugguggcccccgagcuguucaccaccgagaaggccuggaaggcc4200

uuggagaucgccgagaagaaguugcugggcccccugggcaugaagaccuuggaccccgac4260

gacaugguguacugcggcaucuacgacaacgccuuggacaacgacaacuacaaccuggcc4320

aagggcuucaacuaccaccagggccccgaguggcuguggcccaucggcuacuuccugcgg4380

gccaaguuguacuucuccagguugaugggccccgaaaccaccgccaagaccaucguguug4440

gugaagaacgugcugucccggcacuacgugcaccuggagaggucccccuggaagggccug4500

cccgagcugaccaacgagaacgcccaguacugccccuucagcugcgaaacccaggccugg4560

uccaucgccaccauccuggaaacccuguacgacuuguag4599

<210>32

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>32

augggacauagcaagcagauccggaucuugcugcugaaugaaauggaaaagcuggaaaag60

acccuguucagacuggaacagggauacgaacugcaguuccgguugggaccuaccuugcag120

ggaaaggcugugaccguguacaccaauuacccuuucccuggagaaaccuucaauagagaa180

aaguucagaucucuagauugggaaaauccuaccgaaagagaagaugauucugauaaguac240

ugcaagcugaaucugcagcagucuggaucuuuccaguacuacuuccugcagggaaaugaa300

aagagcggaggaggauacaucgugguggauccuaucuugcgggugggagcugauaaucau360

gugcugccuuuggauugcgugacccugcagaccuucuuggcuaagugcuugggaccuuuc420

gaugaaugggaaagcagacugagaguggcuaaggaaucuggauacaauaugauccauuuc480

accccuuugcagacccugggacugucuagaucuugcuacucucuggcuaaucaguuggaa540

uugaauccugauuucucuagaccuaauagaaaguacaccuggaaugaugugggacagcug600

guggaaaaguugaagaaggaauggaaugugaucugcaucaccgaugugguguacaaucau660

accgcugcuaauagcaaguggauccaggaacauccugaaugcgcuuacaaucuggugaau720

ucuccucauuugaagccugcuuggguguuggauagagcucuguggcgguucucuugcgau780

guggcugaaggaaaguacaaggaaaagggaaucccugcuuugaucgaaaaugaucaucau840

augaauucuauccggaagaucaucugggaagauaucuucccuaagcugaagcugugggaa900

uucuuccagguggaugugaauaaggcuguggaacaguucagaagacugcugacccaggaa960

aauagacgggugaccaagucugauccuaaucagcaucugaccaucauccaggauccugaa1020

uacagacgguucggaugcaccguggauaugaauaucgcucugaccaccuucaucccucau1080

gauaagggaccugcugcuaucgaagaaugcugcaauugguuccauaagagaauggaagaa1140

uugaauucugaaaagcaucggcugaucaauuaccaucaggaacaggcugugaauugccug1200

uugggaaauguguucuacgaacggcuggcuggacauggaccuaagcugggaccugugacc1260

agaaagcauccuuuggugaccagauacuucaccuucccuuucgaagaaaucgauuucucu1320

auggaagaaucuaugauccaucugccuaauaaggcuugcuuccugauggcucauaaugga1380

ugggugaugggagaugauccucugcggaauuucgcugaaccuggaucugaaguguaccug1440

agaagagaacugaucugcuggggagauagcgugaaguugcgguacggaaauaagccugaa1500

gauugcccuuaccugugggcucauaugaagaaguacaccgaaaucaccgcuaccuacuuc1560

cagggagugcggcuggauaauugccauucuaccccucugcauguggcugaauacauguug1620

gaugcugcuagaaauuugcagccuaauuuguacgugguggcugaacuguucaccggaagc1680

gaagaucuggauaauguguucgugaccagacugggaaucagcucuuugaucagagaagcu1740

augagcgcuuacaauagccaugaagaaggaagauugguguaccgguacggaggagaaccu1800

gugggaucuuucgugcagccuugcuugaggccuuugaugccugcuaucgcucaugcucug1860

uucauggauaucacccaugauaaugaaugcccuaucgugcauagaucugcuuacgaugcu1920

cugccuagcaccaccaucgugucuauggcuugcugcgcuagcggaagcaccagaggauac1980

gaugaauuggugccucaucagaucucuguggugucugaagaacgguucuacaccaagugg2040

aauccugaagcuuugccuucuaauaccggagaagugaauuuccagagcggaaucaucgcu2100

gcuagaugcgcuaucagcaagcugcaucaggaacugggagcuaagggauucauccaggug2160

uacguggaucagguggaugaagauaucguggcugugaccagacauucuccuagcauccau2220

cagucugugguggcugugucuagaaccgcuuucagaaauccuaagaccucuuucuacagc2280

aaggaagugccucagaugugcaucccuggaaagaucgaagaaguggugcuggaagcuaga2340

accaucgaaagaaauaccaagccuuacagaaaggaugaaaauucuaucaauggaaccccu2400

gauaucaccguggaaaucagagaacauauccagcugaaugaaagcaagaucgugaagcag2460

gcuggaguggcuaccaagggaccuaaugaauacauccaggaaaucgaauucgaaaauuug2520

ucuccuggaagcgugaucaucuucagagugagccuggauccucaugcucagguggcugug2580

ggaauccugcggaaucaucugacccaguucagcccucauuucaagucuggaagccuggcu2640

guggauaaugcugauccuaucuugaagaucccuuucgcuucucuggcuucuagauugacc2700

uuggcugaacugaaucagauccuguaccggugcgaaucugaagaaaaggaagauggagga2760

ggaugcuacgauaucccuaauuggucugcucugaaguacgcuggacugcagggauugaug2820

ucuguguuggcugaaaucagaccuaagaaugauuugggacauccuuucugcaauaauuug2880

agaucuggagauuggaugaucgauuacgugagcaaucggcugaucucucggucuggaacc2940

aucgcugaagugggaaagugguugcaggcuauguucuucuaccugaagcagaucccucgg3000

uaccugaucccuugcuacuucgaugcuaucuugaucggagcuuacaccacccugcuggau3060

accgcuuggaagcagaugucuagcuucgugcagaauggaucuaccuucgugaagcaucug3120

ucuuugggaucugugcagcugugcggagugggaaaguucccuucucugccuauccugucu3180

ccugcucugauggaugugccuuacagauugaaugaaaucaccaaggaaaaggaacagugc3240

ugcgugucucuggcugcuggauugccucauuucucuucuggaaucuuccggugcugggga3300

agagauaccuucaucgcucugagaggaauccugcugaucaccggacgguacguggaagcu3360

agaaauaucaucuuggcuuucgcuggaacccugagacauggacugaucccuaaucugcug3420

ggagaaggaaucuacgcuagauacaauugccgggaugcuguguggugguggcugcagugc3480

auccaggauuacugcaagauggugccuaauggacuggauauccugaagugcccugugucu3540

agaauguacccuaccgaugauucugcuccuuugccugcuggaacccuggaucagccuuug3600

uucgaagugauccaggaagcuaugcagaagcauaugcagggaauccaguuccgggaaaga3660

aaugcuggaccucagaucgaucggaauaugaaggaugaaggauucaauaucaccgcugga3720

guggaugaagaaaccggauucguguacggaggaaaucgguucaauugcggaaccuggaug3780

gauaagaugggagaaagcgauagagcuagaaauagaggaaucccugcuaccccuagagau3840

ggaucugcuguggaaaucgugggacugagcaagucugcugugcggugguugcuggaauug3900

ucuaagaagaauaucuucccuuaccaugaagugaccgugaagagacauggaaaggcuauc3960

aaggugucuuacgaugaauggaauagaaagauccaggauaauuucgaaaagcuguuccau4020

gugucugaagauccuucugauuugaaugaaaagcauccuaaucuggugcauaagcgggga4080

aucuacaaggauagcuacggagcuucuagcccuuggugcgauuaccagcugaggccuaau4140

uucaccaucgcuauggugguggcuccugaacuguucaccaccgaaaaggcuuggaaggcu4200

uuggaaaucgcugaaaagaaguugcugggaccucugggaaugaagaccuuggauccugau4260

gauaugguguacugcggaaucuacgauaaugcuuuggauaaugauaauuacaaucuggcu4320

aagggauucaauuaccaucagggaccugaauggcuguggccuaucggauacuuccugcgg4380

gcuaaguuguacuucucuagauugaugggaccugaaaccaccgcuaagaccaucguguug4440

gugaagaaugugcugucucggcauuacgugcaucuggaaagaucuccuuggaagggacug4500

ccugaacugaccaaugaaaaugcucaguacugcccuuucagcugcgaaacccaggcuugg4560

ucuaucgcuaccauccuggaaacccuguacgauuuguag4599

<210>33

<211>158

<212>rna

<213>patentin版本3.5

<220>

<223>经过修饰的非洲爪蟾β-珠蛋白3'utr

<220>

<221>misc_feature

<222>(2)..(2)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(157)..(157)

<223>n为解锁核单体una-a

<400>33

cnagugacugacuaggaucugguuaccacuaaaccagccucaagaacacccgaauggagu60

cucuaagcuacauaauaccaacuuacacuuacaaaauguugucccccaaaauguagccau120

ucguaucugcuccuaauaaaaagaaaguuucuucacnu158

<210>34

<211>158

<212>rna

<213>patentin版本3.5

<220>

<223>经过修饰的非洲爪蟾β-珠蛋白3'utr

<220>

<221>misc_feature

<222>(2)..(2)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(3)..(3)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(4)..(4)

<223>n为解锁核单体una-g

<220>

<221>misc_feature

<222>(155)..(155)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(156)..(156)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(157)..(157)

<223>n为解锁核单体una-a

<400>34

cnnnugacugacuaggaucugguuaccacuaaaccagccucaagaacacccgaauggagu60

cucuaagcuacauaauaccaacuuacacuuacaaaauguugucccccaaaauguagccau120

ucguaucugcuccuaauaaaaagaaaguuucuucnnnu158

<210>35

<211>158

<212>rna

<213>patentin版本3.5

<220>

<223>经过修饰的非洲爪蟾β-珠蛋白3'utr

<220>

<221>misc_feature

<222>(2)..(2)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(8)..(8)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(14)..(14)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(20)..(20)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(26)..(26)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(32)..(32)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(38)..(38)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(44)..(44)

<223>n为解锁核单体una-g

<220>

<221>misc_feature

<222>(50)..(50)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(56)..(56)

<223>n为解锁核单体una-g

<220>

<221>misc_feature

<222>(62)..(62)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(68)..(68)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(74)..(74)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(80)..(80)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(86)..(86)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(92)..(92)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(98)..(98)

<223>n为解锁核单体una-g

<220>

<221>misc_feature

<222>(104)..(104)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(110)..(110)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(116)..(116)

<223>n为解锁核单体una-g

<220>

<221>misc_feature

<222>(122)..(122)

<223>n为解锁核单体una-c

<220>

<221>misc_feature

<222>(128)..(128)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(134)..(134)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(140)..(140)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(146)..(146)

<223>n为解锁核单体una-a

<220>

<221>misc_feature

<222>(152)..(152)

<223>n为解锁核单体una-u

<220>

<221>misc_feature

<222>(157)..(157)

<223>n为解锁核单体una-a

<400>35

cnaguganugacunggaucngguuancacuanaccagncucaanaacacncgaaungagu60

cncuaagnuacaunauaccnacuuanacuuanaaaaunuugucncccaanauguanccau120

unguaucngcuccnaauaanaagaanguuucnucacnu158

<210>36

<211>158

<212>rna

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aaggaggugccccagaugugcauccccggcaagaucgaggagguggugcuggaggcccgg2340

accaucgagcggaacaccaagcccuaccggaaggacgagaacagcaucaacggcaccccc2400

gacaucaccguggagauccgggagcacauccagcugaacgagagcaagaucgugaagcag2460

gccggcguggccaccaagggccccaacgaguacauccaggagaucgaguucgagaaccug2520

agccccggcagcgugaucaucuuccgggugagccuggacccccacgcccagguggccgug2580

ggcauccugcggaaccaccugacccaguucagcccccacuucaagagcggcagccuggcc2640

guggacaacgccgaccccauccugaagauccccuucgccagccuggccagccggcugacc2700

cuggccgagcugaaccagauccuguaccggugcgagagcgaggagaaggaggacggcggc2760

ggcugcuacgacauccccaacuggagcgcccugaaguacgccggccugcagggccugaug2820

agcgugcuggccgagauccggcccaagaacgaccugggccaccccuucugcaacaaccug2880

cggagcggcgacuggaugaucgacuacgugagcaaccggcugaucagccggagcggcacc2940

aucgccgaggugggcaaguggcugcaggccauguucuucuaccugaagcagaucccccgg3000

uaccugauccccugcuacuucgacgccauccugaucggcgccuacaccacccugcuggac3060

accgccuggaagcagaugagcagcuucgugcagaacggcagcaccuucgugaagcaccug3120

agccugggcagcgugcagcugugcggcgugggcaaguuccccagccugcccauccugagc3180

cccgcccugauggacgugcccuaccggcugaacgagaucaccaaggagaaggagcagugc3240

ugcgugagccuggccgccggccugccccacuucagcagcggcaucuuccggugcuggggc3300

cgggacaccuucaucgcccugcggggcauccugcugaucaccggccgguacguggaggcc3360

cggaacaucauccuggccuucgccggcacccugcggcacggccugauccccaaccugcug3420

ggcgagggcaucuacgcccgguacaacugccgggacgccguguggugguggcugcagugc3480

auccaggacuacugcaagauggugcccaacggccuggacauccugaagugccccgugagc3540

cggauguaccccaccgacgacagcgccccccugcccgccggcacccuggaccagccccug3600

uucgaggugauccaggaggccaugcagaagcacaugcagggcauccaguuccgggagcgg3660

aacgccggcccccagaucgaccggaacaugaaggacgagggcuucaacaucaccgccggc3720

guggacgaggagaccggcuucguguacggcggcaaccgguucaacugcggcaccuggaug3780

gacaagaugggcgagagcgaccgggcccggaaccggggcauccccgccaccccccgggac3840

ggcagcgccguggagaucgugggccugagcaagagcgccgugcgguggcugcuggagcug3900

agcaagaagaacaucuuccccuaccacgaggugaccgugaagcggcacggcaaggccauc3960

aaggugagcuacgacgaguggaaccggaagauccaggacaacuucgagaagcuguuccac4020

gugagcgaggaccccagcgaccugaacgagaagcaccccaaccuggugcacaagcggggc4080

aucuacaaggacagcuacggcgccagcagccccuggugcgacuaccagcugcggcccaac4140

uucaccaucgccauggugguggcccccgagcuguucaccaccgagaaggccuggaaggcc4200

cuggagaucgccgagaagaagcugcugggcccccugggcaugaagacccuggaccccgac4260

gacaugguguacugcggcaucuacgacaacgcccuggacaacgacaacuacaaccuggcc4320

aagggcuucaacuaccaccagggccccgaguggcuguggcccaucggcuacuuccugcgg4380

gccaagcuguacuucagccggcugaugggccccgagaccaccgccaagaccaucgugcug4440

gugaagaacgugcugagccggcacuacgugcaccuggagcggagccccuggaagggccug4500

cccgagcugaccaacgagaacgcccaguacugccccuucagcugcgagacccaggccugg4560

agcaucgccaccauccuggagacccuguacgaccuguag4599

<210>42

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>42

augggccauagcaagcagauccggauccuccugcucaaugagauggaaaagcucgagaaa60

acccucuuuaggcuggagcaaggcuacgaacuccaguuucggcucgggcccacucuccag120

ggcaaggccgugaccgucuacaccaacuaucccuucccuggcgagaccuucaacagggag180

aaguuucggucccucgacugggagaaccccaccgagagggaggacgacuccgacaaguau240

ugcaagcugaaccuccaacaauccggguccuuccaguacuacuuucugcaaggcaacgaa300

aagagcgggggcggguauauuguggucgaucccauccuccgggugggggcugacaaccac360

guccucccccuggauugcgugacucugcagaccuuccucgcuaaaugccugggcccuuuc420

gacgagugggagagcaggcugcggguggccaaggaguccggguauaauaugauccacuuc480

accccccugcagacucugggccucucccgguccuguuauagccuggccaaccagcucgag540

cucaacccugauuucuccaggccuaacaggaaauacaccuggaacgacgugggccagcuc600

gucgagaagcucaagaaagaguggaacgugaucugcaucacugacguggucuauaaccac660

acugcugcuaacagcaaguggauucaggagcaccccgagugcgccuacaaccuggucaac720

uccccccaucucaagccugccuggguccucgauagggcccuguggcgguuuagcugcgac780

guggccgagggcaaguauaaggagaaaggcauuccugcucugaucgagaacgaccaucac840

augaacagcauucggaagauuaucugggaagacaucuuccccaaacugaagcucugggag900

uucuuucaagucgacgucaauaaggcuguggaacaauucaggaggcugcugacccaagag960

aaccggcgggucaccaaauccgaccccaaucaacaucugacuaucauccaagacccugag1020

uauaggcgguucgggugcacugucgacaugaauaucgcccucacuacuuuuauuccccac1080

gauaaaggccccgccgccaucgaggaguguugcaacugguuccacaagaggauggaagag1140

cucaacuccgaaaaacaccggcucaucaauuaccaccaggagcaggccgugaacugucug1200

cugggcaacgucuucuacgagcggcucgcugggcacgggcccaagcucggcccugucacu1260

aggaaacacccucucgugacccgguacuucacuuuucccuucgaggaaauugauuuuagc1320

auggaggaguccaugauccaccuccccaacaaggcuugcuuccucauggcccauaacggc1380

ugggucaugggcgacgacccucugcggaauuucgcugagcccggguccgagguguaucuc1440

cggagggagcugaucuguuggggcgauagcgugaagcuccgguacggcaacaagcccgaa1500

gauugcccuuaccucugggcccauaugaagaaguauacugagauuacugccacuuacuuu1560

cagggcguccggcuggacaauugucauuccaccccucugcaugucgcugaauauaugcug1620

gacgcugcucggaaccugcaacccaaccucuacgucgucgcugagcucuuuaccggcagc1680

gaggaccucgauaacgucuucgugacuaggcucgggaucagcagccucauuagggaagcc1740

augagcgccuacaacagccacgaggaagggaggcucguguaucgguacggcggcgagccu1800

gugggcagcuucgugcagcccugccugcggccucucaugcccgcuaucgcccacgcccuc1860

uucauggacaucacucacgacaacgaaugcccuaucguccacagguccgcuuacgacgcu1920

cugcccagcacuaccaucguguccauggccugcugcgcuagcggcagcaccaggggguac1980

gacgagcucgucccucaccagaucuccgucguguccgaggagcgguucuauacuaaaugg2040

aacccugaggcccugccuuccaauaccggggaggugaacuuucaaagcgggaucaucgcc2100

gcccggugcgcuauuagcaagcugcaccaggaacugggcgccaaaggguucauccagguc2160

uacgucgaccaaguggacgaggauauugucgccgucaccaggcauuccccuagcauucac2220

caguccguggucgcugucuccaggacugcuuuucggaaccccaaaacuuccuucuauagc2280

aaagaggucccucaaauguguauuccugggaagaucgaggaggucgugcuggaggcuagg2340

acuaucgaaaggaauacuaagccuuaccggaaagacgaaaacuccauuaacggcaccccc2400

gacauuaccgucgagaucagggagcacauccagcugaacgagagcaagaucgugaagcaa2460

gcuggcguggccaccaagggccccaacgaguacauccaagagauugaguucgagaaucug2520

ucccccggcagcgugaucauuuuuagggugagccuggacccccacgcccaagucgcugug2580

ggcauccugcggaaccaccucacccaauuuagcccucauuucaaguccgggagccucgcu2640

guggauaacgccgacccuauucucaagaucccuuucgcuucccuggccagcaggcucacu2700

cuggcugaacucaaccagauucuguaucggugcgaguccgaggagaaagaggacgggggc2760

ggcuguuacgauauucccaauugguccgcccugaaguacgccgggcugcaagggcucaug2820

uccguccuggccgagauuaggcccaaaaacgaucugggccacccuuucugcaacaaccug2880

agguccggcgacuggaugaucgauuacgucagcaaucggcugaucucccgguccggcacu2940

aucgcugagguggggaaguggcugcaggcuauguuuuuuuaucucaaacagauuccccgg3000

uaucugauucccugcuauuucgacgcuauucucaucggggccuacaccacucugcucgac3060

accgccuggaaacagauguccagcuucgugcagaacggguccaccuucgucaagcaucug3120

ucccugggguccgugcaacucugcggcgucggcaaguuuccuagccuccccauccugucc3180

ccugcccucauggacgucccuuaccggcucaacgaaauuaccaaggagaaagaacaaugc3240

ugcgugucccucgcugccgggcucccucacuucuccuccgggaucuuucgguguuggggc3300

cgggacacuuucaucgcccugagggggauucuccucaucacuggccgguacgucgaggcc3360

cggaacaucauccucgccuucgcugggacccuccggcacgggcucaucccuaaccuccuc3420

ggggagggcaucuacgccagguauaacugccgggacgcugucuggugguggcuccagugc3480

auucaggacuauugcaagauggugcccaacgggcucgauauccucaaaugucccgugagc3540

aggauguacccuaccgacgacuccgcuccucugccugcugggacccucgaccagccccug3600

uucgaggucauucaggaggccaugcaaaagcauaugcaggggauucaguuucgggagcgg3660

aacgcugggccccagauugaccggaauaugaaagaugagggguucaacauuacugccggc3720

guggacgaggagaccggcuucguguacggcggcaaccgguuuaacugcgggaccuggaug3780

gacaagaugggcgagagcgauagggcuaggaauaggggcauucccgccacccccagggac3840

ggcuccgcugucgagaucgucgggcucagcaaguccgcugugcgguggcugcucgagcuc3900

agcaagaagaacaucuuuccuuaccacgaggucaccgucaagaggcacggcaaagcuauu3960

aaagucuccuacgacgaauggaauaggaagauucaagauaauuucgagaaacucuuccac4020

gugagcgaggauccuuccgaccucaacgagaaacaccccaaccucgugcauaagcggggg4080

auuuauaaggacagcuacggcgcuuccagcccuuggugcgauuaccagcuccggccuaac4140

uucaccauugccaugguggucgccccugaacucuucacuaccgagaaggccuggaaggcu4200

cuggaaaucgccgagaagaagcugcuggggccccuggggaugaagacucucgaccccgac4260

gacaugguguauugcggcaucuacgauaacgcccucgauaacgauaauuauaaccuggcu4320

aagggguuuaacuaccaucaaggcccugaauggcucuggccuaucggcuacuuccugcgg4380

gccaagcucuacuucagcaggcugauggggcccgaaacuacugccaaaacuauugugcug4440

gugaagaacgugcugagccggcacuacgugcaccuggaaaggagcccuuggaagggccug4500

cccgagcucaccaacgaaaacgcccaguauugcccuuuuagcugcgagacccaagccugg4560

uccaucgcuacuauccuggaaacccuguacgaccucuag4599

<210>43

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>43

auggggcacagcaaacaaaucaggauccuccuccucaacgaaauggaaaaacucgaaaaa60

acccucuucaggcucgaacaaggguacgaacuccaauucaggcucgggccgacgcuccaa120

gggaaagcggugacgguguacacgaacuacccguucccgggggaaacguucaacagggaa180

aaauucaggagccucgacugggaaaacccgacggaaagggaagacgacagcgacaaauac240

ugcaaacucaaccuccaacaaagcgggagcuuccaauacuacuuccuccaagggaacgaa300

aaaagcggggggggguacaucgugguggacccgauccucagggugggggcggacaaccac360

gugcucccgcucgacugcgugacgcuccaaacguuccucgcgaaaugccucgggccguuc420

gacgaaugggaaagcaggcucaggguggcgaaagaaagcggguacaacaugauccacuuc480

acgccgcuccaaacgcucgggcucagcaggagcugcuacagccucgcgaaccaacucgaa540

cucaacccggacuucagcaggccgaacaggaaauacacguggaacgacguggggcaacuc600

guggaaaaacucaaaaaagaauggaacgugaucugcaucacggacgugguguacaaccac660

acggcggcgaacagcaaauggauccaagaacacccggaaugcgcguacaaccucgugaac720

agcccgcaccucaaaccggcgugggugcucgacagggcgcucuggagguucagcugcgac780

guggcggaagggaaauacaaagaaaaagggaucccggcgcucaucgaaaacgaccaccac840

augaacagcaucaggaaaaucaucugggaagacaucuucccgaaacucaaacucugggaa900

uucuuccaaguggacgugaacaaagcgguggaacaauucaggaggcuccucacgcaagaa960

aacaggagggugacgaaaagcgacccgaaccaacaccucacgaucauccaagacccggaa1020

uacaggagguucgggugcacgguggacaugaacaucgcgcucacgacguucaucccgcac1080

gacaaagggccggcggcgaucgaagaaugcugcaacugguuccacaaaaggauggaagaa1140

cucaacagcgaaaaacacaggcucaucaacuaccaccaagaacaagcggugaacugccuc1200

cucgggaacguguucuacgaaaggcucgcggggcacgggccgaaacucgggccggugacg1260

aggaaacacccgcucgugacgagguacuucacguucccguucgaagaaaucgacuucagc1320

auggaagaaagcaugauccaccucccgaacaaagcgugcuuccucauggcgcacaacggg1380

ugggugaugggggacgacccgcucaggaacuucgcggaaccggggagcgaaguguaccuc1440

aggagggaacucaucugcuggggggacagcgugaaacucagguacgggaacaaaccggaa1500

gacugcccguaccucugggcgcacaugaaaaaauacacggaaaucacggcgacguacuuc1560

caaggggugaggcucgacaacugccacagcacgccgcuccacguggcggaauacaugcuc1620

gacgcggcgaggaaccuccaaccgaaccucuacgugguggcggaacucuucacggggagc1680

gaagaccucgacaacguguucgugacgaggcucgggaucagcagccucaucagggaagcg1740

augagcgcguacaacagccacgaagaagggaggcucguguacagguacgggggggaaccg1800

guggggagcuucgugcaaccgugccucaggccgcucaugccggcgaucgcgcacgcgcug1860

uucauggacaucacgcacgacaacgaaugcccgaucgugcacaggagcgcguacgacgcg1920

cucccgagcacgacgaucgugagcauggcgugcugcgcgagcgggagcacgaggggguac1980

gacgaacucgugccgcaccaaaucagcguggugagcgaagaaagguucuacacgaaaugg2040

aacccggaagcgcucccgagcaacacgggggaagugaacuuccaaagcgggaucaucgcg2100

gcgaggugcgcgaucagcaaacuccaccaagaacucggggcgaaaggguucauccaagug2160

uacguggaccaaguggacgaagacaucguggcggugacgaggcacagcccgagcauccac2220

caaagcgugguggcggugagcaggacggcguucaggaacccgaaaacgagcuucuacagc2280

aaagaagugccgcaaaugugcaucccggggaaaaucgaagaaguggugcucgaagcgagg2340

acgaucgaaaggaacacgaaaccguacaggaaagacgaaaacagcaucaacgggacgccg2400

gacaucacgguggaaaucagggaacacauccaacucaacgaaagcaaaaucgugaaacaa2460

gcggggguggcgacgaaagggccgaacgaauacauccaagaaaucgaauucgaaaaccuc2520

agcccggggagcgugaucaucuucagggugagccucgacccgcacgcgcaaguggcggug2580

gggauccucaggaaccaccucacgcaauucagcccgcacuucaaaagcgggagccucgcg2640

guggacaacgcggacccgauccucaaaaucccguucgcgagccucgcgagcaggcucacg2700

cucgcggaacucaaccaaauccucuacaggugcgaaagcgaagaaaaagaagacgggggg2760

gggugcuacgacaucccgaacuggagcgcgcucaaauacgcggggcuccaagggcucaug2820

agcgugcucgcggaaaucaggccgaaaaacgaccucgggcacccguucugcaacaaccuc2880

aggagcggggacuggaugaucgacuacgugagcaacaggcucaucagcaggagcgggacg2940

aucgcggaaguggggaaauggcuccaagcgauguucuucuaccucaaacaaaucccgagg3000

uaccucaucccgugcuacuucgacgcgauccucaucggggcguacacgacgcuccucgac3060

acggcguggaaacaaaugagcagcuucgugcaaaacgggagcacguucgugaaacaccuc3120

agccucgggagcgugcaacucugcgggguggggaaauucccgagccucccgauccucagc3180

ccggcgcucauggacgugccguacaggcucaacgaaaucacgaaagaaaaagaacaaugc3240

ugcgugagccucgcggcggggcucccgcacuucagcagcgggaucuucaggugcuggggg3300

agggacacguucaucgcgcucagggggauccuccucaucacggggagguacguggaagcg3360

aggaacaucauccucgcguucgcggggacgcucaggcacgggcucaucccgaaccuccuc3420

ggggaagggaucuacgcgagguacaacugcagggacgcgguguggugguggcuccaaugc3480

auccaagacuacugcaaaauggugccgaacgggcucgacauccucaaaugcccggugagc3540

aggauguacccgacggacgacagcgcgccgcucccggcggggacgcucgaccaaccgcug3600

uucgaagugauccaagaagcgaugcaaaaacacaugcaagggauccaauucagggaaagg3660

aacgcggggccgcaaaucgacaggaacaugaaagacgaaggguucaacaucacggcgggg3720

guggacgaagaaacgggguucguguacggggggaacagguucaacugcgggacguggaug3780

gacaaaaugggggaaagcgacagggcgaggaacagggggaucccggcgacgccgagggac3840

gggagcgcgguggaaaucguggggcucagcaaaagcgcggugagguggcuccucgaacuc3900

agcaaaaaaaacaucuucccguaccacgaagugacggugaaaaggcacgggaaagcgauc3960

aaagugagcuacgacgaauggaacaggaaaauccaagacaacuucgaaaaacucuuccac4020

gugagcgaagacccgagcgaccucaacgaaaaacacccgaaccucgugcacaaaaggggg4080

aucuacaaagacagcuacggggcgagcagcccguggugcgacuaccaacucaggccgaac4140

uucacgaucgcgauggugguggcgccggaacucuucacgacggaaaaagcguggaaagcg4200

cucgaaaucgcggaaaaaaaacuccucgggccgcucgggaugaaaacgcucgacccggac4260

gacaugguguacugcgggaucuacgacaacgcgcucgacaacgacaacuacaaccucgcg4320

aaaggguucaacuaccaccaagggccggaauggcucuggccgaucggguacuuccucagg4380

gcgaaacucuacuucagcaggcucauggggccggaaacgacggcgaaaacgaucgugcuc4440

gugaaaaacgugcucagcaggcacuacgugcaccucgaaaggagcccguggaaagggcuc4500

ccggaacucacgaacgaaaacgcgcaauacugcccguucagcugcgaaacgcaagcgugg4560

agcaucgcgacgauccucgaaacgcucuacgaccucuga4599

<210>44

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>44

augggccacagcaagcagaucaggauccuccuccucaacgaaauggaaaagcucgaaaag60

acacucuucaggcucgaacagggcuacgaacuccaguucaggcucggcccaacacuccag120

ggcaaggccgugacaguguacacaaacuacccauucccaggcgaaacauucaacagggaa180

aaguucaggagccucgacugggaaaacccaacagaaagggaagacgacagcgacaaguac240

ugcaagcucaaccuccagcagagcggcagcuuccaguacuacuuccuccagggcaacgaa300

aagagcggcggcggcuacaucgugguggacccaauccucagggugggcgccgacaaccac360

gugcucccacucgacugcgugacacuccagacauuccucgccaagugccucggcccauuc420

gacgaaugggaaagcaggcucaggguggccaaggaaagcggcuacaacaugauccacuuc480

acaccacuccagacacucggccucagcaggagcugcuacagccucgccaaccagcucgaa540

cucaacccagacuucagcaggccaaacaggaaguacacauggaacgacgugggccagcuc600

guggaaaagcucaagaaggaauggaacgugaucugcaucacagacgugguguacaaccac660

acagccgccaacagcaaguggauccaggaacacccagaaugcgccuacaaccucgugaac720

agcccacaccucaagccagccugggugcucgacagggcccucuggagguucagcugcgac780

guggccgaaggcaaguacaaggaaaagggcaucccagcccucaucgaaaacgaccaccac840

augaacagcaucaggaagaucaucugggaagacaucuucccaaagcucaagcucugggaa900

uucuuccagguggacgugaacaaggccguggaacaguucaggaggcuccucacacaggaa960

aacaggagggugacaaagagcgacccaaaccagcaccucacaaucauccaggacccagaa1020

uacaggagguucggcugcacaguggacaugaacaucgcccucacaacauucaucccacac1080

gacaagggcccagccgccaucgaagaaugcugcaacugguuccacaagaggauggaagaa1140

cucaacagcgaaaagcacaggcucaucaacuaccaccaggaacaggccgugaacugccuc1200

cucggcaacguguucuacgaaaggcucgccggccacggcccaaagcucggcccagugaca1260

aggaagcacccacucgugacaagguacuucacauucccauucgaagaaaucgacuucagc1320

auggaagaaagcaugauccaccucccaaacaaggccugcuuccucauggcccacaacggc1380

ugggugaugggcgacgacccacucaggaacuucgccgaaccaggcagcgaaguguaccuc1440

aggagggaacucaucugcuggggcgacagcgugaagcucagguacggcaacaagccagaa1500

gacugcccauaccucugggcccacaugaagaaguacacagaaaucacagccacauacuuc1560

cagggcgugaggcucgacaacugccacagcacaccacuccacguggccgaauacaugcuc1620

gacgccgccaggaaccuccagccaaaccucuacgugguggccgaacucuucacaggcagc1680

gaagaccucgacaacguguucgugacaaggcucggcaucagcagccucaucagggaagcc1740

augagcgccuacaacagccacgaagaaggcaggcucguguacagguacggcggcgaacca1800

gugggcagcuucgugcagccaugccucaggccacucaugccagccaucgcccacgcccuc1860

uucauggacaucacacacgacaacgaaugcccaaucgugcacaggagcgccuacgacgcc1920

cucccaagcacaacaaucgugagcauggccugcugcgccagcggcagcacaaggggcuac1980

gacgaacucgugccacaccagaucagcguggugagcgaagaaagguucuacacaaagugg2040

aacccagaagcccucccaagcaacacaggcgaagugaacuuccagagcggcaucaucgcc2100

gccaggugcgccaucagcaagcuccaccaggaacucggcgccaagggcuucauccaggug2160

uacguggaccagguggacgaagacaucguggccgugacaaggcacagcccaagcauccac2220

cagagcgugguggccgugagcaggacagccuucaggaacccaaagacaagcuucuacagc2280

aaggaagugccacagaugugcaucccaggcaagaucgaagaaguggugcucgaagccagg2340

acaaucgaaaggaacacaaagccauacaggaaggacgaaaacagcaucaacggcacacca2400

gacaucacaguggaaaucagggaacacauccagcucaacgaaagcaagaucgugaagcag2460

gccggcguggccacaaagggcccaaacgaauacauccaggaaaucgaauucgaaaaccuc2520

agcccaggcagcgugaucaucuucagggugagccucgacccacacgcccagguggccgug2580

ggcauccucaggaaccaccucacacaguucagcccacacuucaagagcggcagccucgcc2640

guggacaacgccgacccaauccucaagaucccauucgccagccucgccagcaggcucaca2700

cucgccgaacucaaccagauccucuacaggugcgaaagcgaagaaaaggaagacggcggc2760

ggcugcuacgacaucccaaacuggagcgcccucaaguacgccggccuccagggccucaug2820

agcgugcucgccgaaaucaggccaaagaacgaccucggccacccauucugcaacaaccuc2880

aggagcggcgacuggaugaucgacuacgugagcaacaggcucaucagcaggagcggcaca2940

aucgccgaagugggcaaguggcuccaggccauguucuucuaccucaagcagaucccaagg3000

uaccucaucccaugcuacuucgacgccauccucaucggcgccuacacaacacuccucgac3060

acagccuggaagcagaugagcagcuucgugcagaacggcagcacauucgugaagcaccuc3120

agccucggcagcgugcagcucugcggcgugggcaaguucccaagccucccaauccucagc3180

ccagcccucauggacgugccauacaggcucaacgaaaucacaaaggaaaaggaacagugc3240

ugcgugagccucgccgccggccucccacacuucagcagcggcaucuucaggugcuggggc3300

agggacacauucaucgcccucaggggcauccuccucaucacaggcagguacguggaagcc3360

aggaacaucauccucgccuucgccggcacacucaggcacggccucaucccaaaccuccuc3420

ggcgaaggcaucuacgccagguacaacugcagggacgccguguggugguggcuccagugc3480

auccaggacuacugcaagauggugccaaacggccucgacauccucaagugcccagugagc3540

aggauguacccaacagacgacagcgccccacucccagccggcacacucgaccagccacuc3600

uucgaagugauccaggaagccaugcagaagcacaugcagggcauccaguucagggaaagg3660

aacgccggcccacagaucgacaggaacaugaaggacgaaggcuucaacaucacagccggc3720

guggacgaagaaacaggcuucguguacggcggcaacagguucaacugcggcacauggaug3780

gacaagaugggcgaaagcgacagggccaggaacaggggcaucccagccacaccaagggac3840

ggcagcgccguggaaaucgugggccucagcaagagcgccgugagguggcuccucgaacuc3900

agcaagaagaacaucuucccauaccacgaagugacagugaagaggcacggcaaggccauc3960

aaggugagcuacgacgaauggaacaggaagauccaggacaacuucgaaaagcuguuccac4020

gugagcgaagacccaagcgaccucaacgaaaagcacccaaaccucgugcacaagaggggc4080

aucuacaaggacagcuacggcgccagcagcccauggugcgacuaccagcucaggccaaac4140

uucacaaucgccauggugguggccccagaacucuucacaacagaaaaggccuggaaggcc4200

cucgaaaucgccgaaaagaagcuccucggcccacucggcaugaagacacucgacccagac4260

gacaugguguacugcggcaucuacgacaacgcccucgacaacgacaacuacaaccucgcc4320

aagggcuucaacuaccaccagggcccagaauggcucuggccaaucggcuacuuccucagg4380

gccaagcucuacuucagcaggcucaugggcccagaaacaacagccaagacaaucgugcuc4440

gugaagaacgugcucagcaggcacuacgugcaccucgaaaggagcccauggaagggccuc4500

ccagaacucacaaacgaaaacgcccaguacugcccauucagcugcgaaacacaggccugg4560

agcaucgccacaauccucgaaacacucuacgaccucuga4599

<210>45

<211>4599

<212>rna

<213>patentin版本3.5

<220>

<223>密码子优化的agl编码序列

<400>45

augggccacagcaagcagauccggaucuugcugcugaacgagauggagaagcuggagaag60

acccuguucaggcuggagcagggcuacgagcugcaguuccgguugggccccaccuugcag120

ggcaaggccgugaccguguacaccaacuaccccuuccccggcgagacguucaacagggag180

aaguuccggucccuggacugggagaaccccaccgagagggaggacgacuccgacaaguac240

ugcaagcugaaccugcagcaguccggcuccuuccaguacuacuuccugcagggcaacgag300

aagaguggcggcggcuacaucgugguggaccccaucuugcgggugggcgccgacaaccac360

gugcugcccuuggacugcgugacccugcagaccuucuuggccaagugcuugggccccuuc420

gacgagugggagagcaggcugaggguggccaaggaguccggcuacaacaugauccacuuc480

acccccuugcagacccugggccuguccagguccugcuacucccuggccaaccaguuggag540

uugaaccccgacuucuccaggcccaacaggaaguacaccuggaacgacgugggccagcug600

guggagaaguugaagaaggaguggaacgugaucugcaucaccgacgugguguacaaccac660

accgccgccaacagcaaguggauccaggagcaccccgagugcgccuacaaccuggugaac720

uccccccacuugaagcccgccuggguguuggacagggcccuguggcgguucuccugcgac780

guggccgagggcaaguacaaggagaagggcauccccgccuugaucgagaacgaccaccac840

augaacuccauccggaagaucaucugggaggacaucuuccccaagcugaagcugugggag900

uucuuccagguggacgugaacaaggccguggagcaguucaggaggcugcugacccaggag960

aacaggcgggugaccaaguccgaccccaaccagcaccugaccaucauccaggaccccgag1020

uacaggcgguucggcugcaccguggacaugaacaucgcccugaccaccuucaucccccac1080

gacaagggccccgccgccaucgaggagugcugcaacugguuccacaagaggauggaggag1140

uugaacuccgagaagcaccggcugaucaacuaccaccaggagcaggccgugaacugccug1200

uugggcaacguguucuacgagcggcuggccggccacggccccaagcugggccccgugacc1260

aggaagcaccccuuggugaccagguacuucaccuuccccuucgaggagaucgacuucucc1320

auggaggaguccaugauccaccugcccaacaaggccugcuuccugauggcccacaacggc1380

ugggugaugggcgacgacccccugcggaacuucgccgagcccggcuccgagguguaccug1440

aggagggagcugaucugcuggggcgacagcgugaaguugcgguacggcaacaagcccgag1500

gacugccccuaccugugggcccacaugaagaaguacaccgagaucaccgccaccuacuuc1560

cagggcgugcggcuggacaacugccacuccaccccccugcacguggccgaguacauguug1620

gacgccgccaggaacuugcagcccaacuuguacgugguggccgagcuguucaccggcagc1680

gaggaccuggacaacguguucgugaccaggcugggcaucagcuccuugaucagggaggcc1740

augagcgccuacaacagccacgaggagggcagguugguguaccgguacggcggcgagccc1800

gugggcuccuucgugcagcccugcuugaggcccuugaugcccgccaucgcccacgcccug1860

uucauggacaucacccacgacaacgagugccccaucgugcacagguccgccuacgacgcc1920

cugcccagcaccaccaucguguccauggccugcugcgccagcggcagcaccaggggcuac1980

gacgaguuggugccccaccagaucuccgugguguccgaggagcgguucuacaccaagugg2040

aaccccgaggccuugcccuccaacaccggcgaggugaacuuccagagcggcaucaucgcc2100

gccaggugcgccaucagcaagcugcaccaggagcugggcgccaagggcuucauccaggug2160

uacguggaccagguggacgaggacaucguggccgugaccaggcacucccccagcauccac2220

caguccgugguggccguguccaggaccgccuucaggaaccccaagaccuccuucuacagc2280

aaggaggugccccagaugugcauccccggcaagaucgaggagguggugcuggaggccagg2340

accaucgagaggaacaccaagcccuacaggaaggacgagaacuccaucaacggcaccccc2400

gacaucaccguggagaucagggagcacauccagcugaacgagagcaagaucgugaagcag2460

gccggcguggccaccaagggccccaacgaguacauccaggagaucgaguucgagaacuug2520

ucccccggcagcgugaucaucuucagggugagccuggacccccacgcccagguggccgug2580

ggcauccugcggaaccaccugacccaguucagcccccacuucaaguccggcagccuggcc2640

guggacaacgccgaccccaucuugaagauccccuucgccucccuggccuccagguugacc2700

uuggccgagcugaaccagauccuguaccggugcgaguccgaggagaaggaggacggcggc2760

ggcugcuacgacauccccaacugguccgcccugaaguacgccggccugcagggcuugaug2820

uccguguuggccgagaucaggcccaagaacgacuugggccaccccuucugcaacaacuug2880

agguccggcgacuggaugaucgacuacgugagcaaccggcugaucucccgguccggcacc2940

aucgccgaggugggcaagugguugcaggccauguucuucuaccugaagcagaucccccgg3000

uaccugauccccugcuacuucgacgccaucuugaucggcgccuacaccacccugcuggac3060

accgccuggaagcagauguccagcuucgugcagaacggcuccaccuucgugaagcaccug3120

uccuugggcuccgugcagcugugcggcgugggcaaguuccccucccugcccauccugucc3180

cccgcccugauggacgugcccuacagguugaacgagaucaccaaggagaaggagcagugc3240

ugcgugucccuggccgccggcuugccccacuucuccuccggcaucuuccggugcuggggc3300

agggacaccuucaucgcccugaggggcauccugcugaucaccggccgguacguggaggcc3360

aggaacaucaucuuggccuucgccggcacccugaggcacggccugauccccaaccugcug3420

ggcgagggcaucuacgccagguacaacugccgggacgccguguggugguggcugcagugc3480

auccaggacuacugcaagauggugcccaacggccuggacauccugaagugccccgugucc3540

aggauguaccccaccgacgacuccgcccccuugcccgccggcacccuggaccagcccuug3600

uucgaggugauccaggaggccaugcagaagcacaugcagggcauccaguuccgggagagg3660

aacgccggcccccagaucgaccggaacaugaaggacgagggcuucaacaucaccgccggc3720

guggacgaggagacuggcuucguguacggcggcaaccgguucaacugcggcaccuggaug3780

gacaagaugggcgagagcgacagggccaggaacaggggcauccccgccacccccagggac3840

ggcuccgccguggagaucgugggccugagcaaguccgccgugcggugguugcuggaguug3900

uccaagaagaacaucuuccccuaccacgaggugaccgugaagaggcacggcaaggccauc3960

aagguguccuacgacgaguggaacaggaagauccaggacaacuucgagaagcuguuccac4020

guguccgaggaccccuccgacuugaacgagaagcaccccaaccuggugcacaagcggggc4080

aucuacaaggacagcuacggcgccuccagccccuggugcgacuaccagcugaggcccaac4140

uucaccaucgccauggugguggcccccgagcuguucaccaccgagaaggccuggaaggcc4200

uuggagaucgccgagaagaaguugcugggcccccugggcaugaagaccuuggaccccgac4260

gacaugguguacugcggcaucuacgacaacgccuuggacaacgacaacuacaaccuggcc4320

aagggcuucaacuaccaccagggccccgaguggcuguggcccaucggcuacuuccugcgg4380

gccaaguuguacuucuccagguugaugggccccgagacgaccgccaagaccaucguguug4440

gugaagaacgugcugucccggcacuacgugcaccuggagaggucccccuggaagggccug4500

cccgagcugaccaacgagaacgcccaguacugccccuucagcugcgagacgcaggccugg4560

uccaucgccaccauccuggagacgcuguacgacuuguag4599