CN112119159A - micro-RNA和肥胖 - Google Patents

micro-RNA和肥胖 Download PDF

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CN112119159A
CN112119159A CN201980032204.4A CN201980032204A CN112119159A CN 112119159 A CN112119159 A CN 112119159A CN 201980032204 A CN201980032204 A CN 201980032204A CN 112119159 A CN112119159 A CN 112119159A
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P·P·潘多雷尔
R·潘内拉
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Beth Israel Deaconess Medical Center Inc
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Abstract

本公开提供了一种通过施用抑制调节代谢的microRNA的活性的试剂来治疗或预防代谢失调的方法。

Description

micro-RNA和肥胖
优先权
本申请要求2018年3月14日提交的美国临时申请号为62/642,934的权益和优先权，其内容通过引用以其全文并入本文。
技术领域
本公开涉及通过施用调节microRNA的活性或表达的试剂来治疗和预防代谢失调。
电子提交的文本文件的说明
一并电子提交的文本文件的内容通过引用以其全文并入本文：序列表的计算机可读格式副本(文件名：BID-005PC1_ST25.txt；创建日期：2019年3月14日；文件大小：323,976字节)。
背景技术
microRNA(miRNA或miR)是调节靶基因表达的核酸分子。miRNA通常是短的(通常为18至24个核苷酸)；并且，当miRNA和其靶mRNA的序列完全互补时，miRNA通过促进靶mRNA的降解来充当其阻遏物，和/或当miRNA含有错配时，miRNA通过抑制翻译来充当靶mRNA的阻遏物。miRNA的功能分析已显示，这些小的非编码RNA有助于不同的生理和代谢过程，包括调节与代谢失调有关的基因。代谢失调的特征在于体内代谢功能的一种或多种异常。代谢失调的特征还在于肥胖和体重增加、胰岛素产生不足或对胰岛素的敏感性不足。一些代谢失调与人体的血糖使用缺陷有关，导致异常的高血糖水平。代谢失调影响全球数百万人，并且可能是威胁生命的病症。随着肥胖的发病率在美国上升，迫切需要开发更有效的疗法以减少健康风险并减轻与肥胖、暴食、过度的体重增加或过度的脂肪积聚有关的症状。如此，需要方法和组合物以治疗、预防代谢失调或延迟其发作。
发明概述
本公开提供了一种通过施用调节microRNA的活性或表达，例如通过抑制microRNA的表达和/或活性的试剂，来治疗或预防代谢失调的新方法。这种抑制可以由序列特异的化学修饰的寡核苷酸，包括例如锁核酸(LNA)介导。基于LNA技术的抑制剂在针对本文公开的调节代谢基因的miRNA时，提供了治疗或预防代谢失调的有效方法。
在一个方面，本公开提供了一种用于治疗或预防代谢失调的方法，该方法包括施用有效量的miR-22的抑制剂给有此需要的受试者。
在一些实施方案中，在施用抑制剂后受试者中miR-22的表达和/或活性降低。
在一些实施方案中，miR-22的抑制剂是基于寡核苷酸的抑制剂。在一些实施方案中，基于寡核苷酸的抑制剂包含与miR-22的成熟序列为至少约75％、约80％、约85％、约90％、约95％、约96％、约97％、约98％、约99％或约100％互补的序列。在一些实施方案中，基于寡核苷酸的抑制剂包含脱氧核苷酸或核糖核苷酸。在一些实施方案中，基于寡核苷酸的抑制剂是单链的。在一些实施方案中，其中基于寡核苷酸的抑制剂是双链的。
在一些实施方案中，基于寡核苷酸的抑制剂包含一个或多个化学修饰的核苷酸。
在一些实施方案中，化学修饰的核苷酸是锁核苷酸(LNA)。
在一些实施方案中，基于寡核苷酸的抑制剂包含约25个、约20个、约15个、约10个、约9个、约8个、约7个、约6个或约5个或更少个核苷酸。在一些实施方案中，基于寡核苷酸的抑制剂与一个或多个N-乙酰半乳糖胺(GalNAc)部分结合。
在一些实施方案中，基于寡核苷酸的抑制剂是反义寡核苷酸抑制剂。在一些实施方案中，基于寡核苷酸的抑制剂是小分子干扰RNA(siRNA)。在一些实施方案中，基于寡核苷酸的抑制剂是适体。
在一些实施方案中，miR-22的抑制剂是基于肽或基于蛋白的抑制剂。在一些实施方案中，基于蛋白的抑制剂是抗体或其抗原结合部分。在一些实施方案中，miR-22的抑制剂是基于小分子的抑制剂。
在一些实施方案中，代谢失调是肥胖症。
在一些实施方案中，受试者患有普拉德-威利综合征(Prader-Willi Syndrome)。
在一些实施方案中，受试者患有高胆固醇血症。
在一些实施方案中，受试者具有脂肪量和肥胖相关蛋白(FTO)变体，和/或显示FTO表达和/或活性的上调。
在一些实施方案中，受试者是肥胖的，并且具有大于约30的体重指数。在一些实施方案中，受试者是超重的，并且具有约25-29.9的体重指数。
在一些实施方案中，该方法引起体重减轻。在一些实施方案中，该方法在受试者中引起约1％、约5％、约10％、约15％、约20％或约25％或更多的总体重减轻。在一些实施方案中，该方法防止体重增加。
在一些实施方案中，该方法减少或防止脂肪组织生长。在一些实施方案中，该方法破坏脂肪细胞分化。
在一些实施方案中，代谢失调是脂肪肝疾病。在一些实施方案中，该脂肪肝疾病选自非酒精性脂肪酸肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)。在一些实施方案中，该方法减少或预防肝脂肪变性。
在一些实施方案中，该方法减少或预防肝纤维化。
在一些实施方案中，该方法降低FTO、ALKB同源蛋白5(ALKBH5)、CCAAT/增强子结合蛋白α(CEBPα)、过氧化物酶体增殖物活化受体γ(PPARγ)和/或ATP柠檬酸裂解酶(ACLY)的活性和/或表达。
在一些实施方案中，该方法增加磷酸酶和张力蛋白同源蛋白(PTEN)和/或tet甲基胞嘧啶双加氧酶2(TET2)的活性和/或表达。
在一些实施方案中，该方法改变PPARγ共激活因子-α(PGC1-α)、特异性蛋白1(SP1)、成纤维细胞生长因子21(FGF-21)、解偶联蛋白1(UCP1)、DNA损伤诱导转录物4(DDIT-4，REDD1)、肿瘤蛋白p63(TP63)、成纤维细胞生长因子1(FGF1)和/或甲基转移酶样蛋白3(METTL3)的活性和/或表达。在一些实施方案中，该方法改变DNA或RNA甲基化的水平，或在RNA水平上影响m6A水平。
本文所述的任何方面或实施方案均可与本文公开的任何其他方面或实施方案组合。
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图1A-C的示意图显示了miR-22的调节谱图。图1A的示意图显示了miR-22在非编码转录物MGC14376的第3外显子中的位置。图1B显示了靶向PTEN的miRNA，图1C显示了miR-22直接靶向PTEN和TET以促进肿瘤发生和转移。
图2A-D显示了miR-22的过表达影响小鼠体重。图2A的照片显示了野生型(WT)和转基因(Tg)小鼠的喂食方案。图2B是WT肝和miR-22Tg小鼠肝的免疫组织化学染色。图2C的图显示了WT的平均重量与miR-22Tg小鼠的平均重量的比较，图2D的条形图显示了WT和miR-22Tg小鼠群体(colony)的平均重量。这些数据表明miR-22的过表达影响小鼠体重。每对数据中右侧条(红色)的数据为miR-2Tg小鼠的数据。
图3A-C是一对条形图和一个线性图，其显示了miR-22null小鼠在高脂饮食(HFD)下没有体重增加。图3A显示了在HFD下2周后整个群体的体重增加百分比，图3B显示了在HFD下4周后整个群体的体重增加百分比。图3C显示了自HFD开始第1周至第8周，KO和WT的克数变化的比较。
图4A-F的一系列条形图显示了miR-22null小鼠在HFD下没有体重增加。图4A显示了在HFD下2周后雌性小鼠的体重增加百分比。图4B显示了在HFD下4周后雌性小鼠的体重增加百分比。图4C显示了在HFD下8周后雌性小鼠的体重增加百分比。图4D显示了2周后，KO与WT小鼠的克数变化的比较。图4E显示了4周后，KO与WT小鼠的克数变化的比较。图4F显示了8周后，KO小鼠与WT小鼠的克数变化的比较。
图5A-D的一系列条形图显示了当喂食HFD时，miR-22null小鼠与WT相比显示出不同的代谢。图5A显示了在HFD前(第0天)和8周后，miR-22KO和WT小鼠的脂体重(Fat mass)和瘦体重(lean mass)(图5B)的百分比(占总体重的百分比)。在HFD下8周后，miR-22KO组与WT相比具有统计学上显著更低的脂肪量。miR-22KO组的瘦体重不受HFD影响，相比之下，顶部的WT组在HFD后脂肪量百分比增加且瘦体重百分比减少。图5C和5D显示了收集自代谢笼的一系列参数。在稳态下，miR-22KO和WT小鼠均具有相同的代谢。一旦小鼠经历HFD挑战，miR-22KO组能不降低其能量消耗，而WT组降低能量消耗。尽管KO小鼠活跃性不如WT，但在miR-22KO组中VCO2和VO2与WT中的VCO2和VO2相比均显著更高。图5C和5D的每个条形图中的右侧条(红色)的数据为miR-22KO小鼠的数据。
图6的条形图显示了WT和KO组在食物消耗(HFD)上没有差异。
图7A-B是条形图和油红-O染色，其显示miR-22的下调破坏了小鼠胚胎成纤维细胞(MEF)分化为脂肪细胞的能力。图7A的条形图显示了MEF中的脂肪细胞分化，表明miR-22-/-MEF显示比WT少27％的脂肪细胞。图7B的油红-O染色显示了来自WT、miR-22+/-和miR-22-/-的在Adipo-分化培养基中培养了5天的MEF。
图8显示了anti-miR-22LNA的设计。
图9显示了在媒介物(VCH)、秩乱对照RNA(SCR)和锁核酸(LNA)的转染后，在HFD下的miR-22-/-和WT小鼠的体内实验的计划和条件。
图10的条形图显示了对于(Δ)媒介物、(◇)SCR、(□)anti-miR-22，经处理和未处理的小鼠在食物消耗上没有差异。
图11A-B的线形图显示了在药理学上体内抑制miR-22防止了小鼠变肥胖。图11A显示了最终的身体增加百分比。图11B显示了miR-22在DIO小鼠体内的沉默。在两个图中，在最终的时间点，数据顺序从上到下为媒介物(绿色)、SCR(红色)和anti-miR-22(蓝色)。
图12是蛋白质印迹，其显示了体内anti-miR-22治疗能够增加肝中主要miR-22靶标的蛋白水平。
图13A-B是一系列条形图(图13A)和免疫组织化学染色(图13B)，其显示了anti-miR-22处理不影响肝脂质组成，但能显著抑制肝脂肪变性。
图14A-B的一系列条形图显示了经VHL、SCR LNA或LNA anti-miR-22处理的小鼠肝中的相对mRNA水平。图14A显示了TET2和PTEN的mRNA表达。图14B显示了FTO、FTO和CEBPa的mRNA表达。
图15A-C的一系列条形图显示了经VHL、SCR LNA或LNA anti-miR-22处理的小鼠的棕色脂肪组织(BAT)中的相对mRNA水平。图15A显示了TET2和PTEN的mRNA表达。图15B显示了FTO、CEBPa和PPARg的mRNA表达，图15C显示了UCP1和CD36的mRNA表达。
图16A-C的一系列条形图显示了经VHL、SCR LNA或LNA anti-miR-22处理的小鼠的白色脂肪组织(WAT)中的相对mRNA水平。图16A的条形图显示了TET2和PTEN的mRNA表达水平。图16B的条形图显示了FTO、CEBPa和PPARg的mRNA表达水平，图16C的条形图显示了UCP1和CD36的表达水平。
图17为治疗方法的图示，其显示了用anti-miR-22-LNA、SCR和VHL处理HFD下的miR-22-/-和WT小鼠，并将这些小鼠置于第二HFD方案。
图18的线形图显示了治疗方法的结果，通过该方法已肥胖并被喂食HFD的小鼠的体重有显著降低。在31/2个月的治疗后，在肥胖(平均体重>40g)并被喂食HFD的小鼠中观察到体重的显著降低。处死小鼠，收集组织，将来自肝的RNA用于RNAseq。
图19A-C的三张图片显示了在药理学上抑制miR-22使小鼠的肥胖表型回复。图19A显示了经VHL处理的小鼠的脂肪垫，图19B显示了经anti-miR-22处理的小鼠的脂肪垫，图19C显示了经SCR处理的小鼠的脂肪垫。
图20是RNA-seq图，其显示了小鼠肝的层次聚类分析，该分析将miR-22的药理学抑制和基因敲除(KO)在一起聚类，表明了治疗是中靶的(on target)，并且使用LNA构建体能够模拟KO表型。
图21是RNA-Seq图，其显示了小鼠肝中的基因本体分析，该分析显示经KO和LNA处理的小鼠中自上而下的调节途径是与脂质的代谢和生物合成有关的。
图22是蛋白质印迹，其显示了体内anti-miR-22治疗大幅下调ATP-柠檬酸裂解酶(ACL)。体内anti-miR-22治疗大幅下调ACL。
图23是油红-O染色，其显示了在药理学上抑制miR-22有效破坏了MEF的脂肪细胞分化。
图24为油红O染色(图24A)和条形图(图24B)，其显示了在有或无LNA anti-miR-22时，在Adipo分化培养基中培养2周的人原始间充质细胞的anti-miR-22处理。无辅助摄取500nM(每2天加入LNA)。在图24B中，每个条形图中右侧条(红色)的数据为经LNA#10处理的细胞的数据。
图25的条形图显示了在药理学上抑制miR-22有效破坏了MEF的脂肪细胞分化。条形图中的数据顺序，当从左到右读取时，对应于从上到下读取时的图例(位于图右)。
图26是miR-22所协调的代谢网络的示意图。miR-22能同时靶向多个代谢参与者(直接或间接)。
图27A-B显示，在脂肪诱导分化期间，miR-22缺陷MEF的脂肪量和肥胖相关蛋白(FTO)的表达显著下调，但WT MEF并不如此。图27A是FTO基因的代表图，图27B的条形图显示了在稳态和分化培养基条件下FTO mRNA表达水平。在图27B中，条形图中从左到右读取的数据顺序是WT(黑色)、miR-22+/-(灰色)和miR-22-/-(蓝色)。
图28A-D显示了(在遗传或药理学上)下调miR-22提高了RNA m6A的水平。图28A显示了化学反应。图28B、图28C和图28D的条形图显示了在HFD下的小鼠中m6A水平的百分比和相对量。
图29是一系列免疫组织化学图像，其显示了在2月龄小鼠中miR-22的遗传耗竭不影响肝功能，n＝8。
图30是一系列免疫组织化学图像，其显示了miR-22的遗传耗竭不影响肝功能，且miR-22KO小鼠在年老时不显示任何与肝有关的疾病或功能障碍。
图31是一系列免疫组织化学图像，其显示了anti-miR-22LNA处理防止饮食诱发的肥胖小鼠中的肝脂肪变性。图像的放大倍数为10x。
图32是一系列免疫组织化学图像，其显示了miR-22的过表达和低表达(underexpression)对肝纤维化的影响。
图33A-C显示了miR-22的过表达影响喂食正常食物时的肝功能：WT-小鼠(图33A)和miR-22Tg小鼠(图33B)中的脂肪肝和纤维化。图33C显示了WT和miR-22Tg小鼠在正常饮食下，小鼠肝中的FSP-1阳性细胞。
图34A-C显示了miR-22的过表达影响肝功能：WT-小鼠(图34A)和miR-22+/-小鼠(图34B)中的脂肪肝和纤维化。图34C显示了WT和miR-22+/-小鼠在HFD下，小鼠肝中的FSP-1阳性细胞。
发明详述
本公开基于以下发现：包括miR-22在内的miRNA能调节与多种代谢失调相关的靶标，这些代谢失调包括肥胖、普拉德·威利综合征、高胆固醇血症、脂肪肝疾病、非脂肪酸肝病(NAFLD)和/或非酒精性脂肪性肝炎(NASH)。
本公开包括用多种抑制剂靶向包括miR-22在内的miRNA以治疗和/或预防病因可通过调节代谢影响的疾病，例如代谢失调，包括肥胖、普拉德-威利综合征、高胆固醇血症、NAFLD和/或NASH。
MiR-22直接靶向磷酸酶和张力蛋白同源蛋白(PTEN)和tet甲基胞嘧啶双加氧酶(TET)，以促进肿瘤发生、转移和代谢失调。在人类癌症中研究了多于60个靶向PTEN的miRNA和不少于30个新的原癌基因座。靶向PTEN的miRNA在脊椎动物间高度进化保守，并在各种组织中普遍表达(Lagos-Quintana等，2001，2002；Neely等，2006)。miR-22由于靶向PTEN而与代谢相关，因为PTEN的降低或升高分别触发Warburg-或anti-Warburg的代谢状态。在一些实施方案中，miR-22靶向的基因调节代谢和脂肪酸氧化或生物发生。
在一个方面，本公开的方法提供了一种用于治疗或预防代谢失调的方法，该方法包括施用有效量的miR-22的抑制剂给有此需要的受试者。
例如，这种抑制可以由序列特异的化学修饰的寡核苷酸介导。示例性修饰有锁核酸(LNA)，其中核酸的核糖部分经修饰具有连接2’氧和4’碳的额外桥，该桥将核糖锁定在3’-内部(3’-endo)构象中。当针对本文公开的调节代谢基因的miRNA时，LNA抑制剂尤其是有成本效益的试剂，其可被高效地递送并具有足够的生物利用度，用于各种代谢失调的治疗和预防。
本公开进一步提供了本文所述的任何方法或组合在制备用于治疗疾病的药物中的用途。这些疾病包括，例如，代谢失调或受调节代谢影响的疾病(例如与脂肪有关的代谢和合成途径)。
在本公开的方法的一些实施方案中，包括miR-22在内的miRNA调节与脂肪有关的代谢和合成途径的靶标和/或基因。在一些实施方案中，与脂肪有关的代谢和合成基因包括脂肪量和肥胖相关蛋白(FTO)、CCAAT/增强子结合蛋白α(CEBPα)、过氧化物酶体增殖物激活受体γ(PPARg)、磷酸酶和张力蛋白同源蛋白(PTEN)、tet甲基胞嘧啶双加氧酶2(TET2)、ATP柠檬酸裂解酶(ACLY)、骨形态发生蛋白7(BMP-7)和/或sirtuin 1(SIRT-1)。
在一些实施方案中，与脂肪有关的代谢和合成基因包括FTO。在一些实施方案中，所述方法降低了脂肪量和肥胖相关蛋白(FTO)、CEBPα和/或PPARγ的活性和/或表达。
在一些实施方案中，所述方法降低了ALKB同源蛋白5(ALKBH5)的活性和/或表达。在一些实施方案中，所述方法增加了PTEN和/或TET2的活性和/或表达。
在一些实施方案中，所述方法改变了PPARγ共激活因子-α(PGC1-α)、特异性蛋白1(SP1)、成纤维细胞生长因子21(FGF-21)、解偶联蛋白1(UCP1)、DNA损伤诱导转录物4(DDIT-4，REDD1)、甲基转移酶样蛋白3(METTL3)、肿瘤蛋白p63(TP63)和/或成纤维细胞生长因子1(FGF1)的活性和/或表达。
在一些实施方案中，所述方法改变了DNA或RNA的甲基化水平，或在RNA水平上影响了m6A水平。
在一些实施方案中，本公开通过抑制miRNA治疗或预防受试者的代谢失调(非限制性示例有肥胖症、普拉德-威利综合征、高胆固醇血症、脂肪肝疾病、NAFLD和/或NASH)。MiRNA是能调节靶基因表达的短核酸分子。参见综述Carrington等人,Science,Vol.301(5631):336-338,2003。miRNA的长度通常在约18至24个核苷酸之间。当miRNA和其靶mRNA的序列完全互补时，miRNA通过促进靶mRNA的降解来充当其阻遏物，和/或当miRNA含有错配时，miRNA通过抑制翻译来充当靶mRNA的阻遏物。
不受理论的束缚，认为成熟miRNA由pol II或pol III产生并起源于被称为pri-miRNA的初始转录物。这些pri-miRNA通常为几千个碱基长，因此经加工被制成短得多的成熟miRNA。这些pri-miRNA可以是多顺反子的，并产生于以可形成许多miRNA的方式组构的若干成簇序列的转录。产生miRNA的过程可为两步。首先，pri-miRNA可在细胞核中被RNaseDrosha加工成约70个至约100个核苷酸的发夹形前体(pre-miRNA)。然后，在转位至细胞质后，发夹pre-miRNA可进一步被RNase Dicer加工以产生双链miRNA。成熟miRNA链随后可引入到RNA诱导沉默复合物(RISC)中，在此成熟miRNA可通过碱基对互补性与其靶mRNA结合，并导致蛋白表达的抑制。没有被优先选择进入RISC沉默复合物的miRNA双链体的另一条链是过客链(passenger strand)或次要miRNA(minor miRNA)或加星号的(*)链。该链可被降解。应当理解，除非另有说明，否则如本文所用，miRNA可指pri-miRNA和/或pre-miRNA和/或成熟miRNA和/或次要的(加星号的)链和/或miRNA的双链体形式。
在一些实施方案中，miRNA基因可位于蛋白编码基因的内含子内或非编码转录单位的内含子或外显子内。内含子miRNA的表达可与宿主转录单元的表达同时发生，因为它们通常朝向相同的方向并与其所寄宿的pre-mRNA协同表达。
在一些实施方案中，miRNA可结合靶基因转录物的3’非翻译区(3’UTR)内的序列。在一些实施方案中，miRNA可结合靶基因转录物的3’UTR外的序列。在一些实施方案中，miRNA可结合靶基因转录物的3’UTR内和外的序列。
在一些实施方案中，miRNA的第二至第七核苷酸(miRNA种子序列)与沿靶标3’UTR的相应序列间可发生核苷酸配对(种子匹配)，用于靶标识别。因此，miRNA与靶标间的结合可包含约5个核苷酸的碱基配对。另外，miRNA与靶标间的结合可包含多于5个核苷酸的碱基配对。在一些实施方案中，miRNA与该miRNA调节的基因间的结合可通过miRNA结合靶核酸的多达2个、多达4个、多达6个、多达8个或多达10个位置介导。
本公开的miRNA可以通过直接结合来调节核酸，这些核酸包括但不限于代谢关键基因，如与代谢失调病因相关的标志物的基因。该结合可以与靶核酸完全互补或含有错配。该结合的影响可以是促进靶标的降解和/或抑制靶标的翻译。
在一些实施方案中，本发明通过抑制如miR-22的miRNA治疗或预防受试者的代谢失调。在一些实施方案中，编码mir-22的核酸包含AAGCUGCCAGUUGAAGAACUGU(SEQ ID NO:1)或由其组成。
预测的miR-22发夹前体完全包含在非编码转录物C17orf91的外显子2内，并且尽管缺乏蛋白编码的潜力，但剪接模式通常在人和小鼠中保守。参见Rodriguez等人，Identification of mammalian microRNA host genes and transcriptionunits.Genome Res.2004年10月；14(10A):1902-10。小鼠模型中包含mir-22的Cl7orf9l的外显子2的缺失已表明，miR-22可通过靶向SIRT1(NAD依赖的脱乙酰基酶sirtuin-1)、HDAC4(组蛋白脱乙酰基酶4)、PURB(富含嘌呤的元件结合蛋白B)和PTEN在心脏肥大和重构中起作用。参见Gurha等人,Targeted deletion of microRNA-22promotes stress-inducedcardiac dilation and contractile dysfunction.Circulation.2012年6月5日；125(22):2751-61；Huang等人,MicroRNA-22regulates cardiac hypertrophy andremodeling in response to stress.Circ Res.2013年4月26日；112(9):1234-43。
另外，已观察到ART(PTEN的下游靶标)激活mir-22转录，这提示了致癌性PI3K/AKT信号传递途径中的调节环。参见Bar等，miR-22forms a regulatory loop in PTEN/AKTpathway and modulates signaling kinetics.PLoS One.2010；5(5):e10859.
在一些实施方案中，本发明证明，miR-22可以充当表观遗传修饰剂和EMT启动子，这独立于其靶向Pten的能力。在一些实施方案中，本公开包括通过阻止脂肪量和肥胖相关蛋白(FTO)变体的增加和/或引起其减少而治疗或预防受试者的代谢失调，和/或本公开显示了FTO表达和/或活性的下调。FTO是在人中由位于16号染色体上的FTO基因编码的酶。作为AlkB家族蛋白的同源物，它是第一个被鉴定出的mRNA去甲基酶。FTO基因的某些变体与人的肥胖有关。
在一些实施方案中，抑制剂的序列在物种间保守。在一些实施方案中，抑制剂的序列部分取自人转录物的序列。在一些实施方案中，选择抑制剂以降低受试者中靶标miRNA(以非限制性示例的方式为miR-22)的表达和/或活性。
在一些实施方案中，miRNA的抑制剂是反义寡核苷酸。反义寡核苷酸可包括核糖核苷酸或脱氧核糖核苷酸或其组合。反义寡核苷酸可具有至少一个化学修饰(非限制性示例为糖或骨架修饰)。
在一些实施方案中，化学修饰是以下的一种或多种：硫代磷酸酯、2’-0-甲基、或2’-O-甲氧乙基、2’-0-烷基-RNA单元、2’-OMe-RNA单元、2’-氨基-DNA单元、2’-氟-DNA单元(包括，但不限于，在位置2’取代为氟(2’F)的DNA类似物)、LNA单元、PNA单元、HNA单元、INA单元和2’MOE RNA单元。
合适的反义寡核苷酸可包含一种或多种构象约束的或二环的糖核苷修饰(BSN)，该糖核苷修饰赋予增强的热稳定性给在含有BSN的寡核苷酸和他们的互补miRNA靶链之间形成的复合物。例如，在一个实施方案中，反义寡核苷酸含有至少一个锁核酸。锁核酸(LNA)含有2’-0,4’-C-亚甲基核糖核苷(结构A)，其中核糖糖部分处于被锁的构象。在另一个实施方案中，反义寡核苷酸含有至少一个2’,4’-C-桥连的2’脱氧核糖核苷(CDNA，结构B)。参见，例如，美国专利号6,403,566和Wang等人，(1999)Bioorganic and Medicinal ChemistryLetters,第9卷:1147-1150，两者均通过引用以其全文并入本文。在还另一个实施方案中，反义寡核苷酸含有至少一个具有结构C中所示结构的修饰的核苷。靶向调节与脂肪有关的代谢和合成途径靶标的miRNA的反义寡核苷酸可含有BSN(LNA、CDNA等)或其他修饰的核苷酸以及核糖核苷酸或脱氧核糖核苷酸的组合。
Figure BDA0002776282790000121
另外，反义寡核苷酸可包含肽核酸(PNA)，该肽核酸含有基于肽的骨架而非糖-磷酸骨架。还考虑对反义寡核苷酸的其他的修饰糖或磷酸二酯修饰。其他化学修饰可以非限制性示例的方式包括2’-o-烷基(例如，2’-0-甲基、2’-o-甲氧乙基)、2’-氟和4’-硫代修饰以及骨架修饰，如一个或多个硫代磷酸酯、吗啉代或膦酰基羧酸酯键(参见，例如，美国专利号6,693,187和7,067,641，其通过引用以其全文并入本文)。在一个实施方案中，靶向致癌miRNA的反义寡核苷酸在每个碱基上都含有2'-0-甲基糖修饰，并通过硫代磷酸酯键连接。反义寡核苷酸，特别是较短长度的那些(例如，少于16个核苷酸，7至8个核苷酸)可包含一个或多个增强亲和力的修饰，例如，但不限于LNA、二环核苷、膦酰基甲酸酯、2’o-烷基修饰等。在一些实施方案中，合适的反义寡核苷酸为2’-0-甲氧乙基间隔体(gapmer)，该间隔体在5’和3’端均含有2’-O-甲氧乙基修饰的核糖核苷酸，且在其中心具有至少十个脱氧核糖核苷酸。这些间隔体能触发RNA靶标的RNase H依赖的降解机制。增强稳定性和提高功效的反义寡核苷酸的其他修饰，如描述于美国专利号6,838,283(其通过引用以其全文并入本文)中的那些，是本领域中已知的，并且适合用于本发明的方法中。例如，且不旨在为限制性地，为促进体内递送和稳定性，可使反义寡核苷酸在其3’端连接类固醇如胆固醇部分、维生素、脂肪酸、碳水化合物或糖苷、肽或其他小分子配体。
在一些实施方案中，用于抑制miRNA活性(包括例如miR-22)的反义寡核苷酸的长度为约5至约25个核苷酸、约10至约30个核苷酸或约20至25个核苷酸。在某些实施方案中，靶向致癌miRNA的反义寡核苷酸的长度为约8至约18个核苷酸，在其他实施方案中的长度为约12至约16个核苷酸，且在其他实施方案中的长度为约7至约8个核苷酸。任何与致癌miRNA互补的7-mer或更长的序列均可使用，即，与miRNA的5’端互补并且在miRNA的整个互补序列上连续的任何anti-miR。以非限制性示例的形式，靶向致癌miRNA(包括例如miR-22)的反义寡核苷酸长度为约5个、或约6个、或约7个、或约8个、或约9个、或约10个、或约11个、或约12个、或约13个、或约14个、或约15个、或约16个、或约17个、或约18个、或约19个、或约20个、或约21个、或约22个、或约23个、或约24个、或约25个、或约26个、或约27个、或约28个、或约29个或约30个核苷酸。
反义寡核苷酸可包括与成熟的或次要的(即，加星号的)致癌miRNA序列为至少部分互补的序列，例如，与成熟的或次要的(即，加星号的)致癌miRNA序列为至少约75％、80％、85％、90％、95％、96％、97％、98％或99％互补。在一些实施方案中，反义寡核苷酸可与成熟的或次要的致癌miRNA序列基本互补，即与靶多核苷酸序列为至少约90％、95％、96％、97％、98％或99％互补。在一个实施方案中，反义寡核苷酸包括与成熟的或次要的致癌miRNA序列为100％互补的序列。
如本文所用，基本上互补指序列与靶多核苷酸序列为至少约95％、96％、97％、98％、99％或100％互补(非限制性示例为例如miR-22的成熟miRNA、次要miRNA、前体miRNA或pri-miRNA序列)。
在一些实施方案中，反义寡核苷酸是antagomir。antagomir是单链的、化学修饰的核糖核苷酸，其与miRNA至少部分互补，因此可沉默这些miRNA。参见，例如，Kriitzfeldt等人，Nature(2005)438(7068)：685-9。antagomir可包含一个或多个修饰的核苷酸，如2’-0-甲基-糖修饰。在一些实施方案中，antagomir仅包含修饰的核苷酸。antagomir还可包含一个或多个硫代磷酸酯连接，形成部分或完全的硫代磷酸酯骨架。为促进体内递送和稳定性，可使antagomir在其3’端连接胆固醇或其他部分。适用于抑制的antagomir的长度可为约15至约50个核苷酸、约18至约30个核苷酸和约20至约25个核苷酸。antagomir可与成熟的或次要的致癌miRNA序列为至少约75％、80％、85％、90％、95％、96％、97％、98％或99％互补。在一些实施方案中，antagomir可与成熟的或次要的致癌miRNA序列基本互补，即与靶多核苷酸序列为至少约95％、96％、97％、98％或99％互补。在其他实施方案中，antagomir与成熟的或次要的致癌miRNA序列为100％互补。
反义寡核苷酸或antagomir可包含与致癌miRNA的前体miRNA序列(pre-miRNA)或初始miRNA序列(pri-miRNA)基本互补的序列。在一些实施方案中，反义寡核苷酸包含位于该miRNA的靶标的3’-非翻译区外的序列。在一些实施方案中，反义寡核苷酸包含位于该miRNA的靶标的3’-非翻译区内的序列。
通过将编码miRNA抑制剂或激动剂的表达载体递送至细胞，可将本文所述的致癌miRNA(包括但不限于miR-22)的任何抑制剂或激动剂递送至靶细胞。载体是可用于将目的核酸递送至细胞内部的物质的组合物。本领域中已知许多载体，包括，但不限于线性多核苷酸、与离子化合物或两亲化合物相连的多核苷酸、质粒和病毒。因此，术语载体包括自主复制的质粒或病毒。病毒载体的示例包括，但不限于腺病毒载体、腺相关病毒载体、逆转录病毒载体等。表达构建体可在活细胞中复制，也可合成制得。为了本申请的目的，术语表达构建体、表达载体和载体互换使用，用于以一般性的说明意义上证明本发明的应用，并且不旨在限制本发明。
在一个实施方案中，用于表达致癌miRNA(例如miR-22)抑制剂的表达载体包含启动子，该启动子可操作地连接编码反义寡核苷酸的多核苷酸。所表达的反义寡核苷酸的序列可与致癌miRNA的成熟或次要序列为部分或完全互补。如本文所用，短语可操作地连接或在转录控制下意指，启动子相对于多核苷酸处于正确的位置和方向，以控制RNA聚合酶的转录起始和多核苷酸的表达。
如本文所用，启动子指被细胞的合成装置或引入的合成装置识别的DNA序列，其为启动基因的特异性转录所需的。合适的启动子包括，但不限于RNA pol I、pol II、pol III和病毒启动子(例如，人巨细胞病毒(CMV)即早基因启动子、SV40早期启动子和劳斯肉瘤病毒长末端重复)。
在某些实施方案中，可操作地连接至编码miRNA抑制剂的多核苷酸或者编码调节代谢基因的miRNA和/或miRNA靶向的与代谢病因相关的标志物的基因的多核苷酸的启动子可以是诱导型启动子。诱导型启动子是本领域中已知的，且包括，但不限于四环素启动子、金属硫蛋白IIA启动子、热休克启动子、类固醇/甲状腺激素/视黄酸应答元件、腺病毒晚期启动子和诱导型小鼠乳腺瘤病毒LTR。
递送表达构建体和核酸至细胞的方法是本领域中已知的，且可以非限制性示例的方式包括磷酸钙共沉淀、电穿孔、微注射、DEAE-葡聚糖、lipofection、采用聚胺转染试剂的转染、细胞超声处理、使用高速微粒的基因枪和受体介导的转染。
本发明还包括在治疗后清扫或清除致癌miRNA的抑制剂。清除剂可以包括与miRNA抑制剂互补或与表达miRNA抑制剂的载体互补的分离的核酸。因此，它们可以与miRNA抑制剂或表达miRNA抑制剂的载体结合，从而阻止miRNA和靶标间的结合。
在一些实施方案中，本公开提供了一种治疗或预防有此需要的受试者中代谢失调的方法。在一些实施方案中，本公开提供了一种治疗或预防受试者的代谢失调的方法，这些代谢失调包括肥胖、普拉德-威利综合征、高胆固醇血症、脂肪肝疾病，非酒精性脂肪肝疾病(NAFLD)和/或非酒精性脂肪性肝炎(NASH)。
代谢失调
在本发明的上下文中使用的术语“代谢失调”指受棕色脂肪组织的存在、水平或活性，血糖浓度，血浆胰岛素水平和/或身体脂肪含量影响的疾病或病况。在一些实施方案中，代谢失调或病况还包括但不限于代谢综合征、受损的葡萄糖耐量、升高的血浆胰岛素浓度和胰岛素抵抗、血脂异常、高血糖症、高脂血症、高血压、脂营养不良、心血管疾病、呼吸问题或病况。尤其感兴趣的代谢失调是肥胖、普拉德-威利综合症、高胆固醇血症、脂肪肝疾病、包括非脂肪酸肝病(NAFLD)和/或非酒精性脂肪性肝炎(NASH)。
肥胖
在一些实施方案中，本公开涉及肥胖。肥胖是一种在现代社会中高度普遍的慢性疾病，其不仅与社会耻辱有关，还与寿命缩短和许多医学问题有关，这些医学问题包括糖尿病、胰岛素抵抗、高血压、高胆固醇血症、胆石症、骨关节炎、骨科损伤、血栓栓塞性疾病、癌症和冠心病。Rissanen等人，British Medical Journal，301：835-837(1990)。在一些实施方案中，使用体重指数(BMI：体重/身高(米)的平方)可以计算肥胖。在一些实施方案中，肥胖被定义为受试者除了具有大于或等于30kg/m2的BMI其他方面都健康，或由此使具有至少一种伴随疾病的受试者具有大于或等于27kg/m2的BMI的疾病。在本公开的方法的一些实施方案中，受试者是肥胖的并且具有大于约30的体重指数。在一些实施方案中，受试者是超重的并且具有约25-29.9的体重指数。在一些实施方案中，该方法引起体重减轻。在一些实施方案中，该方法防止体重增加。在一些实施方案中，该方法防止脂肪组织生长并破坏脂肪细胞分化。
在一些实施方案中，本公开提供了包括施用miR-22(和与miR-22有关的化合物)的抑制剂的治疗方法，和/或miR-22(和与miR-22有关的化合物)在用于治疗肥胖和超重以及相关病况中的用途或者其的制药用途。在一些实施方案中，本公开提供了一种用于治疗或预防肥胖的方法，其包括施用有效量的miR-22(和与抑制miR-22有关的化合物)给有此需要的患者。在一些方面，本公开提供了一种用于体重管理的方法，其包括施用有效量的miR-22的抑制剂(和与抑制miR-22有关的化合物)，以在有此需要的患者中诱导体重减轻和/或防止体重增加。
在一些实施方案中，本公开涉及一种用于引起体重减轻或防止体重增加(或在基本上不改变热量摄入的患者中治疗或预防肥胖或引起体重减轻或防止体重增加)的方法，其包括施用有效量的miR-22(和与miR-22相关的化合物)的抑制剂给以下患者：已经经历或将要经历消化系统的手术；超重大于约80-100磅；BMI大于约35；或具有与肥胖有关的健康问题。
在一些实施方案中，消化系统的手术是归类于ICD-9-CM的那些的一种或多种：消化系统的手术且因此可包括食道的手术；胃的切开和切除；胃的其他手术；肠的切开、切除和吻合术；肠的其他手术；盲肠的手术；直肠、直肠乙状结肠和直肠周组织的手术；肛门的手术；肝的手术；胆囊和胆道的手术；胰的手术；疝修复；和腹部区域的其他手术。
在一些实施方案中，消化系统的手术是限制性手术和/或吸收不良型手术的一种或多种，包括例如垂直捆绑胃成形术(VBG，例如胃缝合术)；胃囊带术(例如LAP-BAND或REALIZE)；袖状胃切除术；胃分流术(例如，Roux-en-Y胃分流)，胆胰分泌转移术和整容手术(例如，吸脂术，例如抽吸辅助吸脂术(SAL)；超声辅助吸脂术(UAL)；动力辅助吸脂术(PAL)；双套管(辅助)吸脂术(TCAL或TCL)；外部超声辅助吸脂术(XUAL或EUAL)；水辅助吸脂术(WAL)；激光辅助吸脂术；肿胀吸脂术和冷冻融脂术)。
在一些实施方案中，与肥胖有关的健康问题选自心血管疾病(例如，高胆固醇、高胆固醇血症、低HDL、高HDL、高血压、冠状动脉病、心力衰竭)、睡眠呼吸暂停(包括阻塞性睡眠呼吸暂停)、骨关节炎、甲状腺问题、痴呆、痛风、哮喘、胃食管反流疾病和慢性肾功能衰竭。在一些实施方案中，与肥胖有关的健康问题是心脏病、睡眠呼吸暂停或高胆固醇。
在一些方面，本公开提供了用于诱导体重减轻或防止体重增加的用途和方法，其包括施用有效量的miR-22的抑制剂(和与抑制miR-22有关的化合物)给有此需要的患者，其中该患者基本上不改变热量摄入。在一些实施方案中，热量摄入相对诸如USDA表的指南较高。在一些实施方案中，患者的热量摄入为2000-10000卡路里/天、或大于约2000卡路里/天、或约2200卡路里/天、或约2400卡路里/天、或约2600卡路里/天、或约2800卡路里/天、或约3000卡路里/天、或约3200卡路里/天、或约3400卡路里/天、或约3600卡路里/天、或约3800卡路里/天、或约4000卡路里/天、或约5000卡路里/天、或约6000卡路里/天。在一些实施方案中，患者具有高热量摄入并且无体重增加或甚至有体重减轻。因此，本公开提供了在不改变生活方式的情况下往往减少患者依从性(例如，节食失败)的效果。在一些实施方案中，限制患者的热量摄入不超过约20％、或不超过约10％、或不超过约5％的治疗开始时患者热量摄入。在一些实施方案中，患者的热量摄入的很大一部分是“空卡路里”，即来自固体脂肪和/或添加的糖的卡路里。在一些实施方案中，患者热量摄入的超过约15％、或20％、或25％、或30％、或35％、或50％为空卡路里。即使在这些实施方案中，患者也可以无体重增加或甚至有体重减轻。
在一些实施方案中，本公开的患者是超重或肥胖的。在一些实施方案中，本公开的患者患有中心性肥胖(central obesity)。在一些实施方案中，肥胖是以下的一种：单纯性肥胖(饮食性肥胖，通常由于卡路里消费多于身体可利用的卡路里造成)、继发性肥胖(通常由于潜在的医学状况，例如库欣综合征和多囊卵巢综合征造成)和儿童肥胖。在一些实施方案中，肥胖被归类于：I类，其包括在30和34.99之间的BMI；II类，其包括35至39.99的BMI；和III类，其包括超过40的BMI。此外，本公开提供了I、II或III类的任一类中的肥胖被进一步归类为严重、病态和超级肥胖。在一些实施方案中，患者处于进一步体重增加的风险中，其通过例如每日热量摄入来评估。
在一些实施方案中，可以使用多种技术和指标评估miR-22(和与miR-22有关的化合物)的抑制剂的体重管理/体重减轻/抗肥胖效果。在一些实施方案中，在治疗之前、期间和之后进行评估。在一些实施方案中，可以使用体重指数(BMI)，即考量身高的人体重的量度。在一些实施方案中，本文所述的患者具有属于“超重”类别的BMI，即25-29.9，例如约25、或约25.5、或约26、或约26.5、或约27、或约27.5、或约28、或约28.5、或约29或约29.5。在一些实施方案中，本文所述的患者具有属于“肥胖”类别的BMI，即大于30，例如，约30、或约31、或约32、或约33、或约34、或约35、或约36、或约37、或约38、或约39、或约40或约50。在一些实施方案中，使用身体体积指数(BVI)。BVI使用3D软件创建人的3D图像，故BVI可以区分具有相同BMI等级但具有不同体形和不同体重分配的人。BVI测量人的体重和脂肪位于身体何处，而不测量总重量或总脂肪含量，并且BVI将重点放在腹部周围的重量，其通常被称为中心性肥胖。在一些实施方案中，使用全身性空气置换体积描记法(ADP)评估miR-22(和与miR-22有关的化合物)的体重管理/体重减轻/抗肥胖效果。在一些实施方案中，在本发明中使用简单的称重。在一些实施方案中，可以使用皮褶卡钳或“抓捏测试”、生物电阻抗分析、水下称重或双能X射线吸收测定法(DEXA)。
在一些实施方案中，可以使用对身体的简单圆周测量。在一些实施方案中，本公开的患者的腰围超过约35英寸、或约36英寸、或约37英寸、或约38英寸、或约39英寸、或约40英寸、或约41英寸、或约42英寸、或约43英寸、或约44英寸、或约45英寸、或约46英寸、或约47英寸、或约48英寸、或约50英寸、或约55英寸、或约60英寸。在一些实施方案中，患者是腰围超过40英寸的男性。在一些实施方案中，患者是腰围超过35英寸的女性。
本公开的方法可用于治疗体脂率高于推荐体脂率的人，即至少在“超重”范围内或至少在“肥胖”范围内。体脂率在男性和女性间会不同。具体地，对于女性，本公开的方法可用于治疗具有至少约25％、高于25％、至少约32％或高于32％的体脂率的女性人类。对于男性，本公开的方法可用于治疗具有至少约14％、高于14％、至少约18％、高于18％、至少约25％或高于25％的体脂率的男性。可以使用本领域中接受的任何方法来评估体脂率，包括例如近红外相互作用(near infrared interactance)、双能X射线吸收测定法、身体密度测量、生物电阻抗分析等。
本公开的方法可用于治疗超重大于100磅和/或腰围超过40英寸的男性患者。本公开的方法可用于治疗具有大于80磅的超重和/或超过35英寸的腰围的女性患者。
在一些实施方案中，本公开提供了使用miR-22的抑制剂(和与抑制miR-22有关的化合物)治疗和/或预防与超重有关的某些病症。例如，发现miR-22(和与miR-22有关的化合物)可用于心血管疾病(例如高胆固醇、高胆固醇血症、低HDL、高HDL、高血压、冠状动脉病，心力衰竭)、睡眠呼吸暂停(包括阻塞性睡眠呼吸暂停)、骨关节炎、甲状腺问题、痴呆、痛风、哮喘、胃食管反流疾病和慢性肾功能衰竭。
在一些实施方案中，miR-22(和与miR-22有关的化合物)的抑制剂的施用和/或用途抑制或减少了脂肪组织生长。在一些实施方案中，miR-22(和与miR-22有关的化合物)影响白色脂肪组织(WAT)和棕色脂肪组织(BAT)的一种或多种，包括例如内脏脂肪组织(VAT)、腹部皮下脂肪组织(ASAT)或异位脂肪。这种影响可通过使用本文所述的任何技术(例如BMI、体重身高指数(weight for-stature)、皮褶测量、电生物阻抗分析等)，以及各种成像技术，包括计算机断层扫描(CT)、磁共振成像(MRI，包括横向身体扫描)、双能X射线吸收测定法(DXA)，来评估。
miR-22(和与miR-22有关的化合物)也可与饮食疗法、行为疗法、物理疗法、运动和减肥手术组合使用，或与两种或更多种这样的疗法组合使用。在一些实施方案中，受试者处于热量受限制的饮食下。在一些实施方案中，受试者参加或将要参加物理锻炼或物理治疗方案。在一些实施方案中，受试者已经经历或将要经历体重减轻手术。在一些实施方案中，miR-22的抑制剂(和与抑制miR-22有关的化合物)可与其他试剂组合或可被施用给正在经历各种试剂治疗的患者。
例如，包括但不限于涉及肥胖和/或体重减少/减轻的实施方案，其他试剂可以包括以下的一种或多种：奥利司他(orlistat)(例如ALLI、XENICAL)、氯卡色林(lorcaserin)(例如BELVIQ)、芬特明-托吡酯(phentermine-topiramate)(例如QSYMIA)、西布曲明(sibutramine)(例如REDUCTIL或MERIDIA)、利莫纳班(rimonabant)(ACOMPLIA)、依泽那太(exenatide)(例如BYETTA)、普兰林肽(pramlintide)(例如SYMLIN)、芬特明、卞非他明(benzphetamine)、安非拉酮(diethylpropion)、苯甲曲秦(phendimetrazine)、安非他酮(bupropion)和二甲双胍(metformin)。
干扰身体吸收食物中特定营养物质的能力的试剂属于其他试剂的范围，例如奥利司他(orlistat)(例如ALLI、XENICAL)、葡甘露聚糖(glucomannan)和瓜耳胶(guar gum)。抑制食欲的药剂也属于其他试剂的范围，例如儿茶酚胺类(catecholamines)和它们的衍生物(如芬特明和其他基于苯丙胺的药物)、各种抗抑郁药和情绪稳定剂(例如安非他酮和托吡酯)、厌食药物(例如硫酸右苯丙胺(dexedrine)、地高辛(digoxin))。提高身体代谢的试剂也属于其他试剂的范围。
在一些实施方案中，其他试剂可以选自食欲抑制剂、神经递质再摄取抑制剂、多巴胺能激动剂、血清素能激动剂、GABA能信号传递调节剂、抗惊厥药、抗抑郁药、单胺氧化酶抑制剂、P物质(NK1)受体拮抗剂、黑皮质素受体激动剂和拮抗剂、脂肪酶抑制剂、脂肪吸收抑制剂、能量摄入或代谢调节剂、大麻素受体调节剂、成瘾治疗剂、代谢综合征治疗剂、过氧化物酶体增殖物激活受体(PPAR)调节剂；二肽基肽酶4(DPP-4)拮抗剂、心血管疾病治疗剂、治疗甘油三酯水平升高的药剂、低HDL治疗剂、高胆固醇血症治疗剂和高血压治疗剂。一些用于心血管疾病的试剂包括他汀类药物(statins)(例如洛伐他汀(lovastatin)、阿托伐他汀(atorvastatin)、氟伐他汀(fluvastatin)、瑞舒伐他汀(rosuvastatin)、辛伐他汀(simvastatin)和普伐他汀(pravastatin))和omega-3试剂(例如LOVAZA、EPANOVA、VASCEPA、酯化omega-3，一般是鱼油、磷虾油、藻油)。在一些实施方案中、其他试剂可以选自苯丙胺类、苯二氮卓类(benzodiazepines)、磺酰脲类(sulfonyl ureas)、氯茴苯酸类(meglitinides)、噻唑啉二酮类(thiazolidinediones)、双胍类(biguanides)、β-阻滞剂(beta-blockers)、ACE抑制剂、利尿药(diuretics)、硝酸盐类、钙通道阻剂、phenlermine、西布曲明、氯卡色林、西替司他(cetilistat)、利莫纳班、他拉纳班(taranabant)、托吡酯、加巴喷丁(gabapentin)、丙戊酸盐、氨己烯酸(vigabatrin)、安非他酮、噻加宾(tiagabine)、舍曲林(sertraline)、氟西汀(fluoxetine)、曲唑酮(trazodone)、唑尼沙胺(zonisamide)、哌甲酯(methylphenidate)、伐尼克兰(varenicline)、纳曲酮(naltrexone)、安非拉酮、苯甲曲秦、瑞格列奈(repaglinide)、那格列胺(nateglinide)、格列美脲(glimepiride)、二甲双胍、吡格列酮(pioglitazone)、罗格列酮(rosiglilazone)和西格列汀(sitagliptin)。
普拉德-威利综合征
在一些实施方案中，该方法涉及普拉德-威利综合征。普拉德-威利综合征是一种复杂的遗传病况，影响身体的许多部位。在婴儿期，该病况的特征是肌张力弱(张力减退)、喂食困难、生长不良和发育延迟。从儿童时期开始，受影响的个体发展出无法满足的食欲，其导致习惯性暴食(饮食过多)和肥胖。在一些实施方案中，受试者患有普拉德-威利综合征。在一些实施方案中，普拉德-威利综合征患者，特别是那些患有肥胖的患者，还形成了2型糖尿病。
脂肪肝疾病
在一些实施方案中，本公开的方法涉及脂肪肝疾病。脂肪肝疾病(也称为非酒精性脂肪性肝炎(NASH))影响相当大的一部分人口。NASH通常与肥胖和糖尿病有关。肝脂肪变性，即肝细胞中存在甘油三酯滴，使肝易患慢性炎症(在活检样品中检测为炎性白细胞的浸润)，其可导致纤维化和肝硬化。尽管脂肪肝疾病的明确诊断往往需要活检，但其检测通常是通过观察到作为肝细胞损伤指标的肝特异酶(例如转氨酶ALT和AST)的血清水平升高，和出现包括疲劳和肝区疼痛的症状。预期优点是肝炎症和脂肪含量减少，导致NASH向纤维化和肝硬化的发展衰减、停止或逆转。在一些实施方案中，该方法减少或预防肝脂肪变性。在一些实施方案中，该方法减少或预防肝纤维化。
在一些实施方案中，该方法是一种通过施用本文所述的miR-22的抑制剂来治疗NASH的方法。NASH患者可以是高危NASH患者。“高危NASH患者”指具有以下的一个或多个特征的患者：NAS≧4；基线纤维化阶段2或3；或具有共病(2型糖尿病、BMI≧30kg/m2或ALT≧60U/L)的基线纤维化阶段1。
在一些实施方案中，miR-22的抑制剂降低以下的一种或多种：脂肪变性、混合性腺泡炎症和肝细胞气球样变性和/或细胞周围纤维化。
在一些实施方案中，miR-22的抑制剂降低一种或多种脂肪变性。
在一些实施方案中，miR-22的抑制剂治疗轻度1级NASH，或中度2级NASH或重度3级NASH，如Brunt等人Am.J.Gastroenterology,第94卷,No.9(1999)中所述，其全文通过引用以其全文并入本文：
轻度，1级包括高达66％的活检的脂肪变性(主要是大泡性的)；偶可见3区气球样变性肝细胞；分散的腺泡内中性粒细胞±腺泡内淋巴细胞；无或轻度的门脉慢性炎症。
中度，2级任何程度的脂肪变性；明显的肝细胞气球样变性(主要是3区)；注意到腺泡内中性粒细胞，可与3区细胞周围纤维化有关；注意到轻度到中度的门脉和腺泡内慢性炎症。
重度，3级全腺泡脂肪变性；明显的气球样变性和无秩序，主要在3区；注意到腺泡内炎症为分散的中性粒细胞，中性粒细胞与气球样变性肝细胞±轻度慢性炎症有关；轻度或中度的门脉慢性炎症(未标记)。
在一些实施方案中，miR-22的抑制剂治疗处于任何以下阶段的NASH：阶段0，无纤维化；阶段1，局部的或广泛的3区细胞周围/肝窦纤维化；阶段2，同阶段1再加上局部的或广泛的门脉纤维化；阶段3，局部的或广泛的桥接纤维化；和阶段4，肝硬化(+/-残留的细胞周围纤维化)。
在一些实施方案中，miR-22的抑制剂治疗任何活性分数(NAS)的NASH，如Kleiner等人,Hepatology,2005.41(6):p.1313-21中所述，其全部内容通过引用以其全文并入本文：
Figure BDA0002776282790000231
*针对小叶炎症，以200x视野对病灶数量进行计数
**少量气球样变性细胞表明了稀少但确定的气球样变性肝细胞以及诊断边界的情况
在一些实施方案中，miR-22的抑制剂使NASH降低至小于8、或小于7、或小于6、或小于5、或小于4、或小于3、或小于2、或小于1。在一些实施方案中，基于AP的使NAS降低至约7、或至约6、或小于5、或小于4、或至约3、至约2或至约1。
在一些实施方案中，miR-22的抑制剂使脂肪变性降低约5％、或约10％、或约15％、或约20％、或约25％、或约30％、或约35％、或约40％、或约45％、或约50％、或约55％、或约60％、或约65％、或约70％、或约75％、或约80％、或约85％、或约90％或约95％。
在一些实施方案中，miR-22的抑制剂使小叶炎症降低至少于4个病灶、或少于3个病灶、或少于2个病灶或少于1个病灶。
在一些实施方案中，miR-22的抑制剂使气球样变性降低至按照上述评分的分数0或1。
在一些实施方案中，miR-22的抑制剂治疗处于NASH的风险中的受试者，例如患有各种获得性代谢疾病，如肥胖、糖尿病(例如2型)、高甘油三酯血症、快速体重减轻和营养不良的受试者。在一些实施方案中，miR-22的抑制剂治疗处于NASH的风险中的受试者，例如患有各种遗传性代谢疾病，如威尔逊病(Wilson disease)、酪氨酸血症和无β脂蛋白血症的受试者。在一些实施方案中，miR-22的抑制剂治疗处于NASH的风险中的受试者，例如遭受多种其他因素，如脂营养不良和空肠回肠旁路术的受试者。在一些实施方案中，miR-22的抑制剂治疗处于NASH的风险中的受试者，例如经历胺碘酮(amiodarone)、化疗剂(例如伊立替康(irinotecan))、他莫昔芬(tamoxifen)、类固醇、雌激素类、己烯雌酚(diethylstilbestrol)、甲氨蝶呤(methotrexate)、钙通道阻滞药(例如，硝苯地平(nifedipine)、维拉帕米(verapamil)和地尔硫卓(diltiazem))的一种或多种的治疗的受试者。
在一些实施方案中，本公开提供了减少或预防纤维化的方法。纤维化的直接标志物包括前胶原类型(I、III、IV型)、基质金属蛋白酶、细胞因子和趋化因子。在一些实施方案中，本发明提供了减少胞外基质合成或防止其增强(例如通过活化的星状细胞)的方法。在一些实施方案中，本发明提供了调节TIMP-1水平的方法。在一些实施方案中，本公开提供了降低或防止透明质酸的血清水平的方法。
在一些实施方案中，使用监测透明质酸、金属蛋白酶-1(TIMP-1)的组织抑制剂和α-2-巨球蛋白(例如FIBROSpect II)的一种或多种的组合测试，来监测miR-22的抑制剂的效果。
在一些实施方案中，本发明提供了减轻或预防肝硬化的方法。
在一些实施方案中，本公开提供了调节血小板计数、凝血酶原时间、白蛋白、总胆红素和血清氨基转移酶的一种或多种的方法。在一些实施方案中，本发明提供了调节血清纤维化标志物(如透明质酸(HA)和α-2-巨球蛋白)的方法。
高胆固醇血症
在一些实施方案中，本公开的方法涉及高胆固醇血症。高胆固醇血症是以血清胆固醇升高为特征的疾病。血清胆固醇水平升高影响相当大的一部分人口，并且是动脉粥样硬化和心肌梗塞的重要危险因素。除本发明的试剂外，还可施用如HMG-CoA还原酶抑制剂(他汀类药物)的降胆固醇药物给高胆固醇血症患者，任选地将其合并成同一药物。在一些实施方案中，低胆固醇血症是家族性高胆固醇血症(on-familialhypercholesterolemia)，该疾病的特征是血清胆固醇升高不是由于单基因突变。在一些实施方案中，高胆固醇血症是多基因高胆固醇血症，该疾病的特征是胆固醇升高是由于多种遗传因素影响。在某些实施方案中，饮食性脂质摄入可使多基因高胆固醇血症加重。在一些实施方案中，高胆固醇血症是家族性高胆固醇血症(FH)，其是以LDL-受体(LDL-R)基因上的突变、LDL-C的显著升高和动脉粥样硬化的过早发作为特征的常染色体显性代谢失调。当个体符合以下标准的一个或多个时，可以作出家族性高胆固醇血症的诊断：基因检测确认2个突变的LDL-受体基因；基因检测确认1个突变的LDL-受体基因；未经治疗的血清LDL-胆固醇大于500mg/dL的历史记录；10岁之前的腱黄瘤(tendinous xanthoma)和/或皮肤黄瘤(cutaneous xanthoma)；或父母双方在降脂疗法前均被记录下血清LDL-胆固醇升高，这与杂合子型家族性高胆固醇血症一致。在一些实施方案中，高胆固醇血症是纯合子型家族性高胆固醇血症或HoFH，该疾病的特征是母源和父源LDL-R基因两者上均有突变。在一些实施方案中，高胆固醇血症是杂合子型家族性高胆固醇血症或HeFH，该疾病的特征是母源或父源LDL-R基因上有突变。
在本公开的方法的一些实施方案中，本公开的野生型人FTO基因由核酸序列(Genbank登录号：NM_001080432.2；SEQ ID NO:13)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人FTO基因由氨基酸序列(Genbank登录号：NP_001073901.1；SEQ ID NO:14)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由核酸序列(Genbank登录号：NM_004364.4，转录物变体1；SEQ ID NO:15)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由氨基酸序列(Genbank登录号：NP_004355.2，转录物变体1；SEQ ID NO:16)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由核酸序列(Genbank登录号：NM_001285829.1，转录物变体2；SEQ ID NO:17)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由氨基酸序列(Genbank登录号：NM_001285829.1，转录物变体2；SEQ ID NO:18)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由核酸序列(Genbank登录号：NM_001287424.1，转录物变体3；SEQ ID NO:19)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由氨基酸序列(Genbank登录号：NP_001274353.1，转录物变体3；SEQ ID NO:20)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由核酸序列(Genbank登录号：NM_001287435.1，转录物变体4；SEQ ID NO:21)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人CEBPa基因由氨基酸序列(Genbank登录号：NP_001274364.1，转录物变体4；SEQ ID NO:22)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由核酸序列(Genbank登录号：NM_138712.3，转录物变体1；SEQ ID NO:23)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由氨基酸序列(Genbank登录号：NP_619726.2，转录物变体1；SEQ ID NO:24)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由核酸序列(Genbank登录号：NM_015869.4，转录物变体2；SEQ ID NO:25)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由氨基酸序列(Genbank登录号：NP_056953.2，转录物变体2；SEQ ID NO:26)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由核酸序列(Genbank登录号：NM_138711.3，转录物变体3；SEQ ID NO:27)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由氨基酸序列(Genbank登录号：NP_619725.2，转录物变体3；SEQ ID NO:28)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由核酸序列Genbank登录号：NM_005037.5，转录物变体4；SEQ ID NO:29)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PPARg基因由氨基酸序列(Genbank登录号：NP_005028.4，转录物变体4；SEQ ID NO:30)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由核酸序列(Genbank登录号：NM_000314.6，转录物变体1；SEQ ID NO:31)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由氨基酸序列(Genbank登录号：NP_000305.3，转录物变体1；SEQ ID NO:32)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由核酸序列(Genbank登录号：NM_001304717.2，转录物变体1；SEQ ID NO:33)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由氨基酸序列(Genbank登录号：NP_001291646.2，转录物变体1；SEQ ID NO:34)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由核酸序列(Genbank登录号：NM_001304718.1，转录物变体2；SEQ ID NO:35)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PTEN基因由氨基酸序列(Genbank登录号：NP_001291647.1，转录物变体2；SEQ ID NO:36)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TET2基因由核酸序列(Genbank登录号：NM_001127208.2，转录物变体1；SEQ ID NO:37)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TET2基因由氨基酸序列(Genbank登录号：NP_001120680.1，转录物变体1；SEQ ID NO:38)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TET2基因由核酸序列(Genbank登录号：NM_017628.4，转录物变体2；SEQ ID NO:39)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TET2基因由氨基酸序列(Genbank登录号：NP_060098.3，转录物变体2；SEQ ID NO:40)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人BMP-7基因由核酸序列(Genbank登录号：NM_001719.2，转录物变体1；SEQ ID NO:41)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人BMP-7基因由氨基酸序列(Genbank登录号：NP_001710.1，转录物变体1；SEQ ID NO:42)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由核酸序列(Genbank登录号：NM_012238.4，转录物变体1；SEQ ID NO:43)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由氨基酸序列(Genbank登录号：NP_036370.2，转录物变体1；SEQ ID NO:44)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由核酸序列(Genbank登录号：NM_001142498.1，转录物变体2；SEQ ID NO:45)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由氨基酸序列(Genbank登录号：NP_001135970.1，转录物变体2；SEQ ID NO:46)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由核酸序列(Genbank登录号：NM_001314049.1，转录物变体3；SEQ ID NO:47)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SIRT-1基因由氨基酸序列(Genbank登录号：NP_001300978.1，转录物变体3；SEQ ID NO:48)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1-α基因由核酸序列(Genbank登录号NM_001330751，转录物变体1；SEQ ID NO:49)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1a基因由氨基酸序列(Genbank登录号NP_001317680：转录物变体2；SEQ ID NO:50)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1-α基因由核酸序列(Genbank登录号NM_013261，转录物变体2；SEQ ID NO:51)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1a基因由氨基酸序列(Genbank登录号NP_037393：转录物变体2；SEQ ID NO:52)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1-α基因由核酸序列(Genbank登录号NM_001330752.1，转录物变体3；SEQ ID NO:53)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1a基因由氨基酸序列(Genbank登录号NP_001317681.1，转录物变体3；SEQ ID NO:54)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1-α基因由核酸序列(Genbank登录号NM_001330753.1，转录物变体4；SEQ ID NO:55)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人PGC1a基因由氨基酸序列(Genbank登录号NP_001317682，转录物变体4；SEQ ID NO:56)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SP-1基因由核酸序列(Genbank登录号NM_138473.2；SEQ ID NO:57)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人SP-1基因由氨基酸序列(Genbank登录号NP_612482；SEQ ID NO:58)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人FGF-21基因由核酸序列(Genbank登录号NM_019113.3；SEQ ID NO:59)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人FGF-21基因由氨基酸序列(Genbank登录号NP 061986.1；SEQ ID NO:60)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人UCP1基因由核酸序列(Genbank登录号NM_021833.4；SEQ ID NO:61)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人UCP1基因由氨基酸序列(Genbank登录号NP_068605.1；SEQ ID NO:62)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人DDIT-4基因由核酸序列(Genbank登录号NM_019058.3；SEQ ID NO:63)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人DDIT-4基因由氨基酸序列(Genbank登录号NP_061931.1；SEQ ID NO:64)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人METTL3基因由核酸序列(Genbank登录号NM_019852.4；SEQ ID NO:65)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人METTL3基因由氨基酸序列(Genbank登录号NP_062826.2；SEQ ID NO:66)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人FGF1基因由核酸序列(Genbank登录号NM_000800.4；SEQ ID NO:67)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人FGF1基因由氨基酸序列(Genbank登录号NP_000791.1；SEQ ID NO:68)组成或包含该氨基酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TP63基因由核酸序列(Genbank登录号NM_001114978.1；SEQ ID NO:69)组成或包含该核酸序列。
在本公开的方法的一些实施方案中，本公开的野生型人TP63基因由氨基酸序列(Genbank登录号NP_001108450.1；SEQ ID NO:70)组成或包含该氨基酸序列。
如本文所用，术语受试者或患者指任何脊椎动物，包括但不限于人和其他灵长类动物(例如，黑猩猩和其他猿类和猴物种)、农场动物(例如，牛、绵羊、猪、山羊和马)、家养动物(例如，狗和猫)、实验动物(例如，啮齿动物，如小鼠、大鼠和豚鼠)和禽类(例如，家养禽类、野生禽类和猎禽类，如鸡、火鸡和其他鹑鸡类禽类，鸭，鹅等)。在一些实施方案中，受试者是哺乳动物。在一些实施方案中，受试者是人。
本发明的另一个实施方案是药物组合物或药物组合物的用途，该药物组合物包含例如miR-22的miRNA的抑制剂和药学上可接受的载体。在考虑临床应用时，可以适合预期应用的形式制备药物组合物。通常，这需要制备基本上不含热原以及其他可对人或动物有害的杂质的组合物。
在一个实施方案中，药物组合物包含有效剂量的miRNA抑制剂(以非限制性示例的形式为针对miR-22的反义寡核苷酸)和药学上可接受的载体。有效剂量为足够产生有益或期望的临床结果的量。本发明的miRNA抑制剂的有效剂量可为约1mg/kg至约100mg/kg、约2.5mg/kg至约50mg/kg或约5mg/kg至约25mg/kg。准确确定何为有效剂量可基于每个患者的个体因素，包括他们的体型大小、年龄、代谢失调的类型以及抑制剂或激动剂的性质(非限制性示例包括antagomir、表达构建体、反义寡核苷酸、多核苷酸双链体等)。因此，本领域中的普通技术人员从本公开和本领域知识可容易地确定剂量。例如，可通过参考Physicians’Desk Reference,第66版,PDR Network；2012版(2011年12月27日)确定剂量，其内容通过引用以其全文并入本文。
有益或期望的治疗结果尤其可以包括与不施用抑制剂时所观察的相比，体重指数的降低、体重减轻或代谢失调的存在有关的标志物的降低。有益的或期望的治疗结果也尤其可以包括与不施用抑制剂时所观察的相比，与代谢失调减少有关的标志物或基因存在的减少或增加。在一些实施方案中，标志物或基因是脂肪量和肥胖相关蛋白(FTO)、CEBPa和/或PPARγ、ALKBH5和ACLY。在一些实施方案中，FTO、CEBPa、PPARa、ACLY、SP-1、PGC1a、ALKBH5、SIRT-1、TP63、FGF1和/或DDIT4的活性和/或表达受到干扰。在一些实施方案中，标志物或基因是脂肪量和肥胖相关蛋白(FTO)。
胶体分散系统，如高分子复合物、纳米胶囊、微球体、珠子和基于脂质的系统(包括油包水乳剂、胶束、混合胶束和脂质体)，可作为递送媒介物用于递送致癌miRNA功能的寡核苷酸抑制剂，编码脂肪相关代谢和合成途径靶标miRNA激动剂的多核苷酸，或表达特定miRNA抑制剂或激动剂的构建体。适用于将本公开的核酸递送至脂肪组织(例如脂肪细胞)的市售脂肪乳剂包括INTRALIPIDO、
Figure BDA0002776282790000321
II、
Figure BDA0002776282790000322
III、Nutrilipid和其他类似的脂质乳剂。用作体内递送媒介物的胶体系统为脂质体(即人造膜囊泡)。这种系统的制备和用途是本领域中熟知的。示例性制剂也公开于US 5,981,505、US6,217,900、US 6,383,512、US 5,783,565、US 7,202,227、US 6,379,965、US 6,127,170、US5,837,533、US 6,747,014和WO 03/093449，以上均通过引用以其全文并入本文。
通常期望采用合适的盐和缓冲液以使递送媒介物稳定并可被靶细胞摄取。本发明的水性组合物包含有效量的递送媒介物，该递送媒介物含有溶解或分散于药学上可接受的载体或水性介质中的抑制剂多寡核苷酸(例如脂质体或其他复合物或表达载体)。短语药学上可接受的或药理学上可接受的指，当施用给动物或人时不产生不利的、过敏的或其他不良的反应的分子实体和组合物。如本文所用，药学上可接受的载体包括可接受用于配制药物(如适合施用给人的药物)的溶剂、缓冲液、溶液、分散介质、包衣、抗细菌和抗真菌剂、等渗剂和吸收延迟剂等。这种介质和试剂用于药物活性物质的用途是本领域中熟知的。除非任何常规介质或试剂与本发明的活性成分不相容，否则考虑这种介质或试剂在治疗组合物中的用途。也可掺入补充的活性成分到组合物中，只要它们不使组合物的载体或多核苷酸失活。
本发明的活性组合物可以包括传统的药物制剂。本发明的这些组合物的施用可以经由任何通常途径进行，只要经由该途径可及于靶组织。这包括经口、经鼻腔或经颊途径。另外，给药可以通过真皮内、皮下、肌肉内、腹膜内或静脉内注射，或通过直接注射到脂肪组织中。本文公开的试剂也可以通过导管系统施用。这样的组合物通常将作为本文所述的药学上可接受的组合物被施用。
活性化合物也可以胃肠道外或腹膜内施用。通过列举说明的方式，可以在适当混合有表面活性剂(如羟丙基纤维素)的水中以游离碱或药理学上可接受的盐制备活性化合物的溶液。也可以在甘油、液态聚乙二醇及其混合物中和在油中制备分散系统。在普通的储存和使用条件下，这些制剂通常含有防腐剂以防止微生物的生长。
合适于注射用途或导管递送的药物形式包括，例如，无菌水溶液或分散系统和无菌粉末，用于临时制备无菌注射溶液或分散系统。通常，这些制剂为无菌流体(至容易注射的程度)。制剂在生产和储存的条件下应是稳定的，且应保存免于微生物如细菌和真菌污染。合适的溶剂或分散介质可包含，例如水、乙醇、多元醇(例如甘油、丙二醇和液态聚乙二醇等)、其合适的混合物和植物油。可例如通过使用包衣如卵磷脂、通过在分散系统的情况下维持所需的粒径以及通过使用表面活性剂，来维持适当的流动性。通过各种抗细菌剂和抗真菌剂，如对羟基苯甲酸酯、三氯叔丁醇、苯酚、山梨酸、硫柳汞等，可防止微生物作用。在许多情况下，优选包括等渗剂例如糖类或氯化钠。通过在组合物中使用延迟吸收的试剂(例如单硬脂酸铝和明胶)，可实现可注射组合物的延长吸收。
通过将适量的活性化合物与所需的任何其他成分(例如，如以上所列举的)一起掺入溶剂中，然后过滤灭菌，可制备无菌可注射溶液。通常，通过将各种灭菌活性成分掺入无菌媒介物中来制备分散系统，该无菌媒介物含有基础分散介质和所需的其他成分，例如以上所列举的。就用于制备无菌可注射溶液的无菌粉末而言，优选的制备方法包括真空干燥和冷冻干燥技术，这两种技术从其先前的无菌过滤溶液中产生活性成分和任何其他所需成分的粉末。
一经配制，溶液可以以与剂量制剂相容的方式且以治疗有效的量来施用。制剂可易于以多种剂型施用，例如注射溶液、药物释放胶囊等。例如，对于在水溶液中的胃肠道外施用，溶液通常经过合适地缓冲，并且首先用例如足够的生理盐水或葡萄糖使液体稀释剂等渗。这样的水溶液可以用于例如静脉内、肌肉内、皮下和腹膜内施用。优选地，采用如本领域技术人员已知的无菌水性介质，根据本发明尤为如此。通过列举说明的方式，可以将单剂量溶解在1ml等渗NaCl溶液中，并且将其加入1000ml皮下输液液体中或在建议的输注位点注射(参见，例如，Remington Pharmaceutical Sciences,第15版,1035-1038页和1570-1580页，其内容通过引用以其全文并入本文)。根据受治疗受试者的病况，剂量上将必然发生一些变化。无论如何，负责施用的人员应确定对于个体受试者的合适剂量。此外，对于人的施用，制剂应符合如FDA生物制品办公室标准所要求的无菌标准、热原标准、通用安全标准和纯度标准。
在一些实施方案中，本公开内容包括一种治疗或预防有此需要的受试者中代谢失调的方法，该方法包括向该受试者施用：第一miRNA的第一抑制剂，其中该miRNA是miR-22，以及第二miRNA的第二抑制剂，其中该miRNA是代谢相关基因的调节剂。在一些实施方案中，第二miRNA是已知的miR抑制剂，以非限制性示例的方式包括在国际专利公开号WO 2012/142313(其内容通过引用以其全文并入本文)中公开的那些。在一些实施方案中，第一和第二抑制剂两者可以以任一顺序(例如，第一然后第二，或第二然后第一)或同时施用。
在一些实施方案中，本公开内容包括一种治疗或预防有此需要的受试者中代谢失调的方法，该方法包括向受试者施用第一试剂和第二试剂，所述第一试剂是或包含miR-22抑制剂，所述第二试剂是或包含至少一种其他代谢失调症的生物制品、治疗物或药物。在一些实施方案中，第一和第二抑制剂两者可以以任一顺序(例如，第一然后第二，或第二然后第一)或同时施用。
本发明还提供了试剂盒，该试剂盒能简化本文所述的任何试剂的施用，例如致癌miRNA的抑制剂(包括针对miR-22的反义寡核苷酸)。本发明的示例性试剂盒以单位剂型包含本文所述的任何组合物。在一个实施方案中，单位剂型是容器，如可以是无菌的预装注射器，其包含本文所述的任何试剂和药学上可接受的载体、稀释剂、赋形剂或媒介物。该试剂盒可以进一步包含指示本文所述任何试剂用途的标签或印刷说明。该试剂盒还可以包含用于施用位置的眼睑窥器(lid speculum)、局部麻醉剂和清洁剂。该试剂盒可进一步包含一种或多种其他试剂，例如致癌miRNA的第二抑制剂，或本文所述的生物制品、治疗物、化疗物或药物。在一个实施方案中，该试剂盒包含含有有效量的本发明的组合物和有效量的另一种组合物(如本文所述的那些)的容器。
实施例
为了可以更有效地理解本文公开的发明，下面提供实施例。应当理解，这些实施例仅用于说明目的，而不应以任何方式解释为限制本发明。
实施例1：MiR-22在肥胖中的作用
miR-22直接靶向PTEN和TET以促进肿瘤发生、转移和其他代谢失调。在人类癌症中研究了超过60个靶向PTEN的miRNA和不少于30个新的原癌基因座。在脊椎动物间高度进化保守，并普遍表达于各种组织中(Lagos-Quintana等，2001，2002；Neely等，2006)。通过靶向PTEN，miR-22保持为代谢相关的，因为PTEN的降低或其升高分别触发Warburg-或anti-Warburg的代谢状态。图2A-D显示了miR-22的过表达影响小鼠体重。
miR-22敲除方法
为了评估对小鼠体重和脂肪积累的影响是否是由于miR-22的过表达引起，并评估期间小鼠体重增加差别和食物消耗差别，将2个月龄小鼠(开始日)、野生型(Wt)和miR-22转基因(Tg)小鼠置于高脂(60％)饮食中。以2次/周监测小鼠体重，并1次/周监测食物用量。(参见图3A-C和图4A-F)。转基因miR-22(Tg)小鼠在非饮食(ND)下发展出肥胖表型，而miR-22敲除(KO)小鼠在HFD下未增加体重。小鼠胚胎成纤维细胞(MEF)miR-22缺陷细胞显示分化脂肪细胞的能力受损。该表型与参与脂肪细胞分化并通常参与脂肪代谢的一组不同基因的基因表达差别有关。另外，结果还表明了miR-22对体重增加的影响与瘦素(或瘦素样)无关(参见图5A-D和图6)。
实施例2：作为肥胖疗法的miR-22抑制
所有LNA anti-miR-22均可用于人和小鼠。宿主基因人和小鼠间显示了49％的互补性，且LNA anti-HG-miR-22主要在人类中起作用。
anti-miR-22锁核酸(LNA)的设计
设计LNA以覆盖种子序列，含有8nt至20nt的长度，具有允许的长度特异的LNA部分和尽可能高的miR-22结合亲和力。
通过优化贴壁细胞系的LNA辅助摄取(Lipo200转染)方案在实验中验证了序列，使用FAM标记的LNA，并通过鉴定在辅助摄取和无辅助摄取下贴壁细胞系中的最有效anti-miR-22(治疗前和后的miR-22水平以及TET2活性和蛋白水平的分析)，来验证生物学效果。目的为在小鼠模型中使用anti-miR，其中将最有效的anti-miR用于体内治疗，确认结果参见图33A-C。在下列序列中，大写字母为修饰的LNA，小写字母为未修饰的；miR-22(SEQ IDNO:1)和anti-miR-22寡核苷酸(SEQ ID NO:2至SEQ ID NO:10)的方向定向为5’至3’。图8显示方向为3’至5’的anti-miR-22寡核苷酸，其与miR-22杂交时即如此。方向为5’至3’的SEQID NO:11和SEQ ID NO:12的寡核苷酸为秩乱序列，且其不与miR-22(SEQ ID NO:1)杂交。
Figure BDA0002776282790000361
Figure BDA0002776282790000371
体内anti-miR-22疗法
参见图9，在用于预防的体内实验计划中，HFD下的2个月龄miR-22-/-和WT用媒介物(VCH)、秩乱对照RNA(SCR)和锁核酸(LNA)转染，并用20mg/kg负荷剂量(第一次)和10mg/kg维持剂量每周IP注射无辅助摄取来处理这些小鼠。经处理和未经处理的小鼠在食物消耗上没有差异，参见图10。在药理学上体内抑制miR-22防止了小鼠变肥胖，且体内anti-miR-22疗法能够增加肝中主要miR-22靶标的蛋白质水平。anti-miR-22治疗不影响肝脂质组成，但显著抑制肝脂肪变性。
为了评估经处理和未经处理的小鼠中的脂肪代谢、合成、分化的潜在基因表达，从经VHL、SCR LNA或LNA anti-miR-22处理的小鼠中提取来自肝、白色脂肪组织(WAT)和棕色脂肪组织(BAT)的RNA，并且确定了参与脂肪相关代谢和合成途径的TET2、PTEN(阳性对照)、FTO、CEBPa、PPARg的mRNA表达以及UCP1和CD36(作为棕色标志物)的mRNA表达(参见图12)。
在治疗方法中，用anti-miR-22-LNA、SCR和VHL处理HFD下的miR-22-/-和WT小鼠，并将这些小鼠置于第二HFD方案。在3.5个月的治疗后，在已肥胖(平均体重>40g)并被喂食HFD的小鼠中观察到体重的显著降低。处死小鼠，收集组织，将来自肝的RNA用于RNAseq(图16A-C，17)。显示在药理学上抑制miR-22使小鼠的肥胖表型回复(图18)。图19A-C是RNA-seq图，其显示了小鼠肝的层次聚类分析，该分析将miR-22的药理学抑制和基因敲除(KO)在一起聚类，表明了治疗是中靶的并且可以使用LNA构建体模拟KO表型；并且图20为显示小鼠肝中基因本体分析的RNA-Seq图，表明经KO和LNA处理的小鼠中自上而下的调节途径与脂质代谢和生物合成有关。体内anti-miR-22疗法强力下调了ACL，并且显示了miR-22的药理学抑制在破坏MEF脂肪细胞分化方面是有效的。
结果表明，anti-miR-22疗法防止在喂食HFD食物时小鼠体重增加，逆转喂食HFD食物的肥胖小鼠的肥胖表型，不影响食物消耗，并有效地体内靶向肝和WAT。另外，anti-miR-22治疗影响miR-22靶基因的蛋白水平，并且不影响任何特定的脂的种类，但能够减少小鼠中全部脂的总量。
实施例3：miR-22控制肥胖以及脂肪量和肥胖相关蛋白(FTO)。
miR-22直接靶向PTEN和TET以促进肿瘤发生和转移。PTEN与许多其他miR-22靶向的基因一样参与代谢和脂肪酸氧化或生物合成，包括例如SIRT-1、BMP-7、PPAR-α、PPAR-γ、SP-1、PGC1a、FGF-21、UCP1、甲基转移酶样蛋白3和DDIT4。在miR-22缺陷MEF中，FTO表达在诱导的脂肪分化期间被显著下调，但WT MEF中并不如此(图26)，并且miR-22的下调(遗传学或药理学上)提高了RNA m6A水平(图27A-B)。显示下调mir-22不影响肝功能或显示年老时任何与肝有关的疾病或功能障碍(图28A-B，29)。
为评估miR-22的过表达是否影响肝功能、脂肪肝和纤维化，以常规饮食喂养8至10个月龄小鼠。显示miR-22OE导致脂肪肝并增加存在的FSP-1阳性细胞。FSP-1识别肝中与纤维化有关的巨噬细胞亚群。
总而言之，miR-22是onco-miR(靶向PTEN，MEF转化，EMT)，miR-22在人和小鼠中100％保守，在ND下miR-22OE导致肥胖表型，在HFD下miR-22KO小鼠不增加体重，在药理学上沉默miR-22破坏了MEF和人MES分化为脂肪细胞，LNA anti-miR-22治疗在预防设定下防止小鼠变肥胖，LNA anti-miR-22治疗使用HFD喂养的肥胖小鼠中的肥胖表型回复，miR-22沉默不显示任何肝毒性，miR-22沉默预防肝的脂肪变性和纤维化，miR-22可以同时靶向与代谢和脂质生物发生有关的多个基因。
其他实施方案
应当理解，尽管已经结合本公开的详细描述描述了本公开，但在前的描述旨在说明，而非限制由所附权利要求的范围限定的本公开的范围。其他方面、优点和修饰都在以下权利要求的范围内。
通过引用并入
本文引用的所有专利和出版物均通过引用以其全文并入本文。
提供本文讨论的出版物仅因为其在本申请提交日期之前公开。本文中的任何内容均不得解释为承认本发明无权凭借在先发明而早于这些出版物。
如本文所用，所有标题仅用于组织，并不旨在以任何方式限制公开内容。
序列表
<110> 贝斯以色列女执事医疗中心（BETH ISRAEL DEACONESS MEDICAL CENTER）
R·潘内拉（PANELLA, Riccardo）
P·P·潘多雷尔（PANDOLFI, Pier Paolo）
<120> micro-RNA和肥胖
<130> BID-005PC1
<150> US 62/642,934
<151> 2018-03-14
<160> 82
<170> PatentIn version 3.5
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<220>
<221> misc_feature
<222> (9)..(9)
<223> LNA
<220>
<221> misc_feature
<222> (11)..(13)
<223> LNA
<220>
<221> misc_feature
<222> (15)..(16)
<223> LNA
<400> 8
tcgacggtca acttct 16
<210> 9
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<220>
<221> misc_feature
<222> (1)..(2)
<223> LNA
<220>
<221> misc_feature
<222> (5)..(7)
<223> LNA
<220>
<221> misc_feature
<222> (10)..(10)
<223> LNA
<220>
<221> misc_feature
<222> (12)..(14)
<223> LNA
<220>
<221> misc_feature
<222> (16)..(17)
<223> LNA
<400> 9
tcgacggtca acttctt 17
<210> 10
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<220>
<221> misc_feature
<222> (1)..(2)
<223> LNA
<220>
<221> misc_feature
<222> (6)..(6)
<223> LNA
<220>
<221> misc_feature
<222> (10)..(10)
<223> LNA
<220>
<221> misc_feature
<222> (13)..(14)
<223> LNA
<220>
<221> misc_feature
<222> (16)..(18)
<223> LNA
<400> 10
tcgacggtca acttcttg 18
<210> 11
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<220>
<221> misc_feature
<222> (1)..(2)
<223> LNA
<220>
<221> misc_feature
<222> (4)..(6)
<223> LNA
<220>
<221> misc_feature
<222> (8)..(8)
<223> LNA
<220>
<221> misc_feature
<222> (11)..(13)
<223> LNA
<220>
<221> misc_feature
<222> (15)..(16)
<223> LNA
<400> 11
gcgatgattg ataagc 16
<210> 12
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<220>
<221> misc_feature
<222> (1)..(2)
<223> LNA
<220>
<221> misc_feature
<222> (4)..(6)
<223> LNA
<220>
<221> misc_feature
<222> (8)..(8)
<223> LNA
<220>
<221> misc_feature
<222> (11)..(13)
<223> LNA
<220>
<221> misc_feature
<222> (15)..(16)
<223> LNA
<400> 12
gcgatgattg ataagc 16
<210> 13
<211> 4313
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 13
ctacgctctt ccagctgtcg gacctgggaa attctcctgt gctaaatccc gtggcgctcg 60
cgggtgtcgc cgcggtgcat cctgggagtt gtagtttttt ctactcagag ggagaatagc 120
tccagacggg agcaggacgc tgagagaact acatgcagga ggcggggtcc agggcgaggg 180
atctacgcag cttgcggtgg cgaaggcggc tttagtggca gcatgaagcg caccccgact 240
gccgaggaac gagagcgcga agctaagaaa ctgaggcttc ttgaagagct tgaagacact 300
tggctccctt atctgacccc caaagatgat gaattctatc agcagtggca gctgaaatat 360
cctaaactaa ttctccgaga agccagcagt gtatctgagg agctccataa agaggttcaa 420
gaagcctttc tcacactgca caagcatggc tgcttatttc gggacctggt taggatccaa 480
ggcaaagatc tgctcactcc ggtatctcgc atcctcattg gtaatccagg ctgcacctac 540
aagtacctga acaccaggct ctttacggtc ccctggccag tgaaagggtc taatataaaa 600
cacaccgagg ctgaaatagc cgctgcttgt gagaccttcc tcaagctcaa tgactacctg 660
cagatagaaa ccatccaggc tttggaagaa cttgctgcca aagagaaggc taatgaggat 720
gctgtgccat tgtgtatgtc tgcagatttc cccagggttg ggatgggttc atcctacaac 780
ggacaagatg aagtggacat taagagcaga gcagcataca acgtaacttt gctgaatttc 840
atggatcctc agaaaatgcc atacctgaaa gaggaacctt attttggcat ggggaaaatg 900
gcagtgagct ggcatcatga tgaaaatctg gtggacaggt cagcggtggc agtgtacagt 960
tatagctgtg aaggccctga agaggaaagt gaggatgact ctcatctcga aggcagggat 1020
cctgatattt ggcatgttgg ttttaagatc tcatgggaca tagagacacc tggtttggcg 1080
ataccccttc accaaggaga ctgctatttc atgcttgatg atctcaatgc cacccaccaa 1140
cactgtgttt tggccggttc acaacctcgg tttagttcca cccaccgagt ggcagagtgc 1200
tcaacaggaa ccttggatta tattttacaa cgctgtcagt tggctctgca gaatgtctgt 1260
gacgatgtgg acaatgatga tgtctctttg aaatcctttg agcctgcagt tttgaaacaa 1320
ggagaagaaa ttcataatga ggtcgagttt gagtggctga ggcagttttg gtttcaaggc 1380
aatcgataca gaaagtgcac tgactggtgg tgtcaaccca tggctcaact ggaagcactg 1440
tggaagaaga tggagggtgt gacaaatgct gtgcttcatg aagttaaaag agaggggctc 1500
cccgtggaac aaaggaatga aatcttgact gccatccttg cctcgctcac tgcacgccag 1560
aacctgagga gagaatggca tgccaggtgc cagtcacgaa ttgcccgaac attacctgct 1620
gatcagaagc cagaatgtcg gccatactgg gaaaaggatg atgcttcgat gcctctgccg 1680
tttgacctca cagacatcgt ttcagaactc agaggtcagc ttctggaagc aaaaccctag 1740
aaggagcaca agtctcaggc ggaggagaaa aagagatcgg cttttctcct ccaacgttgt 1800
catgggctta agcaagagca gtggagactt ctcttggccc ctagattgta gcacccgggt 1860
cccaatccaa aacagctagg aaatggtgcc catgaagttt taaatgtttt aaaatgaccc 1920
tgtgttatag tctgatttgg tgttaaacag gaccttcttc ccccaaaatt gttcagatta 1980
taaaatgtga gccattcagc ccccaaggtc cagggcaggc gacaggaacg agcccagcgt 2040
gtgacaaagc ctaacctact ttcctctttc ccaagctttt tcagagactc tggagtggac 2100
ccagccctct ggggaaagac agaacttaga gacatcccag ttactcacca cacccatagt 2160
gctgtccaat atggtagcca ctagctagct gtggctactt caatttaaat tcagttttaa 2220
ttttaattaa aaatgcagct cttcagtcgc cctggccaca tttcaagtgc ttaacagcct 2280
catgtggcta gtgactgctg tattggacgg tacagatatg gaacattttc atcatcgaag 2340
aaagtcctat tggacaacac ttctataaaa agtttgagag caggaattct catttccatt 2400
cgtctgtagc ttctatcccc aaaggcaaag aaactaaaag agaaatgact cattgaagat 2460
tggcctcttt cctttctcta agacaaacct aagtaaaagc ctgagctttg agtcctatgc 2520
tcagcacacg ggaaggagat gttaataatt aaaataaagt tgatatcctg tctttaggga 2580
gttcccttga tctcttgaaa gagacacagc cccatttaca ttatttcgtg gatttcacca 2640
gcatagtata gtttttttct gtaagtccct cattcttatg taataacagg tggaactgag 2700
gtttgaagaa cctcagtggc ccatcctgat gacattggag actcaaagag acaagagaga 2760
gtagggttta aaacctgagc tttaagactc ccactagctt cgtgtccttt ggcatgttaa 2820
cgtgcctcag tttcctcatc tgtataatgg ggatatatga aaggcaccag tcctaaggtg 2880
aacattaagt gagatgattc tagttacaga cttagaacaa tttccagcac atagttaaat 2940
atccaggaaa ttctggtact gttatgtgtg ggtgagctga cctggatgta gatgttttcc 3000
tctctcttgc tgacccctcc gccagttttg tcttgtgatg ccattaacac atctctccct 3060
ttctgacctg gctcctgccc attggtgtcc caagaaatcg tgagaatagt tagccccccg 3120
tctccccagc ctgttgcttt ctcgtgtagt tgttcacagt agttgagaag ttgaagagct 3180
tttgcctatt gaaggtgcac tgagaataaa ctctttcctg ccaccagaat tgcagtggtt 3240
cacggcctgc actcattccc atgaatgcag ttaatagcca cagaaatgtc acattaagca 3300
aagcagccag ggtctcatcg tgttgagact cgagtctctc agaccttgga ttcattccct 3360
ggtgtctttg agcctcagtt tcctcattgg taaaagagaa gtgaagcagt gtctcacagg 3420
gtcattacag agattaaatg aaataaatga aataacatag accaggaggg cgtggtgttt 3480
aaaagtcaca gatggggcac cctcgggcca tccagcccag tgttttcttt agcccctatg 3540
atgttcattt tttgttatat cccattaggt gcccatattt aaaaattggg agatttcaca 3600
taaaattaaa aggtctgcat tttctttttt cttttctttt tttttttttt tgagacacag 3660
tctcactctg tcaccaggct agagtgcagt ggcacgatct cagctcactg caacctctgc 3720
ctcccaggtt caagtaattc tcctgcctca gcctcccaag tagctgggac tacaggcacg 3780
tgccaccacg cccagctaat ttttgtattt ttagcagaga tggggtttca ccacattggc 3840
caggatggtc tcgatctcaa cctcgtgatc cacccacctc ggtctcccaa agcgctggga 3900
ttacaggcgt gagccaccgc gccaagccaa ggtctgcatt tttctttaga actcagaaca 3960
cccaatagtc ctaggccccc atcctcgcat ggcagcaagc taaataagca tcttcccact 4020
gcgagttggg gcatgaccca gcctatggtt tgccatactc cctctttttc tccgtttttt 4080
cattaattgt gaacctgacc tgcatcaccc tttcatgtca gtgctctcca aacctgcttg 4140
cttgcacccc tctagtcgaa atattttgtg cttaccccaa tatatgtgtg tgactattga 4200
actctattcg tagactgctt gtactaatgt catttgcatc ataaaatatt catatccaat 4260
aaacatatta aaaggatgag ataagaaacc gaaaaaaaaa aaaaaaaaaa aaa 4313
<210> 14
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 14
Met Lys Arg Thr Pro Thr Ala Glu Glu Arg Glu Arg Glu Ala Lys Lys
1 5 10 15
Leu Arg Leu Leu Glu Glu Leu Glu Asp Thr Trp Leu Pro Tyr Leu Thr
20 25 30
Pro Lys Asp Asp Glu Phe Tyr Gln Gln Trp Gln Leu Lys Tyr Pro Lys
35 40 45
Leu Ile Leu Arg Glu Ala Ser Ser Val Ser Glu Glu Leu His Lys Glu
50 55 60
Val Gln Glu Ala Phe Leu Thr Leu His Lys His Gly Cys Leu Phe Arg
65 70 75 80
Asp Leu Val Arg Ile Gln Gly Lys Asp Leu Leu Thr Pro Val Ser Arg
85 90 95
Ile Leu Ile Gly Asn Pro Gly Cys Thr Tyr Lys Tyr Leu Asn Thr Arg
100 105 110
Leu Phe Thr Val Pro Trp Pro Val Lys Gly Ser Asn Ile Lys His Thr
115 120 125
Glu Ala Glu Ile Ala Ala Ala Cys Glu Thr Phe Leu Lys Leu Asn Asp
130 135 140
Tyr Leu Gln Ile Glu Thr Ile Gln Ala Leu Glu Glu Leu Ala Ala Lys
145 150 155 160
Glu Lys Ala Asn Glu Asp Ala Val Pro Leu Cys Met Ser Ala Asp Phe
165 170 175
Pro Arg Val Gly Met Gly Ser Ser Tyr Asn Gly Gln Asp Glu Val Asp
180 185 190
Ile Lys Ser Arg Ala Ala Tyr Asn Val Thr Leu Leu Asn Phe Met Asp
195 200 205
Pro Gln Lys Met Pro Tyr Leu Lys Glu Glu Pro Tyr Phe Gly Met Gly
210 215 220
Lys Met Ala Val Ser Trp His His Asp Glu Asn Leu Val Asp Arg Ser
225 230 235 240
Ala Val Ala Val Tyr Ser Tyr Ser Cys Glu Gly Pro Glu Glu Glu Ser
245 250 255
Glu Asp Asp Ser His Leu Glu Gly Arg Asp Pro Asp Ile Trp His Val
260 265 270
Gly Phe Lys Ile Ser Trp Asp Ile Glu Thr Pro Gly Leu Ala Ile Pro
275 280 285
Leu His Gln Gly Asp Cys Tyr Phe Met Leu Asp Asp Leu Asn Ala Thr
290 295 300
His Gln His Cys Val Leu Ala Gly Ser Gln Pro Arg Phe Ser Ser Thr
305 310 315 320
His Arg Val Ala Glu Cys Ser Thr Gly Thr Leu Asp Tyr Ile Leu Gln
325 330 335
Arg Cys Gln Leu Ala Leu Gln Asn Val Cys Asp Asp Val Asp Asn Asp
340 345 350
Asp Val Ser Leu Lys Ser Phe Glu Pro Ala Val Leu Lys Gln Gly Glu
355 360 365
Glu Ile His Asn Glu Val Glu Phe Glu Trp Leu Arg Gln Phe Trp Phe
370 375 380
Gln Gly Asn Arg Tyr Arg Lys Cys Thr Asp Trp Trp Cys Gln Pro Met
385 390 395 400
Ala Gln Leu Glu Ala Leu Trp Lys Lys Met Glu Gly Val Thr Asn Ala
405 410 415
Val Leu His Glu Val Lys Arg Glu Gly Leu Pro Val Glu Gln Arg Asn
420 425 430
Glu Ile Leu Thr Ala Ile Leu Ala Ser Leu Thr Ala Arg Gln Asn Leu
435 440 445
Arg Arg Glu Trp His Ala Arg Cys Gln Ser Arg Ile Ala Arg Thr Leu
450 455 460
Pro Ala Asp Gln Lys Pro Glu Cys Arg Pro Tyr Trp Glu Lys Asp Asp
465 470 475 480
Ala Ser Met Pro Leu Pro Phe Asp Leu Thr Asp Ile Val Ser Glu Leu
485 490 495
Arg Gly Gln Leu Leu Glu Ala Lys Pro
500 505
<210> 15
<211> 2631
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 15
tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60
cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120
tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180
ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240
ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300
ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360
gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420
gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480
gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540
tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600
ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660
aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720
cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780
gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840
cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900
agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960
gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020
cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080
cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140
ctgagccgcg aactggacac gctgcggggc atcttccgcc agctgccaga gagctccttg 1200
gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260
tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320
gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380
ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440
ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtattta 1500
ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga 1560
gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620
gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680
gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740
aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800
agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860
ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920
gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980
tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040
gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100
gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160
ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220
atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280
tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340
ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400
ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460
tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520
ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580
actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631
<210> 16
<211> 358
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 16
Met Glu Ser Ala Asp Phe Tyr Glu Ala Glu Pro Arg Pro Pro Met Ser
1 5 10 15
Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala Ala Phe Gly
20 25 30
Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro Pro Ala Ala
35 40 45
Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser Ile Asp Ile
50 55 60
Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe Leu Ala Asp
65 70 75 80
Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala Ala Val Gly
85 90 95
Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro Gly Ala Pro
100 105 110
Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His Gly Pro Pro
115 120 125
Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly Arg Leu Glu
130 135 140
Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro Leu Val Ile
145 150 155 160
Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu Ala Leu Ala
165 170 175
Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro Ser His Pro
180 185 190
His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His Leu Gln Phe
195 200 205
Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln Pro Gly His
210 215 220
Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro Ala Pro Ala
225 230 235 240
Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu Lys Gly Leu
245 250 255
Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser Gly Ala Gly
260 265 270
Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr Arg Val Arg
275 280 285
Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp Lys Ala Lys
290 295 300
Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu Thr Ser Asp
305 310 315 320
Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg Glu Leu Asp
325 330 335
Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser Leu Val Lys
340 345 350
Ala Met Gly Asn Cys Ala
355
<210> 17
<211> 2631
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 17
tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60
cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120
tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180
ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240
ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300
ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360
gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420
gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480
gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540
tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600
ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660
aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720
cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780
gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840
cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900
agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960
gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020
cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080
cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140
ctgagccgcg aactggacac gctgcggggc atcttccgcc agctgccaga gagctccttg 1200
gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260
tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320
gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380
ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440
ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtattta 1500
ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga 1560
gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620
gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680
gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740
aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800
agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860
ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920
gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980
tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040
gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100
gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160
ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220
atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280
tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340
ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400
ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460
tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520
ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580
actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631
<210> 18
<211> 239
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 18
Met Pro Gly Gly Ala His Gly Pro Pro Pro Gly Tyr Gly Cys Ala Ala
1 5 10 15
Ala Gly Tyr Leu Asp Gly Arg Leu Glu Pro Leu Tyr Glu Arg Val Gly
20 25 30
Ala Pro Ala Leu Arg Pro Leu Val Ile Lys Gln Glu Pro Arg Glu Glu
35 40 45
Asp Glu Ala Lys Gln Leu Ala Leu Ala Gly Leu Phe Pro Tyr Gln Pro
50 55 60
Pro Pro Pro Pro Pro Pro Ser His Pro His Pro His Pro Pro Pro Ala
65 70 75 80
His Leu Ala Ala Pro His Leu Gln Phe Gln Ile Ala His Cys Gly Gln
85 90 95
Thr Thr Met His Leu Gln Pro Gly His Pro Thr Pro Pro Pro Thr Pro
100 105 110
Val Pro Ser Pro His Pro Ala Pro Ala Leu Gly Ala Ala Gly Leu Pro
115 120 125
Gly Pro Gly Ser Ala Leu Lys Gly Leu Gly Ala Ala His Pro Asp Leu
130 135 140
Arg Ala Ser Gly Gly Ser Gly Ala Gly Lys Ala Lys Lys Ser Val Asp
145 150 155 160
Lys Asn Ser Asn Glu Tyr Arg Val Arg Arg Glu Arg Asn Asn Ile Ala
165 170 175
Val Arg Lys Ser Arg Asp Lys Ala Lys Gln Arg Asn Val Glu Thr Gln
180 185 190
Gln Lys Val Leu Glu Leu Thr Ser Asp Asn Asp Arg Leu Arg Lys Arg
195 200 205
Val Glu Gln Leu Ser Arg Glu Leu Asp Thr Leu Arg Gly Ile Phe Arg
210 215 220
Gln Leu Pro Glu Ser Ser Leu Val Lys Ala Met Gly Asn Cys Ala
225 230 235
<210> 19
<211> 2631
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 19
tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60
cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120
tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180
ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240
ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300
ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360
gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420
gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480
gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540
tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600
ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660
aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720
cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780
gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840
cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900
agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960
gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020
cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080
cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140
ctgagccgcg aactggacac gctgcggggc atcttccgcc agctgccaga gagctccttg 1200
gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260
tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320
gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380
ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440
ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtattta 1500
ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga 1560
gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620
gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680
gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740
aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800
agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860
ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920
gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980
tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040
gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100
gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160
ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220
atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280
tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340
ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400
ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460
tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520
ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580
actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631
<210> 20
<211> 393
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 20
Met Arg Gly Arg Gly Arg Ala Gly Ser Pro Gly Gly Arg Arg Arg Arg
1 5 10 15
Pro Ala Gln Ala Gly Gly Arg Arg Gly Ser Pro Cys Arg Glu Asn Ser
20 25 30
Asn Ser Pro Met Glu Ser Ala Asp Phe Tyr Glu Ala Glu Pro Arg Pro
35 40 45
Pro Met Ser Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala
50 55 60
Ala Phe Gly Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro
65 70 75 80
Pro Ala Ala Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser
85 90 95
Ile Asp Ile Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe
100 105 110
Leu Ala Asp Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala
115 120 125
Ala Val Gly Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro
130 135 140
Gly Ala Pro Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His
145 150 155 160
Gly Pro Pro Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly
165 170 175
Arg Leu Glu Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro
180 185 190
Leu Val Ile Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu
195 200 205
Ala Leu Ala Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro
210 215 220
Ser His Pro His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His
225 230 235 240
Leu Gln Phe Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln
245 250 255
Pro Gly His Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro
260 265 270
Ala Pro Ala Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu
275 280 285
Lys Gly Leu Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser
290 295 300
Gly Ala Gly Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr
305 310 315 320
Arg Val Arg Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp
325 330 335
Lys Ala Lys Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu
340 345 350
Thr Ser Asp Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg
355 360 365
Glu Leu Asp Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser
370 375 380
Leu Val Lys Ala Met Gly Asn Cys Ala
385 390
<210> 21
<211> 2631
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 21
tataaaagct gggccggcgc gggccgggcc attcgcgacc cggaggtgcg cgggcgcggg 60
cgagcagggt ctccgggtgg gcggcggcga cgccccgcgc aggctggagg ccgccgaggc 120
tcgccatgcc gggagaactc taactccccc atggagtcgg ccgacttcta cgaggcggag 180
ccgcggcccc cgatgagcag ccacctgcag agccccccgc acgcgcccag cagcgccgcc 240
ttcggctttc cccggggcgc gggccccgcg cagcctcccg ccccacctgc cgccccggag 300
ccgctgggcg gcatctgcga gcacgagacg tccatcgaca tcagcgccta catcgacccg 360
gccgccttca acgacgagtt cctggccgac ctgttccagc acagccggca gcaggagaag 420
gccaaggcgg ccgtgggccc cacgggcggc ggcggcggcg gcgactttga ctacccgggc 480
gcgcccgcgg gccccggcgg cgccgtcatg cccgggggag cgcacgggcc cccgcccggc 540
tacggctgcg cggccgccgg ctacctggac ggcaggctgg agcccctgta cgagcgcgtc 600
ggggcgccgg cgctgcggcc gctggtgatc aagcaggagc cccgcgagga ggatgaagcc 660
aagcagctgg cgctggccgg cctcttccct taccagccgc cgccgccgcc gccgccctcg 720
cacccgcacc cgcacccgcc gcccgcgcac ctggccgccc cgcacctgca gttccagatc 780
gcgcactgcg gccagaccac catgcacctg cagcccggtc accccacgcc gccgcccacg 840
cccgtgccca gcccgcaccc cgcgcccgcg ctcggtgccg ccggcctgcc gggccctggc 900
agcgcgctca aggggctggg cgccgcgcac cccgacctcc gcgcgagtgg cggcagcggc 960
gcgggcaagg ccaagaagtc ggtggacaag aacagcaacg agtaccgggt gcggcgcgag 1020
cgcaacaaca tcgcggtgcg caagagccgc gacaaggcca agcagcgcaa cgtggagacg 1080
cagcagaagg tgctggagct gaccagtgac aatgaccgcc tgcgcaagcg ggtggaacag 1140
ctgagccgcg aactggacac gctgcggggc atcttccgcc agctgccaga gagctccttg 1200
gtcaaggcca tgggcaactg cgcgtgaggc gcgcggctgt gggaccgccc tgggccagcc 1260
tccggcgggg acccagggag tggtttgggg tcgccggatc tcgaggcttg cccgagccgt 1320
gcgagccagg actaggagat tccggtgcct cctgaaagcc tggcctgctc cgcgtgtccc 1380
ctcccttcct ctgcgccgga cttggtgcgt ctaagatgag ggggccaggc ggtggcttct 1440
ccctgcgagg aggggagaat tcttggggct gagctgggag cccggcaact ctagtattta 1500
ggataacctt gtgccttgga aatgcaaact caccgctcca atgcctactg agtaggggga 1560
gcaaatcgtg ccttgtcatt ttatttggag gtttcctgcc tccttcccga ggctacagca 1620
gacccccatg agagaaggag gggagcaggc ccgtggcagg aggagggctc agggagctga 1680
gatcccgaca agcccgccag ccccagccgc tcctccacgc ctgtccttag aaaggggtgg 1740
aaacataggg acttggggct tggaacctaa ggttgttccc ctagttctac atgaaggtgg 1800
agggtctcta gttccacgcc tctcccacct ccctccgcac acaccccacc ccagcctgct 1860
ataggctggg cttccccttg gggcggaact cactgcgatg ggggtcacca ggtgaccagt 1920
gggagccccc accccgagtc acaccagaaa gctaggtcgt gggtcagctc tgaggatgta 1980
tacccctggt gggagaggga gacctagaga tctggctgtg gggcgggcat ggggggtgaa 2040
gggccactgg gaccctcagc cttgtttgta ctgtatgcct tcagcattgc ctaggaacac 2100
gaagcacgat cagtccatcc cagagggacc ggagttatga caagctttcc aaatattttg 2160
ctttatcagc cgatatcaac acttgtatct ggcctctgtg ccccagcagt gccttgtgca 2220
atgtgaatgt gcgcgtctct gctaaaccac cattttattt ggtttttgtt ttgttttggt 2280
tttgctcgga tacttgccaa aatgagactc tccgtcggca gctgggggaa gggtctgaga 2340
ctccctttcc ttttggtttt gggattactt ttgatcctgg gggaccaatg aggtgagggg 2400
ggttctcctt tgccctcagc tttccccagc ccctccggcc tgggctgccc acaaggcttg 2460
tcccccagag gccctggctc ctggtcggga agggaggtgg cctcccgcca acgcatcact 2520
ggggctggga gcagggaagg acggcttggt tctcttcttt tggggagaac gtagagtctc 2580
actctagatg ttttatgtat tatatctata atataaacat atcaaagtca a 2631
<210> 22
<211> 344
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 22
Met Ser Ser His Leu Gln Ser Pro Pro His Ala Pro Ser Ser Ala Ala
1 5 10 15
Phe Gly Phe Pro Arg Gly Ala Gly Pro Ala Gln Pro Pro Ala Pro Pro
20 25 30
Ala Ala Pro Glu Pro Leu Gly Gly Ile Cys Glu His Glu Thr Ser Ile
35 40 45
Asp Ile Ser Ala Tyr Ile Asp Pro Ala Ala Phe Asn Asp Glu Phe Leu
50 55 60
Ala Asp Leu Phe Gln His Ser Arg Gln Gln Glu Lys Ala Lys Ala Ala
65 70 75 80
Val Gly Pro Thr Gly Gly Gly Gly Gly Gly Asp Phe Asp Tyr Pro Gly
85 90 95
Ala Pro Ala Gly Pro Gly Gly Ala Val Met Pro Gly Gly Ala His Gly
100 105 110
Pro Pro Pro Gly Tyr Gly Cys Ala Ala Ala Gly Tyr Leu Asp Gly Arg
115 120 125
Leu Glu Pro Leu Tyr Glu Arg Val Gly Ala Pro Ala Leu Arg Pro Leu
130 135 140
Val Ile Lys Gln Glu Pro Arg Glu Glu Asp Glu Ala Lys Gln Leu Ala
145 150 155 160
Leu Ala Gly Leu Phe Pro Tyr Gln Pro Pro Pro Pro Pro Pro Pro Ser
165 170 175
His Pro His Pro His Pro Pro Pro Ala His Leu Ala Ala Pro His Leu
180 185 190
Gln Phe Gln Ile Ala His Cys Gly Gln Thr Thr Met His Leu Gln Pro
195 200 205
Gly His Pro Thr Pro Pro Pro Thr Pro Val Pro Ser Pro His Pro Ala
210 215 220
Pro Ala Leu Gly Ala Ala Gly Leu Pro Gly Pro Gly Ser Ala Leu Lys
225 230 235 240
Gly Leu Gly Ala Ala His Pro Asp Leu Arg Ala Ser Gly Gly Ser Gly
245 250 255
Ala Gly Lys Ala Lys Lys Ser Val Asp Lys Asn Ser Asn Glu Tyr Arg
260 265 270
Val Arg Arg Glu Arg Asn Asn Ile Ala Val Arg Lys Ser Arg Asp Lys
275 280 285
Ala Lys Gln Arg Asn Val Glu Thr Gln Gln Lys Val Leu Glu Leu Thr
290 295 300
Ser Asp Asn Asp Arg Leu Arg Lys Arg Val Glu Gln Leu Ser Arg Glu
305 310 315 320
Leu Asp Thr Leu Arg Gly Ile Phe Arg Gln Leu Pro Glu Ser Ser Leu
325 330 335
Val Lys Ala Met Gly Asn Cys Ala
340
<210> 23
<211> 1892
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 23
ggcgcccgcg cccgcccccg cgccgggccc ggctcggccc gacccggctc cgccgcgggc 60
aggcggggcc cagcgcactc ggagcccgag cccgagccgc agccgccgcc tggggcgctt 120
gggtcggcct cgaggacacc ggagaggggc gccacgccgc cgtggccgca gatttgaaag 180
aagccaacac taaaccacaa atatacaaca aggccatttt ctcaaacgag agtcagcctt 240
taacgaaatg accatggttg acacagagat gccattctgg cccaccaact ttgggatcag 300
ctccgtggat ctctccgtaa tggaagacca ctcccactcc tttgatatca agcccttcac 360
tactgttgac ttctccagca tttctactcc acattacgaa gacattccat tcacaagaac 420
agatccagtg gttgcagatt acaagtatga cctgaaactt caagagtacc aaagtgcaat 480
caaagtggag cctgcatctc caccttatta ttctgagaag actcagctct acaataagcc 540
tcatgaagag ccttccaact ccctcatggc aattgaatgt cgtgtctgtg gagataaagc 600
ttctggattt cactatggag ttcatgcttg tgaaggatgc aagggtttct tccggagaac 660
aatcagattg aagcttatct atgacagatg tgatcttaac tgtcggatcc acaaaaaaag 720
tagaaataaa tgtcagtact gtcggtttca gaaatgcctt gcagtgggga tgtctcataa 780
tgccatcagg tttgggcgga tgccacaggc cgagaaggag aagctgttgg cggagatctc 840
cagtgatatc gaccagctga atccagagtc cgctgacctc cgggccctgg caaaacattt 900
gtatgactca tacataaagt ccttcccgct gaccaaagca aaggcgaggg cgatcttgac 960
aggaaagaca acagacaaat caccattcgt tatctatgac atgaattcct taatgatggg 1020
agaagataaa atcaagttca aacacatcac ccccctgcag gagcagagca aagaggtggc 1080
catccgcatc tttcagggct gccagtttcg ctccgtggag gctgtgcagg agatcacaga 1140
gtatgccaaa agcattcctg gttttgtaaa tcttgacttg aacgaccaag taactctcct 1200
caaatatgga gtccacgaga tcatttacac aatgctggcc tccttgatga ataaagatgg 1260
ggttctcata tccgagggcc aaggcttcat gacaagggag tttctaaaga gcctgcgaaa 1320
gccttttggt gactttatgg agcccaagtt tgagtttgct gtgaagttca atgcactgga 1380
attagatgac agcgacttgg caatatttat tgctgtcatt attctcagtg gagaccgccc 1440
aggtttgctg aatgtgaagc ccattgaaga cattcaagac aacctgctac aagccctgga 1500
gctccagctg aagctgaacc accctgagtc ctcacagctg tttgccaagc tgctccagaa 1560
aatgacagac ctcagacaga ttgtcacgga acacgtgcag ctactgcagg tgatcaagaa 1620
gacggagaca gacatgagtc ttcacccgct cctgcaggag atctacaagg acttgtacta 1680
gcagagagtc ctgagccact gccaacattt cccttcttcc agttgcacta ttctgaggga 1740
aaatctgaca cctaagaaat ttactgtgaa aaagcatttt aaaaagaaaa ggttttagaa 1800
tatgatctat tttatgcata ttgtttataa agacacattt acaatttact tttaatatta 1860
aaaattacca tattatgaaa ttgctgatag ta 1892
<210> 24
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 24
Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly
1 5 10 15
Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe
20 25 30
Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro
35 40 45
His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp
50 55 60
Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val
65 70 75 80
Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn
85 90 95
Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg
100 105 110
Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys
115 120 125
Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile
130 135 140
Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Lys Ser Arg Asn
145 150 155 160
Lys Cys Gln Tyr Cys Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser
165 170 175
His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys
180 185 190
Leu Leu Ala Glu Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser
195 200 205
Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys
210 215 220
Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys
225 230 235 240
Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met
245 250 255
Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu
260 265 270
Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg
275 280 285
Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro
290 295 300
Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr
305 310 315 320
Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys
325 330 335
Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe
340 345 350
Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe
355 360 365
Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu
370 375 380
Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu
385 390 395 400
Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala
405 410 415
Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe
420 425 430
Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu
435 440 445
His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser
450 455 460
Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr
465 470 475
<210> 25
<211> 1820
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 25
ttcaagtctt tttcttttaa cggattgatc ttttgctaga tagagacaaa atatcagtgt 60
gaattacagc aaacccctat tccatgctgt tatgggtgaa actctgggag attctcctat 120
tgacccagaa agcgattcct tcactgatac actgtctgca aacatatcac aagaaatgac 180
catggttgac acagagatgc cattctggcc caccaacttt gggatcagct ccgtggatct 240
ctccgtaatg gaagaccact cccactcctt tgatatcaag cccttcacta ctgttgactt 300
ctccagcatt tctactccac attacgaaga cattccattc acaagaacag atccagtggt 360
tgcagattac aagtatgacc tgaaacttca agagtaccaa agtgcaatca aagtggagcc 420
tgcatctcca ccttattatt ctgagaagac tcagctctac aataagcctc atgaagagcc 480
ttccaactcc ctcatggcaa ttgaatgtcg tgtctgtgga gataaagctt ctggatttca 540
ctatggagtt catgcttgtg aaggatgcaa gggtttcttc cggagaacaa tcagattgaa 600
gcttatctat gacagatgtg atcttaactg tcggatccac aaaaaaagta gaaataaatg 660
tcagtactgt cggtttcaga aatgccttgc agtggggatg tctcataatg ccatcaggtt 720
tgggcggatg ccacaggccg agaaggagaa gctgttggcg gagatctcca gtgatatcga 780
ccagctgaat ccagagtccg ctgacctccg ggccctggca aaacatttgt atgactcata 840
cataaagtcc ttcccgctga ccaaagcaaa ggcgagggcg atcttgacag gaaagacaac 900
agacaaatca ccattcgtta tctatgacat gaattcctta atgatgggag aagataaaat 960
caagttcaaa cacatcaccc ccctgcagga gcagagcaaa gaggtggcca tccgcatctt 1020
tcagggctgc cagtttcgct ccgtggaggc tgtgcaggag atcacagagt atgccaaaag 1080
cattcctggt tttgtaaatc ttgacttgaa cgaccaagta actctcctca aatatggagt 1140
ccacgagatc atttacacaa tgctggcctc cttgatgaat aaagatgggg ttctcatatc 1200
cgagggccaa ggcttcatga caagggagtt tctaaagagc ctgcgaaagc cttttggtga 1260
ctttatggag cccaagtttg agtttgctgt gaagttcaat gcactggaat tagatgacag 1320
cgacttggca atatttattg ctgtcattat tctcagtgga gaccgcccag gtttgctgaa 1380
tgtgaagccc attgaagaca ttcaagacaa cctgctacaa gccctggagc tccagctgaa 1440
gctgaaccac cctgagtcct cacagctgtt tgccaagctg ctccagaaaa tgacagacct 1500
cagacagatt gtcacggaac acgtgcagct actgcaggtg atcaagaaga cggagacaga 1560
catgagtctt cacccgctcc tgcaggagat ctacaaggac ttgtactagc agagagtcct 1620
gagccactgc caacatttcc cttcttccag ttgcactatt ctgagggaaa atctgacacc 1680
taagaaattt actgtgaaaa agcattttaa aaagaaaagg ttttagaata tgatctattt 1740
tatgcatatt gtttataaag acacatttac aatttacttt taatattaaa aattaccata 1800
ttatgaaatt gctgatagta 1820
<210> 26
<211> 505
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 26
Met Gly Glu Thr Leu Gly Asp Ser Pro Ile Asp Pro Glu Ser Asp Ser
1 5 10 15
Phe Thr Asp Thr Leu Ser Ala Asn Ile Ser Gln Glu Met Thr Met Val
20 25 30
Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly Ile Ser Ser Val
35 40 45
Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe Asp Ile Lys Pro
50 55 60
Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro His Tyr Glu Asp
65 70 75 80
Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp Tyr Lys Tyr Asp
85 90 95
Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val Glu Pro Ala Ser
100 105 110
Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn Lys Pro His Glu
115 120 125
Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg Val Cys Gly Asp
130 135 140
Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys Glu Gly Cys Lys
145 150 155 160
Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile Tyr Asp Arg Cys
165 170 175
Asp Leu Asn Cys Arg Ile His Lys Lys Ser Arg Asn Lys Cys Gln Tyr
180 185 190
Cys Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser His Asn Ala Ile
195 200 205
Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys Leu Leu Ala Glu
210 215 220
Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser Ala Asp Leu Arg
225 230 235 240
Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys Ser Phe Pro Leu
245 250 255
Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys Thr Thr Asp Lys
260 265 270
Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met Met Gly Glu Asp
275 280 285
Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu Gln Ser Lys Glu
290 295 300
Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg Ser Val Glu Ala
305 310 315 320
Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro Gly Phe Val Asn
325 330 335
Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr Gly Val His Glu
340 345 350
Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys Asp Gly Val Leu
355 360 365
Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe Leu Lys Ser Leu
370 375 380
Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe Glu Phe Ala Val
385 390 395 400
Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu Ala Ile Phe Ile
405 410 415
Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu Leu Asn Val Lys
420 425 430
Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala Leu Glu Leu Gln
435 440 445
Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe Ala Lys Leu Leu
450 455 460
Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu His Val Gln Leu
465 470 475 480
Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser Leu His Pro Leu
485 490 495
Leu Gln Glu Ile Tyr Lys Asp Leu Tyr
500 505
<210> 27
<211> 1919
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 27
ttggtggaag gtgggtgtgt agtcgtggta ctttacgcct cggtgtttag ggaggagcct 60
aaggtaagga gtcagaaacg gggagtaacc gagctgcggc ttttatataa ggtcagtggt 120
aggtaaggaa ggggccttaa cctctgctgg tgaccagaag cctgcatttc tgcattctgc 180
ttaattccct ttccttagat ttgaaagaag ccaacactaa accacaaata tacaacaagg 240
ccattttctc aaacgagagt cagcctttaa cgaaatgacc atggttgaca cagagatgcc 300
attctggccc accaactttg ggatcagctc cgtggatctc tccgtaatgg aagaccactc 360
ccactccttt gatatcaagc ccttcactac tgttgacttc tccagcattt ctactccaca 420
ttacgaagac attccattca caagaacaga tccagtggtt gcagattaca agtatgacct 480
gaaacttcaa gagtaccaaa gtgcaatcaa agtggagcct gcatctccac cttattattc 540
tgagaagact cagctctaca ataagcctca tgaagagcct tccaactccc tcatggcaat 600
tgaatgtcgt gtctgtggag ataaagcttc tggatttcac tatggagttc atgcttgtga 660
aggatgcaag ggtttcttcc ggagaacaat cagattgaag cttatctatg acagatgtga 720
tcttaactgt cggatccaca aaaaaagtag aaataaatgt cagtactgtc ggtttcagaa 780
atgccttgca gtggggatgt ctcataatgc catcaggttt gggcggatgc cacaggccga 840
gaaggagaag ctgttggcgg agatctccag tgatatcgac cagctgaatc cagagtccgc 900
tgacctccgg gccctggcaa aacatttgta tgactcatac ataaagtcct tcccgctgac 960
caaagcaaag gcgagggcga tcttgacagg aaagacaaca gacaaatcac cattcgttat 1020
ctatgacatg aattccttaa tgatgggaga agataaaatc aagttcaaac acatcacccc 1080
cctgcaggag cagagcaaag aggtggccat ccgcatcttt cagggctgcc agtttcgctc 1140
cgtggaggct gtgcaggaga tcacagagta tgccaaaagc attcctggtt ttgtaaatct 1200
tgacttgaac gaccaagtaa ctctcctcaa atatggagtc cacgagatca tttacacaat 1260
gctggcctcc ttgatgaata aagatggggt tctcatatcc gagggccaag gcttcatgac 1320
aagggagttt ctaaagagcc tgcgaaagcc ttttggtgac tttatggagc ccaagtttga 1380
gtttgctgtg aagttcaatg cactggaatt agatgacagc gacttggcaa tatttattgc 1440
tgtcattatt ctcagtggag accgcccagg tttgctgaat gtgaagccca ttgaagacat 1500
tcaagacaac ctgctacaag ccctggagct ccagctgaag ctgaaccacc ctgagtcctc 1560
acagctgttt gccaagctgc tccagaaaat gacagacctc agacagattg tcacggaaca 1620
cgtgcagcta ctgcaggtga tcaagaagac ggagacagac atgagtcttc acccgctcct 1680
gcaggagatc tacaaggact tgtactagca gagagtcctg agccactgcc aacatttccc 1740
ttcttccagt tgcactattc tgagggaaaa tctgacacct aagaaattta ctgtgaaaaa 1800
gcattttaaa aagaaaaggt tttagaatat gatctatttt atgcatattg tttataaaga 1860
cacatttaca atttactttt aatattaaaa attaccatat tatgaaattg ctgatagta 1919
<210> 28
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 28
Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly
1 5 10 15
Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe
20 25 30
Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro
35 40 45
His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp
50 55 60
Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val
65 70 75 80
Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn
85 90 95
Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg
100 105 110
Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys
115 120 125
Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile
130 135 140
Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Lys Ser Arg Asn
145 150 155 160
Lys Cys Gln Tyr Cys Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser
165 170 175
His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys
180 185 190
Leu Leu Ala Glu Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser
195 200 205
Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys
210 215 220
Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys
225 230 235 240
Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met
245 250 255
Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu
260 265 270
Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg
275 280 285
Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro
290 295 300
Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr
305 310 315 320
Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys
325 330 335
Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe
340 345 350
Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe
355 360 365
Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu
370 375 380
Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu
385 390 395 400
Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala
405 410 415
Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe
420 425 430
Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu
435 440 445
His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser
450 455 460
Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr
465 470 475
<210> 29
<211> 1818
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 29
ggcgcccgcg cccgcccccg cgccgggccc ggctcggccc gacccggctc cgccgcgggc 60
aggcggggcc cagcgcactc ggagcccgag cccgagccgc agccgccgcc tggggcgctt 120
gggtcggcct cgaggacacc ggagaggggc gccacgccgc cgtggccgca gaaatgacca 180
tggttgacac agagatgcca ttctggccca ccaactttgg gatcagctcc gtggatctct 240
ccgtaatgga agaccactcc cactcctttg atatcaagcc cttcactact gttgacttct 300
ccagcatttc tactccacat tacgaagaca ttccattcac aagaacagat ccagtggttg 360
cagattacaa gtatgacctg aaacttcaag agtaccaaag tgcaatcaaa gtggagcctg 420
catctccacc ttattattct gagaagactc agctctacaa taagcctcat gaagagcctt 480
ccaactccct catggcaatt gaatgtcgtg tctgtggaga taaagcttct ggatttcact 540
atggagttca tgcttgtgaa ggatgcaagg gtttcttccg gagaacaatc agattgaagc 600
ttatctatga cagatgtgat cttaactgtc ggatccacaa aaaaagtaga aataaatgtc 660
agtactgtcg gtttcagaaa tgccttgcag tggggatgtc tcataatgcc atcaggtttg 720
ggcggatgcc acaggccgag aaggagaagc tgttggcgga gatctccagt gatatcgacc 780
agctgaatcc agagtccgct gacctccggg ccctggcaaa acatttgtat gactcataca 840
taaagtcctt cccgctgacc aaagcaaagg cgagggcgat cttgacagga aagacaacag 900
acaaatcacc attcgttatc tatgacatga attccttaat gatgggagaa gataaaatca 960
agttcaaaca catcaccccc ctgcaggagc agagcaaaga ggtggccatc cgcatctttc 1020
agggctgcca gtttcgctcc gtggaggctg tgcaggagat cacagagtat gccaaaagca 1080
ttcctggttt tgtaaatctt gacttgaacg accaagtaac tctcctcaaa tatggagtcc 1140
acgagatcat ttacacaatg ctggcctcct tgatgaataa agatggggtt ctcatatccg 1200
agggccaagg cttcatgaca agggagtttc taaagagcct gcgaaagcct tttggtgact 1260
ttatggagcc caagtttgag tttgctgtga agttcaatgc actggaatta gatgacagcg 1320
acttggcaat atttattgct gtcattattc tcagtggaga ccgcccaggt ttgctgaatg 1380
tgaagcccat tgaagacatt caagacaacc tgctacaagc cctggagctc cagctgaagc 1440
tgaaccaccc tgagtcctca cagctgtttg ccaagctgct ccagaaaatg acagacctca 1500
gacagattgt cacggaacac gtgcagctac tgcaggtgat caagaagacg gagacagaca 1560
tgagtcttca cccgctcctg caggagatct acaaggactt gtactagcag agagtcctga 1620
gccactgcca acatttccct tcttccagtt gcactattct gagggaaaat ctgacaccta 1680
agaaatttac tgtgaaaaag cattttaaaa agaaaaggtt ttagaatatg atctatttta 1740
tgcatattgt ttataaagac acatttacaa tttactttta atattaaaaa ttaccatatt 1800
atgaaattgc tgatagta 1818
<210> 30
<211> 477
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 30
Met Thr Met Val Asp Thr Glu Met Pro Phe Trp Pro Thr Asn Phe Gly
1 5 10 15
Ile Ser Ser Val Asp Leu Ser Val Met Glu Asp His Ser His Ser Phe
20 25 30
Asp Ile Lys Pro Phe Thr Thr Val Asp Phe Ser Ser Ile Ser Thr Pro
35 40 45
His Tyr Glu Asp Ile Pro Phe Thr Arg Thr Asp Pro Val Val Ala Asp
50 55 60
Tyr Lys Tyr Asp Leu Lys Leu Gln Glu Tyr Gln Ser Ala Ile Lys Val
65 70 75 80
Glu Pro Ala Ser Pro Pro Tyr Tyr Ser Glu Lys Thr Gln Leu Tyr Asn
85 90 95
Lys Pro His Glu Glu Pro Ser Asn Ser Leu Met Ala Ile Glu Cys Arg
100 105 110
Val Cys Gly Asp Lys Ala Ser Gly Phe His Tyr Gly Val His Ala Cys
115 120 125
Glu Gly Cys Lys Gly Phe Phe Arg Arg Thr Ile Arg Leu Lys Leu Ile
130 135 140
Tyr Asp Arg Cys Asp Leu Asn Cys Arg Ile His Lys Lys Ser Arg Asn
145 150 155 160
Lys Cys Gln Tyr Cys Arg Phe Gln Lys Cys Leu Ala Val Gly Met Ser
165 170 175
His Asn Ala Ile Arg Phe Gly Arg Met Pro Gln Ala Glu Lys Glu Lys
180 185 190
Leu Leu Ala Glu Ile Ser Ser Asp Ile Asp Gln Leu Asn Pro Glu Ser
195 200 205
Ala Asp Leu Arg Ala Leu Ala Lys His Leu Tyr Asp Ser Tyr Ile Lys
210 215 220
Ser Phe Pro Leu Thr Lys Ala Lys Ala Arg Ala Ile Leu Thr Gly Lys
225 230 235 240
Thr Thr Asp Lys Ser Pro Phe Val Ile Tyr Asp Met Asn Ser Leu Met
245 250 255
Met Gly Glu Asp Lys Ile Lys Phe Lys His Ile Thr Pro Leu Gln Glu
260 265 270
Gln Ser Lys Glu Val Ala Ile Arg Ile Phe Gln Gly Cys Gln Phe Arg
275 280 285
Ser Val Glu Ala Val Gln Glu Ile Thr Glu Tyr Ala Lys Ser Ile Pro
290 295 300
Gly Phe Val Asn Leu Asp Leu Asn Asp Gln Val Thr Leu Leu Lys Tyr
305 310 315 320
Gly Val His Glu Ile Ile Tyr Thr Met Leu Ala Ser Leu Met Asn Lys
325 330 335
Asp Gly Val Leu Ile Ser Glu Gly Gln Gly Phe Met Thr Arg Glu Phe
340 345 350
Leu Lys Ser Leu Arg Lys Pro Phe Gly Asp Phe Met Glu Pro Lys Phe
355 360 365
Glu Phe Ala Val Lys Phe Asn Ala Leu Glu Leu Asp Asp Ser Asp Leu
370 375 380
Ala Ile Phe Ile Ala Val Ile Ile Leu Ser Gly Asp Arg Pro Gly Leu
385 390 395 400
Leu Asn Val Lys Pro Ile Glu Asp Ile Gln Asp Asn Leu Leu Gln Ala
405 410 415
Leu Glu Leu Gln Leu Lys Leu Asn His Pro Glu Ser Ser Gln Leu Phe
420 425 430
Ala Lys Leu Leu Gln Lys Met Thr Asp Leu Arg Gln Ile Val Thr Glu
435 440 445
His Val Gln Leu Leu Gln Val Ile Lys Lys Thr Glu Thr Asp Met Ser
450 455 460
Leu His Pro Leu Leu Gln Glu Ile Tyr Lys Asp Leu Tyr
465 470 475
<210> 31
<211> 8718
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 31
cctcccctcg cccggcgcgg tcccgtccgc ctctcgctcg cctcccgcct cccctcggtc 60
ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcgggcggt 120
gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180
gcgctcagtt ctctcctctc ggaagctgca gccatgatgg aagtttgaga gttgagccgc 240
tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300
gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360
gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420
cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480
aggcgcggcg gcggcggcgg cacctcccgc tcctggagcg ggggggagaa gcggcggcgg 540
cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600
gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660
ggcggcggca catccaggga cccgggccgg ttttaaacct cccgtccgcc gccgccgcac 720
cccccgtggc ccgggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780
cttctcccca ttccgctgcc gccgctgcca ggcctctggc tgctgaggag aagcaggccc 840
agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900
aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960
agaagaagcc ccgccaccag cagcttctgc catctctctc ctcctttttc ttcagccaca 1020
ggctcccaga catgacagcc atcatcaaag agatcgttag cagaaacaaa aggagatatc 1080
aagaggatgg attcgactta gacttgacct atatttatcc aaacattatt gctatgggat 1140
ttcctgcaga aagacttgaa ggcgtataca ggaacaatat tgatgatgta gtaaggtttt 1200
tggattcaaa gcataaaaac cattacaaga tatacaatct ttgtgctgaa agacattatg 1260
acaccgccaa atttaattgc agagttgcac aatatccttt tgaagaccat aacccaccac 1320
agctagaact tatcaaaccc ttttgtgaag atcttgacca atggctaagt gaagatgaca 1380
atcatgttgc agcaattcac tgtaaagctg gaaagggacg aactggtgta atgatatgtg 1440
catatttatt acatcggggc aaatttttaa aggcacaaga ggccctagat ttctatgggg 1500
aagtaaggac cagagacaaa aagggagtaa ctattcccag tcagaggcgc tatgtgtatt 1560
attatagcta cctgttaaag aatcatctgg attatagacc agtggcactg ttgtttcaca 1620
agatgatgtt tgaaactatt ccaatgttca gtggcggaac ttgcaatcct cagtttgtgg 1680
tctgccagct aaaggtgaag atatattcct ccaattcagg acccacacga cgggaagaca 1740
agttcatgta ctttgagttc cctcagccgt tacctgtgtg tggtgatatc aaagtagagt 1800
tcttccacaa acagaacaag atgctaaaaa aggacaaaat gtttcacttt tgggtaaata 1860
cattcttcat accaggacca gaggaaacct cagaaaaagt agaaaatgga agtctatgtg 1920
atcaagaaat cgatagcatt tgcagtatag agcgtgcaga taatgacaag gaatatctag 1980
tacttacttt aacaaaaaat gatcttgaca aagcaaataa agacaaagcc aaccgatact 2040
tttctccaaa ttttaaggtg aagctgtact tcacaaaaac agtagaggag ccgtcaaatc 2100
cagaggctag cagttcaact tctgtaacac cagatgttag tgacaatgaa cctgatcatt 2160
atagatattc tgacaccact gactctgatc cagagaatga accttttgat gaagatcagc 2220
atacacaaat tacaaaagtc tgaatttttt tttatcaaga gggataaaac accatgaaaa 2280
taaacttgaa taaactgaaa atggaccttt ttttttttaa tggcaatagg acattgtgtc 2340
agattaccag ttataggaac aattctcttt tcctgaccaa tcttgtttta ccctatacat 2400
ccacagggtt ttgacacttg ttgtccagtt gaaaaaaggt tgtgtagctg tgtcatgtat 2460
ataccttttt gtgtcaaaag gacatttaaa attcaattag gattaataaa gatggcactt 2520
tcccgtttta ttccagtttt ataaaaagtg gagacagact gatgtgtata cgtaggaatt 2580
ttttcctttt gtgttctgtc accaactgaa gtggctaaag agctttgtga tatactggtt 2640
cacatcctac ccctttgcac ttgtggcaac agataagttt gcagttggct aagagaggtt 2700
tccgaagggt tttgctacat tctaatgcat gtattcgggt taggggaatg gagggaatgc 2760
tcagaaagga aataatttta tgctggactc tggaccatat accatctcca gctatttaca 2820
cacacctttc tttagcatgc tacagttatt aatctggaca ttcgaggaat tggccgctgt 2880
cactgcttgt tgtttgcgca ttttttttta aagcatattg gtgctagaaa aggcagctaa 2940
aggaagtgaa tctgtattgg ggtacaggaa tgaaccttct gcaacatctt aagatccaca 3000
aatgaaggga tataaaaata atgtcatagg taagaaacac agcaacaatg acttaaccat 3060
ataaatgtgg aggctatcaa caaagaatgg gcttgaaaca ttataaaaat tgacaatgat 3120
ttattaaata tgttttctca attgtaacga cttctccatc tcctgtgtaa tcaaggccag 3180
tgctaaaatt cagatgctgt tagtacctac atcagtcaac aacttacact tattttacta 3240
gttttcaatc ataatacctg ctgtggatgc ttcatgtgct gcctgcaagc ttcttttttc 3300
tcattaaata taaaatattt tgtaatgctg cacagaaatt ttcaatttga gattctacag 3360
taagcgtttt ttttctttga agatttatga tgcacttatt caatagctgt cagccgttcc 3420
acccttttga ccttacacat tctattacaa tgaattttgc agttttgcac attttttaaa 3480
tgtcattaac tgttagggaa ttttacttga atactgaata catataatgt ttatattaaa 3540
aaggacattt gtgttaaaaa ggaaattaga gttgcagtaa actttcaatg ctgcacacaa 3600
aaaaaagaca tttgattttt cagtagaaat tgtcctacat gtgctttatt gatttgctat 3660
tgaaagaata gggttttttt tttttttttt tttttttttt ttaaatgtgc agtgttgaat 3720
catttcttca tagtgctccc ccgagttggg actagggctt caatttcact tcttaaaaaa 3780
aatcatcata tatttgatat gcccagactg catacgattt taagcggagt acaactacta 3840
ttgtaaagct aatgtgaaga tattattaaa aaggtttttt tttccagaaa tttggtgtct 3900
tcaaattata ccttcacctt gacatttgaa tatccagcca ttttgtttct taatggtata 3960
aaattccatt ttcaataact tattggtgct gaaattgttc actagctgtg gtctgaccta 4020
gttaatttac aaatacagat tgaataggac ctactagagc agcatttata gagtttgatg 4080
gcaaatagat taggcagaac ttcatctaaa atattcttag taaataatgt tgacacgttt 4140
tccatacctt gtcagtttca ttcaacaatt tttaaatttt taacaaagct cttaggattt 4200
acacatttat atttaaacat tgatatatag agtattgatt gattgctcat aagttaaatt 4260
ggtaaagtta gagacaacta ttctaacacc tcaccattga aatttatatg ccaccttgtc 4320
tttcataaaa gctgaaaatt gttacctaaa atgaaaatca acttcatgtt ttgaagatag 4380
ttataaatat tgttctttgt tacaatttcg ggcaccgcat attaaaacgt aactttattg 4440
ttccaatatg taacatggag ggccaggtca taaataatga cattataatg ggcttttgca 4500
ctgttattat ttttcctttg gaatgtgaag gtctgaatga gggttttgat tttgaatgtt 4560
tcaatgtttt tgagaagcct tgcttacatt ttatggtgta gtcattggaa atggaaaaat 4620
ggcattatat atattatata tataaatata tattatacat actctcctta ctttatttca 4680
gttaccatcc ccatagaatt tgacaagaat tgctatgact gaaaggtttt cgagtcctaa 4740
ttaaaacttt atttatggca gtattcataa ttagcctgaa atgcattctg taggtaatct 4800
ctgagtttct ggaatatttt cttagacttt ttggatgtgc agcagcttac atgtctgaag 4860
ttacttgaag gcatcacttt taagaaagct tacagttggg ccctgtacca tcccaagtcc 4920
tttgtagctc ctcttgaaca tgtttgccat acttttaaaa gggtagttga ataaatagca 4980
tcaccattct ttgctgtggc acaggttata aacttaagtg gagtttaccg gcagcatcaa 5040
atgtttcagc tttaaaaaat aaaagtaggg tacaagttta atgtttagtt ctagaaattt 5100
tgtgcaatat gttcataacg atggctgtgg ttgccacaaa gtgcctcgtt tacctttaaa 5160
tactgttaat gtgtcatgca tgcagatgga aggggtggaa ctgtgcacta aagtgggggc 5220
tttaactgta gtatttggca gagttgcctt ctacctgcca gttcaaaagt tcaacctgtt 5280
ttcatataga atatatatac taaaaaattt cagtctgtta aacagcctta ctctgattca 5340
gcctcttcag atactcttgt gctgtgcagc agtggctctg tgtgtaaatg ctatgcactg 5400
aggatacaca aaaataccaa tatgatgtgt acaggataat gcctcatccc aatcagatgt 5460
ccatttgtta ttgtgtttgt taacaaccct ttatctctta gtgttataaa ctccacttaa 5520
aactgattaa agtctcattc ttgtcattgt gtgggtgttt tattaaatga gagtttataa 5580
ttcaaattgc ttaagtccat tgaagtttta attaatgggc agccaaatgt gaatacaaag 5640
ttttcagttt ttttttttcc tgctgtcctt caaagcctac tgtttaaaaa aaaaaaaaaa 5700
aaaaaacatg gcctgagagt agagtatctg tctactcatg tttaattaag gaaaaacact 5760
tatttttagg gctttagtca tcacttcata aattgtataa gcacattaaa tagcgttcta 5820
gtcctgaaaa agtccaagat tcttagaaaa ttgtgcatat ttttattatg acagatgttt 5880
gaagataatt ccccagaatg gatttgatac tttagatttc aattttgtgg cttttgtcta 5940
ttattctgta ctctgccatc agcatatgga aagcttcatt tactcatcat gacttgtgcc 6000
atataaaaat tgatatttcg gaatagtcta aaggactttt tgtacttgaa tttaatcatg 6060
ttgtttctaa tattcttaaa agcttgaaga ctaaagcata tcctttcaac aaagcatagt 6120
aaggtaataa gaaagtgtag tttgtacaag tgttaaaaaa ataaagtaga caatgttaca 6180
gtgggactta ttatttcaag tttacatttt ctccatgtaa ttttttaaaa agtaaatgaa 6240
aaaatgtgca ataatgtaaa atatgaagtg tatgtgtaca cacattttat ttttcggtat 6300
cttgggtata cgtatggttg aaaactatac tggagtctaa aagtattcta atttataaga 6360
agacattttg gtgatgtttg aaaaatagaa atgtgctagt tttgttttta tatcatgtcc 6420
tttgtacgtt gtaatatgag ctggcttggt tcagtaaatg ccatcaccat ttccattgag 6480
aatttaaaac tcaccagtgt ttaatatgca ggcttccaaa ggcttatgaa aaaaatcaag 6540
acccttaaat ctagttaatt tgctgctaac atgaaactct ttggttcttt tatttttgcc 6600
agataattag acacacatct aaagcttagt cttaaatggc ttaagtgtag ctattgatta 6660
gtgctgttgc tagttcagaa agaaatgttt gtgaatggaa acaagaatat tcagtccaaa 6720
ctgttgtaag gacagtacct gaaaaccagg aaacaggata atggaaaaag tcttttaaag 6780
atgaaatgtt ggagccaact ttcttataga attaattgta tgtggctata gaaagcctaa 6840
tgattgttgc ttatttttga gagcatatta ttcttttatg accataatct tgctgttttt 6900
ccatcttcca aaagatcttc cttctaatat gtatatcaga atgtgggtag ccagtcagac 6960
aaattcatat tggttggtag ctttaaaaag tttgtaatgt gaagacagga aaggacaaaa 7020
tagtttgctt tggtggtagt actctggttg ttaagctagg tattttgaga ctacttcccc 7080
atcacaacaa caataaaata atcactcata atcctatcac ctggagacat agccatcgtt 7140
aatatgttag tgactataca atcatgtttt cttctgtata tccatgtata ttctttaaaa 7200
atgaaattta tactgtacct gatctcaaag ctttttagct tagtatatct gtcatgaatt 7260
tgtaggatgt tccattgcat cagaaaacgg acagtgattt gattactttc taatgccaca 7320
gatgcagatt acatgtagtt attgagaatc ctttcgaatt cagtggctta atcatgaatg 7380
tctaaatatt gttgacatta ggatgataca tgtaaattaa agttacattt gtttagcata 7440
gacaagctta acattgtaga tgtttctctt caaaaatcat cttaaacatt tgcatttgga 7500
attgtgttaa atagaatgtg tgaaacactg tattagtaaa cttcatcacc tttctacttc 7560
cttatagttt gaacttttca gtttttgtag ttcccaaaca gttgctcaat ttagagcaaa 7620
ttaatttaac acctgccaaa aaaaggctgc tgttggctta tcagttgtct ttaaattcaa 7680
atgctcatgt gacttttatc acatcaaaaa atatttcatt aatgattcac ctttagctct 7740
gaaaattacc gcgtttagta attatagtgg gcttataaaa acatgcaact ctttttgata 7800
gttatttgag aattttggtg aaaaatattt agctgagggc agtatagaac ttataaacca 7860
atatattgat atttttaaaa catttttaca tataagtaaa ctgccatctt tgagcataac 7920
tacatttaaa aataaagctg catattttta aatcaagtgt ttaacaagaa tttatatttt 7980
ttatttttta aaattaaaaa taatttatat ttcctctgtt gcatgaggat tctcatctgt 8040
gcttataatg gttagagatt ttatttgtgt ggaatgaagt gaggcttgta gtcatggttc 8100
tagtgtttca gtttgccaag tctgtttact gcagtgaaat tcatcaaatg tttcagtgtg 8160
gttttctgta gcctatcatt tactggctat ttttttatgt acacctttag gattttctgc 8220
ctactctatc cagttgtcca aatgatatcc tacattttac aaatgccctt tcagtttcta 8280
ttttcttttt ccattaaatt gccctcatgt cctaatgtgc agtttgtaag tgtgtgtgtg 8340
tgtgtctgtg tgtgtgtgaa tttgattttc aagagtgcta gacttccaat ttgagagatt 8400
aaataattta attcaggcaa acatttttca ttggaatttc acagttcatt gtaatgaaaa 8460
tgttaatcct ggatgacctt tgacatacag taatgaatct tggatattaa tgaatttgtt 8520
agtagcatct tgatgtgtgt tttaatgagt tattttcaaa gttgtgcatt aaaccaaagt 8580
tggcatactg gaagtgttta tatcaagttc catttggcta ctgatggaca aaaaatagaa 8640
atgccttcct atggagagta tttttccttt aaaaaattaa aaaggttaat tattttgact 8700
aaaaaaaaaa aaaaaaaa 8718
<210> 32
<211> 403
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 32
Met Thr Ala Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr
1 5 10 15
Gln Glu Asp Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile
20 25 30
Ile Ala Met Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn
35 40 45
Asn Ile Asp Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His
50 55 60
Tyr Lys Ile Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys
65 70 75 80
Phe Asn Cys Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro
85 90 95
Gln Leu Glu Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu
100 105 110
Ser Glu Asp Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys
115 120 125
Gly Arg Thr Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys
130 135 140
Phe Leu Lys Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val Arg Thr
145 150 155 160
Arg Asp Lys Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr
165 170 175
Tyr Tyr Ser Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro Val Ala
180 185 190
Leu Leu Phe His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly
195 200 205
Gly Thr Cys Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile
210 215 220
Tyr Ser Ser Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr
225 230 235 240
Phe Glu Phe Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu
245 250 255
Phe Phe His Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His
260 265 270
Phe Trp Val Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu
275 280 285
Lys Val Glu Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys
290 295 300
Ser Ile Glu Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu
305 310 315 320
Thr Lys Asn Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr
325 330 335
Phe Ser Pro Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu
340 345 350
Glu Pro Ser Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp
355 360 365
Val Ser Asp Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp
370 375 380
Ser Asp Pro Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile
385 390 395 400
Thr Lys Val
<210> 33
<211> 8718
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 33
cctcccctcg cccggcgcgg tcccgtccgc ctctcgctcg cctcccgcct cccctcggtc 60
ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcgggcggt 120
gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180
gcgctcagtt ctctcctctc ggaagctgca gccatgatgg aagtttgaga gttgagccgc 240
tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300
gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360
gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420
cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480
aggcgcggcg gcggcggcgg cacctcccgc tcctggagcg ggggggagaa gcggcggcgg 540
cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600
gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660
ggcggcggca catccaggga cccgggccgg ttttaaacct cccgtccgcc gccgccgcac 720
cccccgtggc ccgggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780
cttctcccca ttccgctgcc gccgctgcca ggcctctggc tgctgaggag aagcaggccc 840
agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900
aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960
agaagaagcc ccgccaccag cagcttctgc catctctctc ctcctttttc ttcagccaca 1020
ggctcccaga catgacagcc atcatcaaag agatcgttag cagaaacaaa aggagatatc 1080
aagaggatgg attcgactta gacttgacct atatttatcc aaacattatt gctatgggat 1140
ttcctgcaga aagacttgaa ggcgtataca ggaacaatat tgatgatgta gtaaggtttt 1200
tggattcaaa gcataaaaac cattacaaga tatacaatct ttgtgctgaa agacattatg 1260
acaccgccaa atttaattgc agagttgcac aatatccttt tgaagaccat aacccaccac 1320
agctagaact tatcaaaccc ttttgtgaag atcttgacca atggctaagt gaagatgaca 1380
atcatgttgc agcaattcac tgtaaagctg gaaagggacg aactggtgta atgatatgtg 1440
catatttatt acatcggggc aaatttttaa aggcacaaga ggccctagat ttctatgggg 1500
aagtaaggac cagagacaaa aagggagtaa ctattcccag tcagaggcgc tatgtgtatt 1560
attatagcta cctgttaaag aatcatctgg attatagacc agtggcactg ttgtttcaca 1620
agatgatgtt tgaaactatt ccaatgttca gtggcggaac ttgcaatcct cagtttgtgg 1680
tctgccagct aaaggtgaag atatattcct ccaattcagg acccacacga cgggaagaca 1740
agttcatgta ctttgagttc cctcagccgt tacctgtgtg tggtgatatc aaagtagagt 1800
tcttccacaa acagaacaag atgctaaaaa aggacaaaat gtttcacttt tgggtaaata 1860
cattcttcat accaggacca gaggaaacct cagaaaaagt agaaaatgga agtctatgtg 1920
atcaagaaat cgatagcatt tgcagtatag agcgtgcaga taatgacaag gaatatctag 1980
tacttacttt aacaaaaaat gatcttgaca aagcaaataa agacaaagcc aaccgatact 2040
tttctccaaa ttttaaggtg aagctgtact tcacaaaaac agtagaggag ccgtcaaatc 2100
cagaggctag cagttcaact tctgtaacac cagatgttag tgacaatgaa cctgatcatt 2160
atagatattc tgacaccact gactctgatc cagagaatga accttttgat gaagatcagc 2220
atacacaaat tacaaaagtc tgaatttttt tttatcaaga gggataaaac accatgaaaa 2280
taaacttgaa taaactgaaa atggaccttt ttttttttaa tggcaatagg acattgtgtc 2340
agattaccag ttataggaac aattctcttt tcctgaccaa tcttgtttta ccctatacat 2400
ccacagggtt ttgacacttg ttgtccagtt gaaaaaaggt tgtgtagctg tgtcatgtat 2460
ataccttttt gtgtcaaaag gacatttaaa attcaattag gattaataaa gatggcactt 2520
tcccgtttta ttccagtttt ataaaaagtg gagacagact gatgtgtata cgtaggaatt 2580
ttttcctttt gtgttctgtc accaactgaa gtggctaaag agctttgtga tatactggtt 2640
cacatcctac ccctttgcac ttgtggcaac agataagttt gcagttggct aagagaggtt 2700
tccgaagggt tttgctacat tctaatgcat gtattcgggt taggggaatg gagggaatgc 2760
tcagaaagga aataatttta tgctggactc tggaccatat accatctcca gctatttaca 2820
cacacctttc tttagcatgc tacagttatt aatctggaca ttcgaggaat tggccgctgt 2880
cactgcttgt tgtttgcgca ttttttttta aagcatattg gtgctagaaa aggcagctaa 2940
aggaagtgaa tctgtattgg ggtacaggaa tgaaccttct gcaacatctt aagatccaca 3000
aatgaaggga tataaaaata atgtcatagg taagaaacac agcaacaatg acttaaccat 3060
ataaatgtgg aggctatcaa caaagaatgg gcttgaaaca ttataaaaat tgacaatgat 3120
ttattaaata tgttttctca attgtaacga cttctccatc tcctgtgtaa tcaaggccag 3180
tgctaaaatt cagatgctgt tagtacctac atcagtcaac aacttacact tattttacta 3240
gttttcaatc ataatacctg ctgtggatgc ttcatgtgct gcctgcaagc ttcttttttc 3300
tcattaaata taaaatattt tgtaatgctg cacagaaatt ttcaatttga gattctacag 3360
taagcgtttt ttttctttga agatttatga tgcacttatt caatagctgt cagccgttcc 3420
acccttttga ccttacacat tctattacaa tgaattttgc agttttgcac attttttaaa 3480
tgtcattaac tgttagggaa ttttacttga atactgaata catataatgt ttatattaaa 3540
aaggacattt gtgttaaaaa ggaaattaga gttgcagtaa actttcaatg ctgcacacaa 3600
aaaaaagaca tttgattttt cagtagaaat tgtcctacat gtgctttatt gatttgctat 3660
tgaaagaata gggttttttt tttttttttt tttttttttt ttaaatgtgc agtgttgaat 3720
catttcttca tagtgctccc ccgagttggg actagggctt caatttcact tcttaaaaaa 3780
aatcatcata tatttgatat gcccagactg catacgattt taagcggagt acaactacta 3840
ttgtaaagct aatgtgaaga tattattaaa aaggtttttt tttccagaaa tttggtgtct 3900
tcaaattata ccttcacctt gacatttgaa tatccagcca ttttgtttct taatggtata 3960
aaattccatt ttcaataact tattggtgct gaaattgttc actagctgtg gtctgaccta 4020
gttaatttac aaatacagat tgaataggac ctactagagc agcatttata gagtttgatg 4080
gcaaatagat taggcagaac ttcatctaaa atattcttag taaataatgt tgacacgttt 4140
tccatacctt gtcagtttca ttcaacaatt tttaaatttt taacaaagct cttaggattt 4200
acacatttat atttaaacat tgatatatag agtattgatt gattgctcat aagttaaatt 4260
ggtaaagtta gagacaacta ttctaacacc tcaccattga aatttatatg ccaccttgtc 4320
tttcataaaa gctgaaaatt gttacctaaa atgaaaatca acttcatgtt ttgaagatag 4380
ttataaatat tgttctttgt tacaatttcg ggcaccgcat attaaaacgt aactttattg 4440
ttccaatatg taacatggag ggccaggtca taaataatga cattataatg ggcttttgca 4500
ctgttattat ttttcctttg gaatgtgaag gtctgaatga gggttttgat tttgaatgtt 4560
tcaatgtttt tgagaagcct tgcttacatt ttatggtgta gtcattggaa atggaaaaat 4620
ggcattatat atattatata tataaatata tattatacat actctcctta ctttatttca 4680
gttaccatcc ccatagaatt tgacaagaat tgctatgact gaaaggtttt cgagtcctaa 4740
ttaaaacttt atttatggca gtattcataa ttagcctgaa atgcattctg taggtaatct 4800
ctgagtttct ggaatatttt cttagacttt ttggatgtgc agcagcttac atgtctgaag 4860
ttacttgaag gcatcacttt taagaaagct tacagttggg ccctgtacca tcccaagtcc 4920
tttgtagctc ctcttgaaca tgtttgccat acttttaaaa gggtagttga ataaatagca 4980
tcaccattct ttgctgtggc acaggttata aacttaagtg gagtttaccg gcagcatcaa 5040
atgtttcagc tttaaaaaat aaaagtaggg tacaagttta atgtttagtt ctagaaattt 5100
tgtgcaatat gttcataacg atggctgtgg ttgccacaaa gtgcctcgtt tacctttaaa 5160
tactgttaat gtgtcatgca tgcagatgga aggggtggaa ctgtgcacta aagtgggggc 5220
tttaactgta gtatttggca gagttgcctt ctacctgcca gttcaaaagt tcaacctgtt 5280
ttcatataga atatatatac taaaaaattt cagtctgtta aacagcctta ctctgattca 5340
gcctcttcag atactcttgt gctgtgcagc agtggctctg tgtgtaaatg ctatgcactg 5400
aggatacaca aaaataccaa tatgatgtgt acaggataat gcctcatccc aatcagatgt 5460
ccatttgtta ttgtgtttgt taacaaccct ttatctctta gtgttataaa ctccacttaa 5520
aactgattaa agtctcattc ttgtcattgt gtgggtgttt tattaaatga gagtttataa 5580
ttcaaattgc ttaagtccat tgaagtttta attaatgggc agccaaatgt gaatacaaag 5640
ttttcagttt ttttttttcc tgctgtcctt caaagcctac tgtttaaaaa aaaaaaaaaa 5700
aaaaaacatg gcctgagagt agagtatctg tctactcatg tttaattaag gaaaaacact 5760
tatttttagg gctttagtca tcacttcata aattgtataa gcacattaaa tagcgttcta 5820
gtcctgaaaa agtccaagat tcttagaaaa ttgtgcatat ttttattatg acagatgttt 5880
gaagataatt ccccagaatg gatttgatac tttagatttc aattttgtgg cttttgtcta 5940
ttattctgta ctctgccatc agcatatgga aagcttcatt tactcatcat gacttgtgcc 6000
atataaaaat tgatatttcg gaatagtcta aaggactttt tgtacttgaa tttaatcatg 6060
ttgtttctaa tattcttaaa agcttgaaga ctaaagcata tcctttcaac aaagcatagt 6120
aaggtaataa gaaagtgtag tttgtacaag tgttaaaaaa ataaagtaga caatgttaca 6180
gtgggactta ttatttcaag tttacatttt ctccatgtaa ttttttaaaa agtaaatgaa 6240
aaaatgtgca ataatgtaaa atatgaagtg tatgtgtaca cacattttat ttttcggtat 6300
cttgggtata cgtatggttg aaaactatac tggagtctaa aagtattcta atttataaga 6360
agacattttg gtgatgtttg aaaaatagaa atgtgctagt tttgttttta tatcatgtcc 6420
tttgtacgtt gtaatatgag ctggcttggt tcagtaaatg ccatcaccat ttccattgag 6480
aatttaaaac tcaccagtgt ttaatatgca ggcttccaaa ggcttatgaa aaaaatcaag 6540
acccttaaat ctagttaatt tgctgctaac atgaaactct ttggttcttt tatttttgcc 6600
agataattag acacacatct aaagcttagt cttaaatggc ttaagtgtag ctattgatta 6660
gtgctgttgc tagttcagaa agaaatgttt gtgaatggaa acaagaatat tcagtccaaa 6720
ctgttgtaag gacagtacct gaaaaccagg aaacaggata atggaaaaag tcttttaaag 6780
atgaaatgtt ggagccaact ttcttataga attaattgta tgtggctata gaaagcctaa 6840
tgattgttgc ttatttttga gagcatatta ttcttttatg accataatct tgctgttttt 6900
ccatcttcca aaagatcttc cttctaatat gtatatcaga atgtgggtag ccagtcagac 6960
aaattcatat tggttggtag ctttaaaaag tttgtaatgt gaagacagga aaggacaaaa 7020
tagtttgctt tggtggtagt actctggttg ttaagctagg tattttgaga ctacttcccc 7080
atcacaacaa caataaaata atcactcata atcctatcac ctggagacat agccatcgtt 7140
aatatgttag tgactataca atcatgtttt cttctgtata tccatgtata ttctttaaaa 7200
atgaaattta tactgtacct gatctcaaag ctttttagct tagtatatct gtcatgaatt 7260
tgtaggatgt tccattgcat cagaaaacgg acagtgattt gattactttc taatgccaca 7320
gatgcagatt acatgtagtt attgagaatc ctttcgaatt cagtggctta atcatgaatg 7380
tctaaatatt gttgacatta ggatgataca tgtaaattaa agttacattt gtttagcata 7440
gacaagctta acattgtaga tgtttctctt caaaaatcat cttaaacatt tgcatttgga 7500
attgtgttaa atagaatgtg tgaaacactg tattagtaaa cttcatcacc tttctacttc 7560
cttatagttt gaacttttca gtttttgtag ttcccaaaca gttgctcaat ttagagcaaa 7620
ttaatttaac acctgccaaa aaaaggctgc tgttggctta tcagttgtct ttaaattcaa 7680
atgctcatgt gacttttatc acatcaaaaa atatttcatt aatgattcac ctttagctct 7740
gaaaattacc gcgtttagta attatagtgg gcttataaaa acatgcaact ctttttgata 7800
gttatttgag aattttggtg aaaaatattt agctgagggc agtatagaac ttataaacca 7860
atatattgat atttttaaaa catttttaca tataagtaaa ctgccatctt tgagcataac 7920
tacatttaaa aataaagctg catattttta aatcaagtgt ttaacaagaa tttatatttt 7980
ttatttttta aaattaaaaa taatttatat ttcctctgtt gcatgaggat tctcatctgt 8040
gcttataatg gttagagatt ttatttgtgt ggaatgaagt gaggcttgta gtcatggttc 8100
tagtgtttca gtttgccaag tctgtttact gcagtgaaat tcatcaaatg tttcagtgtg 8160
gttttctgta gcctatcatt tactggctat ttttttatgt acacctttag gattttctgc 8220
ctactctatc cagttgtcca aatgatatcc tacattttac aaatgccctt tcagtttcta 8280
ttttcttttt ccattaaatt gccctcatgt cctaatgtgc agtttgtaag tgtgtgtgtg 8340
tgtgtctgtg tgtgtgtgaa tttgattttc aagagtgcta gacttccaat ttgagagatt 8400
aaataattta attcaggcaa acatttttca ttggaatttc acagttcatt gtaatgaaaa 8460
tgttaatcct ggatgacctt tgacatacag taatgaatct tggatattaa tgaatttgtt 8520
agtagcatct tgatgtgtgt tttaatgagt tattttcaaa gttgtgcatt aaaccaaagt 8580
tggcatactg gaagtgttta tatcaagttc catttggcta ctgatggaca aaaaatagaa 8640
atgccttcct atggagagta tttttccttt aaaaaattaa aaaggttaat tattttgact 8700
aaaaaaaaaa aaaaaaaa 8718
<210> 34
<211> 576
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 34
Leu Glu Arg Gly Gly Glu Ala Ala Ala Ala Ala Ala Ala Ala Ala Ala
1 5 10 15
Ala Pro Gly Arg Gly Ser Glu Ser Pro Val Thr Ile Ser Arg Ala Gly
20 25 30
Asn Ala Gly Glu Leu Val Ser Pro Leu Leu Leu Pro Pro Thr Arg Arg
35 40 45
Arg Arg Arg Arg His Ile Gln Gly Pro Gly Pro Val Leu Asn Leu Pro
50 55 60
Ser Ala Ala Ala Ala Pro Pro Val Ala Arg Ala Pro Glu Ala Ala Gly
65 70 75 80
Gly Gly Ser Arg Ser Glu Asp Tyr Ser Ser Ser Pro His Ser Ala Ala
85 90 95
Ala Ala Ala Arg Pro Leu Ala Ala Glu Glu Lys Gln Ala Gln Ser Leu
100 105 110
Gln Pro Ser Ser Ser Arg Arg Ser Ser His Tyr Pro Ala Ala Val Gln
115 120 125
Ser Gln Ala Ala Ala Glu Arg Gly Ala Ser Ala Thr Ala Lys Ser Arg
130 135 140
Ala Ile Ser Ile Leu Gln Lys Lys Pro Arg His Gln Gln Leu Leu Pro
145 150 155 160
Ser Leu Ser Ser Phe Phe Phe Ser His Arg Leu Pro Asp Met Thr Ala
165 170 175
Ile Ile Lys Glu Ile Val Ser Arg Asn Lys Arg Arg Tyr Gln Glu Asp
180 185 190
Gly Phe Asp Leu Asp Leu Thr Tyr Ile Tyr Pro Asn Ile Ile Ala Met
195 200 205
Gly Phe Pro Ala Glu Arg Leu Glu Gly Val Tyr Arg Asn Asn Ile Asp
210 215 220
Asp Val Val Arg Phe Leu Asp Ser Lys His Lys Asn His Tyr Lys Ile
225 230 235 240
Tyr Asn Leu Cys Ala Glu Arg His Tyr Asp Thr Ala Lys Phe Asn Cys
245 250 255
Arg Val Ala Gln Tyr Pro Phe Glu Asp His Asn Pro Pro Gln Leu Glu
260 265 270
Leu Ile Lys Pro Phe Cys Glu Asp Leu Asp Gln Trp Leu Ser Glu Asp
275 280 285
Asp Asn His Val Ala Ala Ile His Cys Lys Ala Gly Lys Gly Arg Thr
290 295 300
Gly Val Met Ile Cys Ala Tyr Leu Leu His Arg Gly Lys Phe Leu Lys
305 310 315 320
Ala Gln Glu Ala Leu Asp Phe Tyr Gly Glu Val Arg Thr Arg Asp Lys
325 330 335
Lys Gly Val Thr Ile Pro Ser Gln Arg Arg Tyr Val Tyr Tyr Tyr Ser
340 345 350
Tyr Leu Leu Lys Asn His Leu Asp Tyr Arg Pro Val Ala Leu Leu Phe
355 360 365
His Lys Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly Gly Thr Cys
370 375 380
Asn Pro Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile Tyr Ser Ser
385 390 395 400
Asn Ser Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr Phe Glu Phe
405 410 415
Pro Gln Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu Phe Phe His
420 425 430
Lys Gln Asn Lys Met Leu Lys Lys Asp Lys Met Phe His Phe Trp Val
435 440 445
Asn Thr Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu Lys Val Glu
450 455 460
Asn Gly Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys Ser Ile Glu
465 470 475 480
Arg Ala Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu Thr Lys Asn
485 490 495
Asp Leu Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr Phe Ser Pro
500 505 510
Asn Phe Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu Glu Pro Ser
515 520 525
Asn Pro Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp Val Ser Asp
530 535 540
Asn Glu Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp Ser Asp Pro
545 550 555 560
Glu Asn Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile Thr Lys Val
565 570 575
<210> 35
<211> 8833
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 35
cctcccctcg cccggcgcgg tcccgtccgc ctctcgctcg cctcccgcct cccctcggtc 60
ttccgaggcg cccgggctcc cggcgcggcg gcggaggggg cgggcaggcc ggcgggcggt 120
gatgtggcgg gactctttat gcgctgcggc aggatacgcg ctcggcgctg ggacgcgact 180
gcgctcagtt ctctcctctc ggaagctgca gccatgatgg aagtttgaga gttgagccgc 240
tgtgaggcga ggccgggctc aggcgaggga gatgagagac ggcggcggcc gcggcccgga 300
gcccctctca gcgcctgtga gcagccgcgg gggcagcgcc ctcggggagc cggccggcct 360
gcggcggcgg cagcggcggc gtttctcgcc tcctcttcgt cttttctaac cgtgcagcct 420
cttcctcggc ttctcctgaa agggaaggtg gaagccgtgg gctcgggcgg gagccggctg 480
aggcgcggcg gcggcggcgg cacctcccgc tcctggagcg ggggggagaa gcggcggcgg 540
cggcggccgc ggcggctgca gctccaggga gggggtctga gtcgcctgtc accatttcca 600
gggctgggaa cgccggagag ttggtctctc cccttctact gcctccaaca cggcggcggc 660
ggcggcggca catccaggga cccgggccgg ttttaaacct cccgtccgcc gccgccgcac 720
cccccgtggc ccgggctccg gaggccgccg gcggaggcag ccgttcggag gattattcgt 780
cttctcccca ttccgctgcc gccgctgcca ggcctctggc tgctgaggag aagcaggccc 840
agtcgctgca accatccagc agccgccgca gcagccatta cccggctgcg gtccagagcc 900
aagcggcggc agagcgaggg gcatcagcta ccgccaagtc cagagccatt tccatcctgc 960
agaagaagcc ccgccaccag cagcttctgc catctctctc ctcctttttc ttcagccaca 1020
ggctcccaga catgacagcc atcatcaaag agatcgttag cagaaacaaa aggagatatc 1080
aagaggatgg attcgactta gacttgacct atatttatcc aaacattatt gctatgggat 1140
ttcctgcaga aagacttgaa ggcgtataca ggaacaatat tgatgatgta gtaagttgtg 1200
ctgaaagaca ttatgacacc gccaaattta attgcagagt tgcacaatat ccttttgaag 1260
accataaccc accacagcta gaacttatca aacccttttg tgaagatctt gaccaatggc 1320
taagtgaaga tgacaatcat gttgcagcaa ttcactgtaa agctggaaag ggacgaactg 1380
gtgtaatgat atgtgcatat ttattacatc ggggcaaatt tttaaaggca caagaggccc 1440
tagatttcta tggggaagta aggaccagag acaaaaaggc agatcctaca ggaggtattc 1500
cagataaagg cattattgtc ataggagatg gcagctccat ggatgttatt gccccttaag 1560
accttccagt gggacaagat gtataggtgg aagacagtga tattgatgat cctgaccttg 1620
tagaggccaa ggctaaagga gtaactattc ccagtcagag gcgctatgtg tattattata 1680
gctacctgtt aaagaatcat ctggattata gaccagtggc actgttgttt cacaagatga 1740
tgtttgaaac tattccaatg ttcagtggcg gaacttgcaa tcctcagttt gtggtctgcc 1800
agctaaaggt gaagatatat tcctccaatt caggacccac acgacgggaa gacaagttca 1860
tgtactttga gttccctcag ccgttacctg tgtgtggtga tatcaaagta gagttcttcc 1920
acaaacagaa caagatgcta aaaaaggaca aaatgtttca cttttgggta aatacattct 1980
tcataccagg accagaggaa acctcagaaa aagtagaaaa tggaagtcta tgtgatcaag 2040
aaatcgatag catttgcagt atagagcgtg cagataatga caaggaatat ctagtactta 2100
ctttaacaaa aaatgatctt gacaaagcaa ataaagacaa agccaaccga tacttttctc 2160
caaattttaa ggtgaagctg tacttcacaa aaacagtaga ggagccgtca aatccagagg 2220
ctagcagttc aacttctgta acaccagatg ttagtgacaa tgaacctgat cattatagat 2280
attctgacac cactgactct gatccagaga atgaaccttt tgatgaagat cagcatacac 2340
aaattacaaa agtctgaatt tttttttatc aagagggata aaacaccatg aaaataaact 2400
tgaataaact gaaaatggac cttttttttt ttaatggcaa taggacattg tgtcagatta 2460
ccagttatag gaacaattct cttttcctga ccaatcttgt tttaccctat acatccacag 2520
ggttttgaca cttgttgtcc agttgaaaaa aggttgtgta gctgtgtcat gtatatacct 2580
ttttgtgtca aaaggacatt taaaattcaa ttaggattaa taaagatggc actttcccgt 2640
tttattccag ttttataaaa agtggagaca gactgatgtg tatacgtagg aattttttcc 2700
ttttgtgttc tgtcaccaac tgaagtggct aaagagcttt gtgatatact ggttcacatc 2760
ctaccccttt gcacttgtgg caacagataa gtttgcagtt ggctaagaga ggtttccgaa 2820
gggttttgct acattctaat gcatgtattc gggttagggg aatggaggga atgctcagaa 2880
aggaaataat tttatgctgg actctggacc atataccatc tccagctatt tacacacacc 2940
tttctttagc atgctacagt tattaatctg gacattcgag gaattggccg ctgtcactgc 3000
ttgttgtttg cgcatttttt tttaaagcat attggtgcta gaaaaggcag ctaaaggaag 3060
tgaatctgta ttggggtaca ggaatgaacc ttctgcaaca tcttaagatc cacaaatgaa 3120
gggatataaa aataatgtca taggtaagaa acacagcaac aatgacttaa ccatataaat 3180
gtggaggcta tcaacaaaga atgggcttga aacattataa aaattgacaa tgatttatta 3240
aatatgtttt ctcaattgta acgacttctc catctcctgt gtaatcaagg ccagtgctaa 3300
aattcagatg ctgttagtac ctacatcagt caacaactta cacttatttt actagttttc 3360
aatcataata cctgctgtgg atgcttcatg tgctgcctgc aagcttcttt tttctcatta 3420
aatataaaat attttgtaat gctgcacaga aattttcaat ttgagattct acagtaagcg 3480
ttttttttct ttgaagattt atgatgcact tattcaatag ctgtcagccg ttccaccctt 3540
ttgaccttac acattctatt acaatgaatt ttgcagtttt gcacattttt taaatgtcat 3600
taactgttag ggaattttac ttgaatactg aatacatata atgtttatat taaaaaggac 3660
atttgtgtta aaaaggaaat tagagttgca gtaaactttc aatgctgcac acaaaaaaaa 3720
gacatttgat ttttcagtag aaattgtcct acatgtgctt tattgatttg ctattgaaag 3780
aatagggttt tttttttttt tttttttttt ttttttaaat gtgcagtgtt gaatcatttc 3840
ttcatagtgc tcccccgagt tgggactagg gcttcaattt cacttcttaa aaaaaatcat 3900
catatatttg atatgcccag actgcatacg attttaagcg gagtacaact actattgtaa 3960
agctaatgtg aagatattat taaaaaggtt tttttttcca gaaatttggt gtcttcaaat 4020
tataccttca ccttgacatt tgaatatcca gccattttgt ttcttaatgg tataaaattc 4080
cattttcaat aacttattgg tgctgaaatt gttcactagc tgtggtctga cctagttaat 4140
ttacaaatac agattgaata ggacctacta gagcagcatt tatagagttt gatggcaaat 4200
agattaggca gaacttcatc taaaatattc ttagtaaata atgttgacac gttttccata 4260
ccttgtcagt ttcattcaac aatttttaaa tttttaacaa agctcttagg atttacacat 4320
ttatatttaa acattgatat atagagtatt gattgattgc tcataagtta aattggtaaa 4380
gttagagaca actattctaa cacctcacca ttgaaattta tatgccacct tgtctttcat 4440
aaaagctgaa aattgttacc taaaatgaaa atcaacttca tgttttgaag atagttataa 4500
atattgttct ttgttacaat ttcgggcacc gcatattaaa acgtaacttt attgttccaa 4560
tatgtaacat ggagggccag gtcataaata atgacattat aatgggcttt tgcactgtta 4620
ttatttttcc tttggaatgt gaaggtctga atgagggttt tgattttgaa tgtttcaatg 4680
tttttgagaa gccttgctta cattttatgg tgtagtcatt ggaaatggaa aaatggcatt 4740
atatatatta tatatataaa tatatattat acatactctc cttactttat ttcagttacc 4800
atccccatag aatttgacaa gaattgctat gactgaaagg ttttcgagtc ctaattaaaa 4860
ctttatttat ggcagtattc ataattagcc tgaaatgcat tctgtaggta atctctgagt 4920
ttctggaata ttttcttaga ctttttggat gtgcagcagc ttacatgtct gaagttactt 4980
gaaggcatca cttttaagaa agcttacagt tgggccctgt accatcccaa gtcctttgta 5040
gctcctcttg aacatgtttg ccatactttt aaaagggtag ttgaataaat agcatcacca 5100
ttctttgctg tggcacaggt tataaactta agtggagttt accggcagca tcaaatgttt 5160
cagctttaaa aaataaaagt agggtacaag tttaatgttt agttctagaa attttgtgca 5220
atatgttcat aacgatggct gtggttgcca caaagtgcct cgtttacctt taaatactgt 5280
taatgtgtca tgcatgcaga tggaaggggt ggaactgtgc actaaagtgg gggctttaac 5340
tgtagtattt ggcagagttg ccttctacct gccagttcaa aagttcaacc tgttttcata 5400
tagaatatat atactaaaaa atttcagtct gttaaacagc cttactctga ttcagcctct 5460
tcagatactc ttgtgctgtg cagcagtggc tctgtgtgta aatgctatgc actgaggata 5520
cacaaaaata ccaatatgat gtgtacagga taatgcctca tcccaatcag atgtccattt 5580
gttattgtgt ttgttaacaa ccctttatct cttagtgtta taaactccac ttaaaactga 5640
ttaaagtctc attcttgtca ttgtgtgggt gttttattaa atgagagttt ataattcaaa 5700
ttgcttaagt ccattgaagt tttaattaat gggcagccaa atgtgaatac aaagttttca 5760
gttttttttt ttcctgctgt ccttcaaagc ctactgttta aaaaaaaaaa aaaaaaaaaa 5820
catggcctga gagtagagta tctgtctact catgtttaat taaggaaaaa cacttatttt 5880
tagggcttta gtcatcactt cataaattgt ataagcacat taaatagcgt tctagtcctg 5940
aaaaagtcca agattcttag aaaattgtgc atatttttat tatgacagat gtttgaagat 6000
aattccccag aatggatttg atactttaga tttcaatttt gtggcttttg tctattattc 6060
tgtactctgc catcagcata tggaaagctt catttactca tcatgacttg tgccatataa 6120
aaattgatat ttcggaatag tctaaaggac tttttgtact tgaatttaat catgttgttt 6180
ctaatattct taaaagcttg aagactaaag catatccttt caacaaagca tagtaaggta 6240
ataagaaagt gtagtttgta caagtgttaa aaaaataaag tagacaatgt tacagtggga 6300
cttattattt caagtttaca ttttctccat gtaatttttt aaaaagtaaa tgaaaaaatg 6360
tgcaataatg taaaatatga agtgtatgtg tacacacatt ttatttttcg gtatcttggg 6420
tatacgtatg gttgaaaact atactggagt ctaaaagtat tctaatttat aagaagacat 6480
tttggtgatg tttgaaaaat agaaatgtgc tagttttgtt tttatatcat gtcctttgta 6540
cgttgtaata tgagctggct tggttcagta aatgccatca ccatttccat tgagaattta 6600
aaactcacca gtgtttaata tgcaggcttc caaaggctta tgaaaaaaat caagaccctt 6660
aaatctagtt aatttgctgc taacatgaaa ctctttggtt cttttatttt tgccagataa 6720
ttagacacac atctaaagct tagtcttaaa tggcttaagt gtagctattg attagtgctg 6780
ttgctagttc agaaagaaat gtttgtgaat ggaaacaaga atattcagtc caaactgttg 6840
taaggacagt acctgaaaac caggaaacag gataatggaa aaagtctttt aaagatgaaa 6900
tgttggagcc aactttctta tagaattaat tgtatgtggc tatagaaagc ctaatgattg 6960
ttgcttattt ttgagagcat attattcttt tatgaccata atcttgctgt ttttccatct 7020
tccaaaagat cttccttcta atatgtatat cagaatgtgg gtagccagtc agacaaattc 7080
atattggttg gtagctttaa aaagtttgta atgtgaagac aggaaaggac aaaatagttt 7140
gctttggtgg tagtactctg gttgttaagc taggtatttt gagactactt ccccatcaca 7200
acaacaataa aataatcact cataatccta tcacctggag acatagccat cgttaatatg 7260
ttagtgacta tacaatcatg ttttcttctg tatatccatg tatattcttt aaaaatgaaa 7320
tttatactgt acctgatctc aaagcttttt agcttagtat atctgtcatg aatttgtagg 7380
atgttccatt gcatcagaaa acggacagtg atttgattac tttctaatgc cacagatgca 7440
gattacatgt agttattgag aatcctttcg aattcagtgg cttaatcatg aatgtctaaa 7500
tattgttgac attaggatga tacatgtaaa ttaaagttac atttgtttag catagacaag 7560
cttaacattg tagatgtttc tcttcaaaaa tcatcttaaa catttgcatt tggaattgtg 7620
ttaaatagaa tgtgtgaaac actgtattag taaacttcat cacctttcta cttccttata 7680
gtttgaactt ttcagttttt gtagttccca aacagttgct caatttagag caaattaatt 7740
taacacctgc caaaaaaagg ctgctgttgg cttatcagtt gtctttaaat tcaaatgctc 7800
atgtgacttt tatcacatca aaaaatattt cattaatgat tcacctttag ctctgaaaat 7860
taccgcgttt agtaattata gtgggcttat aaaaacatgc aactcttttt gatagttatt 7920
tgagaatttt ggtgaaaaat atttagctga gggcagtata gaacttataa accaatatat 7980
tgatattttt aaaacatttt tacatataag taaactgcca tctttgagca taactacatt 8040
taaaaataaa gctgcatatt tttaaatcaa gtgtttaaca agaatttata ttttttattt 8100
tttaaaatta aaaataattt atatttcctc tgttgcatga ggattctcat ctgtgcttat 8160
aatggttaga gattttattt gtgtggaatg aagtgaggct tgtagtcatg gttctagtgt 8220
ttcagtttgc caagtctgtt tactgcagtg aaattcatca aatgtttcag tgtggttttc 8280
tgtagcctat catttactgg ctattttttt atgtacacct ttaggatttt ctgcctactc 8340
tatccagttg tccaaatgat atcctacatt ttacaaatgc cctttcagtt tctattttct 8400
ttttccatta aattgccctc atgtcctaat gtgcagtttg taagtgtgtg tgtgtgtgtc 8460
tgtgtgtgtg tgaatttgat tttcaagagt gctagacttc caatttgaga gattaaataa 8520
tttaattcag gcaaacattt ttcattggaa tttcacagtt cattgtaatg aaaatgttaa 8580
tcctggatga cctttgacat acagtaatga atcttggata ttaatgaatt tgttagtagc 8640
atcttgatgt gtgttttaat gagttatttt caaagttgtg cattaaacca aagttggcat 8700
actggaagtg tttatatcaa gttccatttg gctactgatg gacaaaaaat agaaatgcct 8760
tcctatggag agtatttttc ctttaaaaaa ttaaaaaggt taattatttt gactaaaaaa 8820
aaaaaaaaaa aaa 8833
<210> 36
<211> 206
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 36
Met Met Phe Glu Thr Ile Pro Met Phe Ser Gly Gly Thr Cys Asn Pro
1 5 10 15
Gln Phe Val Val Cys Gln Leu Lys Val Lys Ile Tyr Ser Ser Asn Ser
20 25 30
Gly Pro Thr Arg Arg Glu Asp Lys Phe Met Tyr Phe Glu Phe Pro Gln
35 40 45
Pro Leu Pro Val Cys Gly Asp Ile Lys Val Glu Phe Phe His Lys Gln
50 55 60
Asn Lys Met Leu Lys Lys Asp Lys Met Phe His Phe Trp Val Asn Thr
65 70 75 80
Phe Phe Ile Pro Gly Pro Glu Glu Thr Ser Glu Lys Val Glu Asn Gly
85 90 95
Ser Leu Cys Asp Gln Glu Ile Asp Ser Ile Cys Ser Ile Glu Arg Ala
100 105 110
Asp Asn Asp Lys Glu Tyr Leu Val Leu Thr Leu Thr Lys Asn Asp Leu
115 120 125
Asp Lys Ala Asn Lys Asp Lys Ala Asn Arg Tyr Phe Ser Pro Asn Phe
130 135 140
Lys Val Lys Leu Tyr Phe Thr Lys Thr Val Glu Glu Pro Ser Asn Pro
145 150 155 160
Glu Ala Ser Ser Ser Thr Ser Val Thr Pro Asp Val Ser Asp Asn Glu
165 170 175
Pro Asp His Tyr Arg Tyr Ser Asp Thr Thr Asp Ser Asp Pro Glu Asn
180 185 190
Glu Pro Phe Asp Glu Asp Gln His Thr Gln Ile Thr Lys Val
195 200 205
<210> 37
<211> 9796
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 37
ggcagtggca gcggcgagag cttgggcggc cgccgccgcc tcctcgcgag cgccgcgcgc 60
ccgggtcccg ctcgcatgca agtcacgtcc gccccctcgg cgcggccgcc ccgagacgcc 120
ggccccgctg agtgatgaga acagacgtca aactgcctta tgaatattga tgcggaggct 180
aggctgcttt cgtagagaag cagaaggaag caagatggct gccctttagg atttgttaga 240
aaggagaccc gactgcaact gctggattgc tgcaaggctg agggacgaga acgaggctgg 300
caaacattca gcagcacacc ctctcaagat tgtttacttg cctttgctcc tgttgagtta 360
caacgcttgg aagcaggaga tgggctcagc agcagccaat aggacatgat ccaggaagag 420
cagtaaggga ctgagctgct gaattcaact agagggcagc cttgtggatg gccccgaagc 480
aagcctgatg gaacaggata gaaccaacca tgttgagggc aacagactaa gtccattcct 540
gataccatca cctcccattt gccagacaga acctctggct acaaagctcc agaatggaag 600
cccactgcct gagagagctc atccagaagt aaatggagac accaagtggc actctttcaa 660
aagttattat ggaataccct gtatgaaggg aagccagaat agtcgtgtga gtcctgactt 720
tacacaagaa agtagagggt attccaagtg tttgcaaaat ggaggaataa aacgcacagt 780
tagtgaacct tctctctctg ggctccttca gatcaagaaa ttgaaacaag accaaaaggc 840
taatggagaa agacgtaact tcggggtaag ccaagaaaga aatccaggtg aaagcagtca 900
accaaatgtc tccgatttga gtgataagaa agaatctgtg agttctgtag cccaagaaaa 960
tgcagttaaa gatttcacca gtttttcaac acataactgc agtgggcctg aaaatccaga 1020
gcttcagatt ctgaatgagc aggaggggaa aagtgctaat taccatgaca agaacattgt 1080
attacttaaa aacaaggcag tgctaatgcc taatggtgct acagtttctg cctcttccgt 1140
ggaacacaca catggtgaac tcctggaaaa aacactgtct caatattatc cagattgtgt 1200
ttccattgcg gtgcagaaaa ccacatctca cataaatgcc attaacagtc aggctactaa 1260
tgagttgtcc tgtgagatca ctcacccatc gcatacctca gggcagatca attccgcaca 1320
gacctctaac tctgagctgc ctccaaagcc agctgcagtg gtgagtgagg cctgtgatgc 1380
tgatgatgct gataatgcca gtaaactagc tgcaatgcta aatacctgtt cctttcagaa 1440
accagaacaa ctacaacaac aaaaatcagt ttttgagata tgcccatctc ctgcagaaaa 1500
taacatccag ggaaccacaa agctagcgtc tggtgaagaa ttctgttcag gttccagcag 1560
caatttgcaa gctcctggtg gcagctctga acggtattta aaacaaaatg aaatgaatgg 1620
tgcttacttc aagcaaagct cagtgttcac taaggattcc ttttctgcca ctaccacacc 1680
accaccacca tcacaattgc ttctttctcc ccctcctcct cttccacagg ttcctcagct 1740
tccttcagaa ggaaaaagca ctctgaatgg tggagtttta gaagaacacc accactaccc 1800
caaccaaagt aacacaacac ttttaaggga agtgaaaata gagggtaaac ctgaggcacc 1860
accttcccag agtcctaatc catctacaca tgtatgcagc ccttctccga tgctttctga 1920
aaggcctcag aataattgtg tgaacaggaa tgacatacag actgcaggga caatgactgt 1980
tccattgtgt tctgagaaaa caagaccaat gtcagaacac ctcaagcata acccaccaat 2040
ttttggtagc agtggagagc tacaggacaa ctgccagcag ttgatgagaa acaaagagca 2100
agagattctg aagggtcgag acaaggagca aacacgagat cttgtgcccc caacacagca 2160
ctatctgaaa ccaggatgga ttgaattgaa ggcccctcgt tttcaccaag cggaatccca 2220
tctaaaacgt aatgaggcat cactgccatc aattcttcag tatcaaccca atctctccaa 2280
tcaaatgacc tccaaacaat acactggaaa ttccaacatg cctggggggc tcccaaggca 2340
agcttacacc cagaaaacaa cacagctgga gcacaagtca caaatgtacc aagttgaaat 2400
gaatcaaggg cagtcccaag gtacagtgga ccaacatctc cagttccaaa aaccctcaca 2460
ccaggtgcac ttctccaaaa cagaccattt accaaaagct catgtgcagt cactgtgtgg 2520
cactagattt cattttcaac aaagagcaga ttcccaaact gaaaaactta tgtccccagt 2580
gttgaaacag cacttgaatc aacaggcttc agagactgag ccattttcaa actcacacct 2640
tttgcaacat aagcctcata aacaggcagc acaaacacaa ccatcccaga gttcacatct 2700
ccctcaaaac cagcaacagc agcaaaaatt acaaataaag aataaagagg aaatactcca 2760
gacttttcct cacccccaaa gcaacaatga tcagcaaaga gaaggatcat tctttggcca 2820
gactaaagtg gaagaatgtt ttcatggtga aaatcagtat tcaaaatcaa gcgagttcga 2880
gactcataat gtccaaatgg gactggagga agtacagaat ataaatcgta gaaattcccc 2940
ttatagtcag accatgaaat caagtgcatg caaaatacag gtttcttgtt caaacaatac 3000
acacctagtt tcagagaata aagaacagac tacacatcct gaactttttg caggaaacaa 3060
gacccaaaac ttgcatcaca tgcaatattt tccaaataat gtgatcccaa agcaagatct 3120
tcttcacagg tgctttcaag aacaggagca gaagtcacaa caagcttcag ttctacaggg 3180
atataaaaat agaaaccaag atatgtctgg tcaacaagct gcgcaacttg ctcagcaaag 3240
gtacttgata cataaccatg caaatgtttt tcctgtgcct gaccagggag gaagtcacac 3300
tcagacccct ccccagaagg acactcaaaa gcatgctgct ctaaggtggc atctcttaca 3360
gaagcaagaa cagcagcaaa cacagcaacc ccaaactgag tcttgccata gtcagatgca 3420
caggccaatt aaggtggaac ctggatgcaa gccacatgcc tgtatgcaca cagcaccacc 3480
agaaaacaaa acatggaaaa aggtaactaa gcaagagaat ccacctgcaa gctgtgataa 3540
tgtgcagcaa aagagcatca ttgagaccat ggagcagcat ctgaagcagt ttcacgccaa 3600
gtcgttattt gaccataagg ctcttactct caaatcacag aagcaagtaa aagttgaaat 3660
gtcagggcca gtcacagttt tgactagaca aaccactgct gcagaacttg atagccacac 3720
cccagcttta gagcagcaaa caacttcttc agaaaagaca ccaaccaaaa gaacagctgc 3780
ttctgttctc aataatttta tagagtcacc ttccaaatta ctagatactc ctataaaaaa 3840
tttattggat acacctgtca agactcaata tgatttccca tcttgcagat gtgtagagca 3900
aattattgaa aaagatgaag gtccttttta tacccatcta ggagcaggtc ctaatgtggc 3960
agctattaga gaaatcatgg aagaaaggtt tggacagaag ggtaaagcta ttaggattga 4020
aagagtcatc tatactggta aagaaggcaa aagttctcag ggatgtccta ttgctaagtg 4080
ggtggttcgc agaagcagca gtgaagagaa gctactgtgt ttggtgcggg agcgagctgg 4140
ccacacctgt gaggctgcag tgattgtgat tctcatcctg gtgtgggaag gaatcccgct 4200
gtctctggct gacaaactct actcggagct taccgagacg ctgaggaaat acggcacgct 4260
caccaatcgc cggtgtgcct tgaatgaaga gagaacttgc gcctgtcagg ggctggatcc 4320
agaaacctgt ggtgcctcct tctcttttgg ttgttcatgg agcatgtact acaatggatg 4380
taagtttgcc agaagcaaga tcccaaggaa gtttaagctg cttggggatg acccaaaaga 4440
ggaagagaaa ctggagtctc atttgcaaaa cctgtccact cttatggcac caacatataa 4500
gaaacttgca cctgatgcat ataataatca gattgaatat gaacacagag caccagagtg 4560
ccgtctgggt ctgaaggaag gccgtccatt ctcaggggtc actgcatgtt tggacttctg 4620
tgctcatgcc cacagagact tgcacaacat gcagaatggc agcacattgg tatgcactct 4680
cactagagaa gacaatcgag aatttggagg aaaacctgag gatgagcagc ttcacgttct 4740
gcctttatac aaagtctctg acgtggatga gtttgggagt gtggaagctc aggaggagaa 4800
aaaacggagt ggtgccattc aggtactgag ttcttttcgg cgaaaagtca ggatgttagc 4860
agagccagtc aagacttgcc gacaaaggaa actagaagcc aagaaagctg cagctgaaaa 4920
gctttcctcc ctggagaaca gctcaaataa aaatgaaaag gaaaagtcag ccccatcacg 4980
tacaaaacaa actgaaaacg caagccaggc taaacagttg gcagaacttt tgcgactttc 5040
aggaccagtc atgcagcagt cccagcagcc ccagcctcta cagaagcagc caccacagcc 5100
ccagcagcag cagagacccc agcagcagca gccacatcac cctcagacag agtctgtcaa 5160
ctcttattct gcttctggat ccaccaatcc atacatgaga cggcccaatc cagttagtcc 5220
ttatccaaac tcttcacaca cttcagatat ctatggaagc accagcccta tgaacttcta 5280
ttccacctca tctcaagctg caggttcata tttgaattct tctaatccca tgaaccctta 5340
ccctgggctt ttgaatcaga atacccaata tccatcatat caatgcaatg gaaacctatc 5400
agtggacaac tgctccccat atctgggttc ctattctccc cagtctcagc cgatggatct 5460
gtataggtat ccaagccaag accctctgtc taagctcagt ctaccaccca tccatacact 5520
ttaccagcca aggtttggaa atagccagag ttttacatct aaatacttag gttatggaaa 5580
ccaaaatatg cagggagatg gtttcagcag ttgtaccatt agaccaaatg tacatcatgt 5640
agggaaattg cctccttatc ccactcatga gatggatggc cacttcatgg gagccacctc 5700
tagattacca cccaatctga gcaatccaaa catggactat aaaaatggtg aacatcattc 5760
accttctcac ataatccata actacagtgc agctccgggc atgttcaaca gctctcttca 5820
tgccctgcat ctccaaaaca aggagaatga catgctttcc cacacagcta atgggttatc 5880
aaagatgctt ccagctctta accatgatag aactgcttgt gtccaaggag gcttacacaa 5940
attaagtgat gctaatggtc aggaaaagca gccattggca ctagtccagg gtgtggcttc 6000
tggtgcagag gacaacgatg aggtctggtc agacagcgag cagagctttc tggatcctga 6060
cattggggga gtggccgtgg ctccaactca tgggtcaatt ctcattgagt gtgcaaagcg 6120
tgagctgcat gccacaaccc ctttaaagaa tcccaatagg aatcacccca ccaggatctc 6180
cctcgtcttt taccagcata agagcatgaa tgagccaaaa catggcttgg ctctttggga 6240
agccaaaatg gctgaaaaag cccgtgagaa agaggaagag tgtgaaaagt atggcccaga 6300
ctatgtgcct cagaaatccc atggcaaaaa agtgaaacgg gagcctgctg agccacatga 6360
aacttcagag cccacttacc tgcgtttcat caagtctctt gccgaaagga ccatgtccgt 6420
gaccacagac tccacagtaa ctacatctcc atatgccttc actcgggtca cagggcctta 6480
caacagatat atatgatatc accccctttt gttggttacc tcacttgaaa agaccacaac 6540
caacctgtca gtagtatagt tctcatgacg tgggcagtgg ggaaaggtca cagtattcat 6600
gacaaatgtg gtgggaaaaa cctcagctca ccagcaacaa aagaggttat cttaccatag 6660
cacttaattt tcactggctc ccaagtggtc acagatggca tctaggaaaa gaccaaagca 6720
ttctatgcaa aaagaaggtg gggaagaaag tgttccgcaa tttacatttt taaacactgg 6780
ttctattatt ggacgagatg atatgtaaat gtgatccccc ccccccgctt acaactctac 6840
acatctgtga ccacttttaa taatatcaag tttgcatagt catggaacac aaatcaaaca 6900
agtactgtag tattacagtg acaggaatct taaaatacca tctggtgctg aatatatgat 6960
gtactgaaat actggaatta tggctttttg aaatgcagtt tttactgtaa tcttaacttt 7020
tatttatcaa aatagctaca ggaaacatga atagcaggaa aacactgaat ttgtttggat 7080
gttctaagaa atggtgctaa gaaaatggtg tctttaatag ctaaaaattt aatgccttta 7140
tatcatcaag atgctatcag tgtactccag tgcccttgaa taataggggt accttttcat 7200
tcaagttttt atcataatta cctattctta cacaagctta gtttttaaaa tgtggacatt 7260
ttaaaggcct ctggattttg ctcatccagt gaagtccttg taggacaata aacgtatata 7320
tgtacatata tacacaaaca tgtatatgtg cacacacatg tatatgtata aatattttaa 7380
atggtgtttt agaagcactt tgtctaccta agctttgaca acttgaacaa tgctaaggta 7440
ctgagatgtt taaaaaacaa gtttactttc attttagaat gcaaagttga tttttttaag 7500
gaaacaaaga aagcttttaa aatatttttg cttttagcca tgcatctgct gatgagcaat 7560
tgtgtccatt tttaacacag ccagttaaat ccaccatggg gcttactgga ttcaagggaa 7620
tacgttagtc cacaaaacat gttttctggt gctcatctca catgctatac tgtaaaacag 7680
ttttatacaa aattgtatga caagttcatt gctcaaaaat gtacagtttt aagaattttc 7740
tattaactgc aggtaataat tagctgcatg ctgcagactc aacaaagcta gttcactgaa 7800
gcctatgcta ttttatggat cataggctct tcagagaact gaatggcagt ctgcctttgt 7860
gttgataatt atgtacattg tgacgttgtc atttcttagc ttaagtgtcc tctttaacaa 7920
gaggattgag cagactgatg cctgcataag atgaataaac agggttagtt ccatgtgaat 7980
ctgtcagtta aaaagaaaca aaaacaggca gctggtttgc tgtggtggtt ttaaatcatt 8040
aatttgtata aagaagtgaa agagttgtat agtaaattaa attgtaaaca aaactttttt 8100
aatgcaatgc tttagtattt tagtactgta aaaaaattaa atatatacat atatatatat 8160
atatatatat atatatatat gagtttgaag cagaattcac atcatgatgg tgctactcag 8220
cctgctacaa atatatcata atgtgagcta agaattcatt aaatgtttga gtgatgttcc 8280
tacttgtcat atacctcaac actagtttgg caataggata ttgaactgag agtgaaagca 8340
ttgtgtacca tcattttttt ccaagtcctt ttttttattg ttaaaaaaaa aagcatacct 8400
tttttcaata cttgatttct tagcaagtat aacttgaact tcaacctttt tgttctaaaa 8460
attcagggat atttcagctc atgctctccc tatgccaaca tgtcacctgt gtttatgtaa 8520
aattgttgta ggttaataaa tatattcttt gtcagggatt taaccctttt attttgaatc 8580
ccttctattt tacttgtaca tgtgctgatg taactaaaac taattttgta aatctgttgg 8640
ctctttttat tgtaaagaaa agcattttaa aagtttgagg aatcttttga ctgtttcaag 8700
caggaaaaaa aaattacatg aaaatagaat gcactgagtt gataaaggga aaaattgtaa 8760
ggcaggagtt tggcaagtgg ctgttggcca gagacttact tgtaactctc taaatgaagt 8820
ttttttgatc ctgtaatcac tgaaggtaca tactccatgt ggacttccct taaacaggca 8880
aacacctaca ggtatggtgt gcaacagatt gtacaattac attttggcct aaatacattt 8940
ttgcttacta gtatttaaaa taaattctta atcagaggag gcctttgggt tttattggtc 9000
aaatctttgt aagctggctt ttgtcttttt aaaaaatttc ttgaatttgt ggttgtgtcc 9060
aatttgcaaa catttccaaa aatgtttgct ttgcttacaa accacatgat tttaatgttt 9120
tttgtatacc ataatatcta gccccaaaca tttgattact acatgtgcat tggtgatttt 9180
gatcatccat tcttaatatt tgatttctgt gtcacctact gtcatttgtt aaactgctgg 9240
ccaacaagaa caggaagtat agtttggggg gttggggaga gtttacataa ggaagagaag 9300
aaattgagtg gcatattgta aatatcagat ctataattgt aaatataaaa cctgcctcag 9360
ttagaatgaa tggaaagcag atctacaatt tgctaatata ggaatatcag gttgactata 9420
tagccatact tgaaaatgct tctgagtggt gtcaacttta cttgaatgaa tttttcatct 9480
tgattgacgc acagtgatgt acagttcact tctgaagcta gtggttaact tgtgtaggaa 9540
acttttgcag tttgacacta agataacttc tgtgtgcatt tttctatgct tttttaaaaa 9600
ctagtttcat ttcattttca tgagatgttt ggtttataag atctgaggat ggttataaat 9660
actgtaagta ttgtaatgtt atgaatgcag gttatttgaa agctgtttat tattatatca 9720
ttcctgataa tgctatgtga gtgtttttaa taaaatttat atttatttaa tgcactctaa 9780
aaaaaaaaaa aaaaaa 9796
<210> 38
<211> 2002
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 38
Met Glu Gln Asp Arg Thr Asn His Val Glu Gly Asn Arg Leu Ser Pro
1 5 10 15
Phe Leu Ile Pro Ser Pro Pro Ile Cys Gln Thr Glu Pro Leu Ala Thr
20 25 30
Lys Leu Gln Asn Gly Ser Pro Leu Pro Glu Arg Ala His Pro Glu Val
35 40 45
Asn Gly Asp Thr Lys Trp His Ser Phe Lys Ser Tyr Tyr Gly Ile Pro
50 55 60
Cys Met Lys Gly Ser Gln Asn Ser Arg Val Ser Pro Asp Phe Thr Gln
65 70 75 80
Glu Ser Arg Gly Tyr Ser Lys Cys Leu Gln Asn Gly Gly Ile Lys Arg
85 90 95
Thr Val Ser Glu Pro Ser Leu Ser Gly Leu Leu Gln Ile Lys Lys Leu
100 105 110
Lys Gln Asp Gln Lys Ala Asn Gly Glu Arg Arg Asn Phe Gly Val Ser
115 120 125
Gln Glu Arg Asn Pro Gly Glu Ser Ser Gln Pro Asn Val Ser Asp Leu
130 135 140
Ser Asp Lys Lys Glu Ser Val Ser Ser Val Ala Gln Glu Asn Ala Val
145 150 155 160
Lys Asp Phe Thr Ser Phe Ser Thr His Asn Cys Ser Gly Pro Glu Asn
165 170 175
Pro Glu Leu Gln Ile Leu Asn Glu Gln Glu Gly Lys Ser Ala Asn Tyr
180 185 190
His Asp Lys Asn Ile Val Leu Leu Lys Asn Lys Ala Val Leu Met Pro
195 200 205
Asn Gly Ala Thr Val Ser Ala Ser Ser Val Glu His Thr His Gly Glu
210 215 220
Leu Leu Glu Lys Thr Leu Ser Gln Tyr Tyr Pro Asp Cys Val Ser Ile
225 230 235 240
Ala Val Gln Lys Thr Thr Ser His Ile Asn Ala Ile Asn Ser Gln Ala
245 250 255
Thr Asn Glu Leu Ser Cys Glu Ile Thr His Pro Ser His Thr Ser Gly
260 265 270
Gln Ile Asn Ser Ala Gln Thr Ser Asn Ser Glu Leu Pro Pro Lys Pro
275 280 285
Ala Ala Val Val Ser Glu Ala Cys Asp Ala Asp Asp Ala Asp Asn Ala
290 295 300
Ser Lys Leu Ala Ala Met Leu Asn Thr Cys Ser Phe Gln Lys Pro Glu
305 310 315 320
Gln Leu Gln Gln Gln Lys Ser Val Phe Glu Ile Cys Pro Ser Pro Ala
325 330 335
Glu Asn Asn Ile Gln Gly Thr Thr Lys Leu Ala Ser Gly Glu Glu Phe
340 345 350
Cys Ser Gly Ser Ser Ser Asn Leu Gln Ala Pro Gly Gly Ser Ser Glu
355 360 365
Arg Tyr Leu Lys Gln Asn Glu Met Asn Gly Ala Tyr Phe Lys Gln Ser
370 375 380
Ser Val Phe Thr Lys Asp Ser Phe Ser Ala Thr Thr Thr Pro Pro Pro
385 390 395 400
Pro Ser Gln Leu Leu Leu Ser Pro Pro Pro Pro Leu Pro Gln Val Pro
405 410 415
Gln Leu Pro Ser Glu Gly Lys Ser Thr Leu Asn Gly Gly Val Leu Glu
420 425 430
Glu His His His Tyr Pro Asn Gln Ser Asn Thr Thr Leu Leu Arg Glu
435 440 445
Val Lys Ile Glu Gly Lys Pro Glu Ala Pro Pro Ser Gln Ser Pro Asn
450 455 460
Pro Ser Thr His Val Cys Ser Pro Ser Pro Met Leu Ser Glu Arg Pro
465 470 475 480
Gln Asn Asn Cys Val Asn Arg Asn Asp Ile Gln Thr Ala Gly Thr Met
485 490 495
Thr Val Pro Leu Cys Ser Glu Lys Thr Arg Pro Met Ser Glu His Leu
500 505 510
Lys His Asn Pro Pro Ile Phe Gly Ser Ser Gly Glu Leu Gln Asp Asn
515 520 525
Cys Gln Gln Leu Met Arg Asn Lys Glu Gln Glu Ile Leu Lys Gly Arg
530 535 540
Asp Lys Glu Gln Thr Arg Asp Leu Val Pro Pro Thr Gln His Tyr Leu
545 550 555 560
Lys Pro Gly Trp Ile Glu Leu Lys Ala Pro Arg Phe His Gln Ala Glu
565 570 575
Ser His Leu Lys Arg Asn Glu Ala Ser Leu Pro Ser Ile Leu Gln Tyr
580 585 590
Gln Pro Asn Leu Ser Asn Gln Met Thr Ser Lys Gln Tyr Thr Gly Asn
595 600 605
Ser Asn Met Pro Gly Gly Leu Pro Arg Gln Ala Tyr Thr Gln Lys Thr
610 615 620
Thr Gln Leu Glu His Lys Ser Gln Met Tyr Gln Val Glu Met Asn Gln
625 630 635 640
Gly Gln Ser Gln Gly Thr Val Asp Gln His Leu Gln Phe Gln Lys Pro
645 650 655
Ser His Gln Val His Phe Ser Lys Thr Asp His Leu Pro Lys Ala His
660 665 670
Val Gln Ser Leu Cys Gly Thr Arg Phe His Phe Gln Gln Arg Ala Asp
675 680 685
Ser Gln Thr Glu Lys Leu Met Ser Pro Val Leu Lys Gln His Leu Asn
690 695 700
Gln Gln Ala Ser Glu Thr Glu Pro Phe Ser Asn Ser His Leu Leu Gln
705 710 715 720
His Lys Pro His Lys Gln Ala Ala Gln Thr Gln Pro Ser Gln Ser Ser
725 730 735
His Leu Pro Gln Asn Gln Gln Gln Gln Gln Lys Leu Gln Ile Lys Asn
740 745 750
Lys Glu Glu Ile Leu Gln Thr Phe Pro His Pro Gln Ser Asn Asn Asp
755 760 765
Gln Gln Arg Glu Gly Ser Phe Phe Gly Gln Thr Lys Val Glu Glu Cys
770 775 780
Phe His Gly Glu Asn Gln Tyr Ser Lys Ser Ser Glu Phe Glu Thr His
785 790 795 800
Asn Val Gln Met Gly Leu Glu Glu Val Gln Asn Ile Asn Arg Arg Asn
805 810 815
Ser Pro Tyr Ser Gln Thr Met Lys Ser Ser Ala Cys Lys Ile Gln Val
820 825 830
Ser Cys Ser Asn Asn Thr His Leu Val Ser Glu Asn Lys Glu Gln Thr
835 840 845
Thr His Pro Glu Leu Phe Ala Gly Asn Lys Thr Gln Asn Leu His His
850 855 860
Met Gln Tyr Phe Pro Asn Asn Val Ile Pro Lys Gln Asp Leu Leu His
865 870 875 880
Arg Cys Phe Gln Glu Gln Glu Gln Lys Ser Gln Gln Ala Ser Val Leu
885 890 895
Gln Gly Tyr Lys Asn Arg Asn Gln Asp Met Ser Gly Gln Gln Ala Ala
900 905 910
Gln Leu Ala Gln Gln Arg Tyr Leu Ile His Asn His Ala Asn Val Phe
915 920 925
Pro Val Pro Asp Gln Gly Gly Ser His Thr Gln Thr Pro Pro Gln Lys
930 935 940
Asp Thr Gln Lys His Ala Ala Leu Arg Trp His Leu Leu Gln Lys Gln
945 950 955 960
Glu Gln Gln Gln Thr Gln Gln Pro Gln Thr Glu Ser Cys His Ser Gln
965 970 975
Met His Arg Pro Ile Lys Val Glu Pro Gly Cys Lys Pro His Ala Cys
980 985 990
Met His Thr Ala Pro Pro Glu Asn Lys Thr Trp Lys Lys Val Thr Lys
995 1000 1005
Gln Glu Asn Pro Pro Ala Ser Cys Asp Asn Val Gln Gln Lys Ser
1010 1015 1020
Ile Ile Glu Thr Met Glu Gln His Leu Lys Gln Phe His Ala Lys
1025 1030 1035
Ser Leu Phe Asp His Lys Ala Leu Thr Leu Lys Ser Gln Lys Gln
1040 1045 1050
Val Lys Val Glu Met Ser Gly Pro Val Thr Val Leu Thr Arg Gln
1055 1060 1065
Thr Thr Ala Ala Glu Leu Asp Ser His Thr Pro Ala Leu Glu Gln
1070 1075 1080
Gln Thr Thr Ser Ser Glu Lys Thr Pro Thr Lys Arg Thr Ala Ala
1085 1090 1095
Ser Val Leu Asn Asn Phe Ile Glu Ser Pro Ser Lys Leu Leu Asp
1100 1105 1110
Thr Pro Ile Lys Asn Leu Leu Asp Thr Pro Val Lys Thr Gln Tyr
1115 1120 1125
Asp Phe Pro Ser Cys Arg Cys Val Glu Gln Ile Ile Glu Lys Asp
1130 1135 1140
Glu Gly Pro Phe Tyr Thr His Leu Gly Ala Gly Pro Asn Val Ala
1145 1150 1155
Ala Ile Arg Glu Ile Met Glu Glu Arg Phe Gly Gln Lys Gly Lys
1160 1165 1170
Ala Ile Arg Ile Glu Arg Val Ile Tyr Thr Gly Lys Glu Gly Lys
1175 1180 1185
Ser Ser Gln Gly Cys Pro Ile Ala Lys Trp Val Val Arg Arg Ser
1190 1195 1200
Ser Ser Glu Glu Lys Leu Leu Cys Leu Val Arg Glu Arg Ala Gly
1205 1210 1215
His Thr Cys Glu Ala Ala Val Ile Val Ile Leu Ile Leu Val Trp
1220 1225 1230
Glu Gly Ile Pro Leu Ser Leu Ala Asp Lys Leu Tyr Ser Glu Leu
1235 1240 1245
Thr Glu Thr Leu Arg Lys Tyr Gly Thr Leu Thr Asn Arg Arg Cys
1250 1255 1260
Ala Leu Asn Glu Glu Arg Thr Cys Ala Cys Gln Gly Leu Asp Pro
1265 1270 1275
Glu Thr Cys Gly Ala Ser Phe Ser Phe Gly Cys Ser Trp Ser Met
1280 1285 1290
Tyr Tyr Asn Gly Cys Lys Phe Ala Arg Ser Lys Ile Pro Arg Lys
1295 1300 1305
Phe Lys Leu Leu Gly Asp Asp Pro Lys Glu Glu Glu Lys Leu Glu
1310 1315 1320
Ser His Leu Gln Asn Leu Ser Thr Leu Met Ala Pro Thr Tyr Lys
1325 1330 1335
Lys Leu Ala Pro Asp Ala Tyr Asn Asn Gln Ile Glu Tyr Glu His
1340 1345 1350
Arg Ala Pro Glu Cys Arg Leu Gly Leu Lys Glu Gly Arg Pro Phe
1355 1360 1365
Ser Gly Val Thr Ala Cys Leu Asp Phe Cys Ala His Ala His Arg
1370 1375 1380
Asp Leu His Asn Met Gln Asn Gly Ser Thr Leu Val Cys Thr Leu
1385 1390 1395
Thr Arg Glu Asp Asn Arg Glu Phe Gly Gly Lys Pro Glu Asp Glu
1400 1405 1410
Gln Leu His Val Leu Pro Leu Tyr Lys Val Ser Asp Val Asp Glu
1415 1420 1425
Phe Gly Ser Val Glu Ala Gln Glu Glu Lys Lys Arg Ser Gly Ala
1430 1435 1440
Ile Gln Val Leu Ser Ser Phe Arg Arg Lys Val Arg Met Leu Ala
1445 1450 1455
Glu Pro Val Lys Thr Cys Arg Gln Arg Lys Leu Glu Ala Lys Lys
1460 1465 1470
Ala Ala Ala Glu Lys Leu Ser Ser Leu Glu Asn Ser Ser Asn Lys
1475 1480 1485
Asn Glu Lys Glu Lys Ser Ala Pro Ser Arg Thr Lys Gln Thr Glu
1490 1495 1500
Asn Ala Ser Gln Ala Lys Gln Leu Ala Glu Leu Leu Arg Leu Ser
1505 1510 1515
Gly Pro Val Met Gln Gln Ser Gln Gln Pro Gln Pro Leu Gln Lys
1520 1525 1530
Gln Pro Pro Gln Pro Gln Gln Gln Gln Arg Pro Gln Gln Gln Gln
1535 1540 1545
Pro His His Pro Gln Thr Glu Ser Val Asn Ser Tyr Ser Ala Ser
1550 1555 1560
Gly Ser Thr Asn Pro Tyr Met Arg Arg Pro Asn Pro Val Ser Pro
1565 1570 1575
Tyr Pro Asn Ser Ser His Thr Ser Asp Ile Tyr Gly Ser Thr Ser
1580 1585 1590
Pro Met Asn Phe Tyr Ser Thr Ser Ser Gln Ala Ala Gly Ser Tyr
1595 1600 1605
Leu Asn Ser Ser Asn Pro Met Asn Pro Tyr Pro Gly Leu Leu Asn
1610 1615 1620
Gln Asn Thr Gln Tyr Pro Ser Tyr Gln Cys Asn Gly Asn Leu Ser
1625 1630 1635
Val Asp Asn Cys Ser Pro Tyr Leu Gly Ser Tyr Ser Pro Gln Ser
1640 1645 1650
Gln Pro Met Asp Leu Tyr Arg Tyr Pro Ser Gln Asp Pro Leu Ser
1655 1660 1665
Lys Leu Ser Leu Pro Pro Ile His Thr Leu Tyr Gln Pro Arg Phe
1670 1675 1680
Gly Asn Ser Gln Ser Phe Thr Ser Lys Tyr Leu Gly Tyr Gly Asn
1685 1690 1695
Gln Asn Met Gln Gly Asp Gly Phe Ser Ser Cys Thr Ile Arg Pro
1700 1705 1710
Asn Val His His Val Gly Lys Leu Pro Pro Tyr Pro Thr His Glu
1715 1720 1725
Met Asp Gly His Phe Met Gly Ala Thr Ser Arg Leu Pro Pro Asn
1730 1735 1740
Leu Ser Asn Pro Asn Met Asp Tyr Lys Asn Gly Glu His His Ser
1745 1750 1755
Pro Ser His Ile Ile His Asn Tyr Ser Ala Ala Pro Gly Met Phe
1760 1765 1770
Asn Ser Ser Leu His Ala Leu His Leu Gln Asn Lys Glu Asn Asp
1775 1780 1785
Met Leu Ser His Thr Ala Asn Gly Leu Ser Lys Met Leu Pro Ala
1790 1795 1800
Leu Asn His Asp Arg Thr Ala Cys Val Gln Gly Gly Leu His Lys
1805 1810 1815
Leu Ser Asp Ala Asn Gly Gln Glu Lys Gln Pro Leu Ala Leu Val
1820 1825 1830
Gln Gly Val Ala Ser Gly Ala Glu Asp Asn Asp Glu Val Trp Ser
1835 1840 1845
Asp Ser Glu Gln Ser Phe Leu Asp Pro Asp Ile Gly Gly Val Ala
1850 1855 1860
Val Ala Pro Thr His Gly Ser Ile Leu Ile Glu Cys Ala Lys Arg
1865 1870 1875
Glu Leu His Ala Thr Thr Pro Leu Lys Asn Pro Asn Arg Asn His
1880 1885 1890
Pro Thr Arg Ile Ser Leu Val Phe Tyr Gln His Lys Ser Met Asn
1895 1900 1905
Glu Pro Lys His Gly Leu Ala Leu Trp Glu Ala Lys Met Ala Glu
1910 1915 1920
Lys Ala Arg Glu Lys Glu Glu Glu Cys Glu Lys Tyr Gly Pro Asp
1925 1930 1935
Tyr Val Pro Gln Lys Ser His Gly Lys Lys Val Lys Arg Glu Pro
1940 1945 1950
Ala Glu Pro His Glu Thr Ser Glu Pro Thr Tyr Leu Arg Phe Ile
1955 1960 1965
Lys Ser Leu Ala Glu Arg Thr Met Ser Val Thr Thr Asp Ser Thr
1970 1975 1980
Val Thr Thr Ser Pro Tyr Ala Phe Thr Arg Val Thr Gly Pro Tyr
1985 1990 1995
Asn Arg Tyr Ile
2000
<210> 39
<211> 9236
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 39
aaacagaagg tgggccgggg cggggagaaa cagaactcgg tcaatttccc agtttgtcgg 60
gtctttaaaa atacaggccc ctaaagcact aagggcatgc cctcggtgaa acaggggagc 120
gcttctgctg aatgagatta aagcgacaga aaagggaaag gagagcgcgg gcaacgggat 180
ctaaagggag atagagacgc gggcctctga gggctggcaa acattcagca gcacaccctc 240
tcaagattgt ttacttgcct ttgctcctgt tgagttacaa cgcttggaag caggagatgg 300
gctcagcagc agccaatagg acatgatcca ggaagagcag taagggactg agctgctgaa 360
ttcaactaga gggcagcctt gtggatggcc ccgaagcaag cctgatggaa caggatagaa 420
ccaaccatgt tgagggcaac agactaagtc cattcctgat accatcacct cccatttgcc 480
agacagaacc tctggctaca aagctccaga atggaagccc actgcctgag agagctcatc 540
cagaagtaaa tggagacacc aagtggcact ctttcaaaag ttattatgga ataccctgta 600
tgaagggaag ccagaatagt cgtgtgagtc ctgactttac acaagaaagt agagggtatt 660
ccaagtgttt gcaaaatgga ggaataaaac gcacagttag tgaaccttct ctctctgggc 720
tccttcagat caagaaattg aaacaagacc aaaaggctaa tggagaaaga cgtaacttcg 780
gggtaagcca agaaagaaat ccaggtgaaa gcagtcaacc aaatgtctcc gatttgagtg 840
ataagaaaga atctgtgagt tctgtagccc aagaaaatgc agttaaagat ttcaccagtt 900
tttcaacaca taactgcagt gggcctgaaa atccagagct tcagattctg aatgagcagg 960
aggggaaaag tgctaattac catgacaaga acattgtatt acttaaaaac aaggcagtgc 1020
taatgcctaa tggtgctaca gtttctgcct cttccgtgga acacacacat ggtgaactcc 1080
tggaaaaaac actgtctcaa tattatccag attgtgtttc cattgcggtg cagaaaacca 1140
catctcacat aaatgccatt aacagtcagg ctactaatga gttgtcctgt gagatcactc 1200
acccatcgca tacctcaggg cagatcaatt ccgcacagac ctctaactct gagctgcctc 1260
caaagccagc tgcagtggtg agtgaggcct gtgatgctga tgatgctgat aatgccagta 1320
aactagctgc aatgctaaat acctgttcct ttcagaaacc agaacaacta caacaacaaa 1380
aatcagtttt tgagatatgc ccatctcctg cagaaaataa catccaggga accacaaagc 1440
tagcgtctgg tgaagaattc tgttcaggtt ccagcagcaa tttgcaagct cctggtggca 1500
gctctgaacg gtatttaaaa caaaatgaaa tgaatggtgc ttacttcaag caaagctcag 1560
tgttcactaa ggattccttt tctgccacta ccacaccacc accaccatca caattgcttc 1620
tttctccccc tcctcctctt ccacaggttc ctcagcttcc ttcagaagga aaaagcactc 1680
tgaatggtgg agttttagaa gaacaccacc actaccccaa ccaaagtaac acaacacttt 1740
taagggaagt gaaaatagag ggtaaacctg aggcaccacc ttcccagagt cctaatccat 1800
ctacacatgt atgcagccct tctccgatgc tttctgaaag gcctcagaat aattgtgtga 1860
acaggaatga catacagact gcagggacaa tgactgttcc attgtgttct gagaaaacaa 1920
gaccaatgtc agaacacctc aagcataacc caccaatttt tggtagcagt ggagagctac 1980
aggacaactg ccagcagttg atgagaaaca aagagcaaga gattctgaag ggtcgagaca 2040
aggagcaaac acgagatctt gtgcccccaa cacagcacta tctgaaacca ggatggattg 2100
aattgaaggc ccctcgtttt caccaagcgg aatcccatct aaaacgtaat gaggcatcac 2160
tgccatcaat tcttcagtat caacccaatc tctccaatca aatgacctcc aaacaataca 2220
ctggaaattc caacatgcct ggggggctcc caaggcaagc ttacacccag aaaacaacac 2280
agctggagca caagtcacaa atgtaccaag ttgaaatgaa tcaagggcag tcccaaggta 2340
cagtggacca acatctccag ttccaaaaac cctcacacca ggtgcacttc tccaaaacag 2400
accatttacc aaaagctcat gtgcagtcac tgtgtggcac tagatttcat tttcaacaaa 2460
gagcagattc ccaaactgaa aaacttatgt ccccagtgtt gaaacagcac ttgaatcaac 2520
aggcttcaga gactgagcca ttttcaaact cacacctttt gcaacataag cctcataaac 2580
aggcagcaca aacacaacca tcccagagtt cacatctccc tcaaaaccag caacagcagc 2640
aaaaattaca aataaagaat aaagaggaaa tactccagac ttttcctcac ccccaaagca 2700
acaatgatca gcaaagagaa ggatcattct ttggccagac taaagtggaa gaatgttttc 2760
atggtgaaaa tcagtattca aaatcaagcg agttcgagac tcataatgtc caaatgggac 2820
tggaggaagt acagaatata aatcgtagaa attcccctta tagtcagacc atgaaatcaa 2880
gtgcatgcaa aatacaggtt tcttgttcaa acaatacaca cctagtttca gagaataaag 2940
aacagactac acatcctgaa ctttttgcag gaaacaagac ccaaaacttg catcacatgc 3000
aatattttcc aaataatgtg atcccaaagc aagatcttct tcacaggtgc tttcaagaac 3060
aggagcagaa gtcacaacaa gcttcagttc tacagggata taaaaataga aaccaagata 3120
tgtctggtca acaagctgcg caacttgctc agcaaaggta cttgatacat aaccatgcaa 3180
atgtttttcc tgtgcctgac cagggaggaa gtcacactca gacccctccc cagaaggaca 3240
ctcaaaagca tgctgctcta aggtggcatc tcttacagaa gcaagaacag cagcaaacac 3300
agcaacccca aactgagtct tgccatagtc agatgcacag gccaattaag gtggaacctg 3360
gatgcaagcc acatgcctgt atgcacacag caccaccaga aaacaaaaca tggaaaaagg 3420
taactaagca agagaatcca cctgcaagct gtgataatgt gcagcaaaag agcatcattg 3480
agaccatgga gcagcatctg aagcagtttc acgccaagtc gttatttgac cataaggctc 3540
ttactctcaa atcacagaag caagtaaaag ttgaaatgtc agggccagtc acagttttga 3600
ctagacaaac cactgctgca gaacttgata gccacacccc agctttagag cagcaaacaa 3660
cttcttcaga aaagacacca accaaaagaa cagctgcttc tgttctcaat aattttatag 3720
agtcaccttc caaattacta gatactccta taaaaaattt attggataca cctgtcaaga 3780
ctcaatatga tttcccatct tgcagatgtg taggtaagtg ccagaaatgt actgagacac 3840
atggcgttta tccagaatta gcaaatttat cttcagatat gggattttcc ttcttttttt 3900
aaatcttgag tctggcagca atttgtaaag gctcataaaa atctgaagct tacatttttt 3960
gtcaagttac cgatgcttgt gtcttgtgaa agagaacttc acttacatgc agtttttcca 4020
aaagaattaa ataatcgtgc atgtttattt ttccctctct tcagatcctg taaaatttga 4080
atgtatctgt tttagatcaa ttcgcctatt tagctctttg tatattatct cctggagaga 4140
cagctaggca gcaaaaaaac aatctattaa aatgagaaaa taacgaccat aggcagtcta 4200
atgtacgaac tttaaatatt ttttaattca aggtaaaata tattagtttc acaagatttc 4260
tggctaatag ggaaattatt atcttcagtc ttcatgagtt gggggaaatg ataatgctga 4320
cactcttagt gctcctaaag tttccttttc tccatttata catttggaat gttgtgattt 4380
atattcattt tgattccctt ttctctaaaa tttcatcttt ttgattaaaa aatatgatac 4440
aggcatacct cagagatatt gtgggtttgg ctccatacca caataaaatg aatattacaa 4500
taaagcaagt tgtaaggact ttttggtttc tcactgtatg taaaagttat ttatatacta 4560
tactgtaaca tactaagtgt gcaatagcat tgtgtctaaa aaatatatac tttaaaaata 4620
atttattgtt aaaaaaatgc caacaattat ctgggccttt agtgagtgct aatctttttg 4680
ctggtggagg gtcgtgcttc agtattgatc gctgtggact gatcatggtg gtagttgctg 4740
aaggttgctg ggatggctgt gtgtgtggca atttcttaaa ataagacaac agtgaagtgc 4800
tgtatcaatt gatttttcca ttcacaaaag atttctctgt agcatgcaat gctgtttgat 4860
agcatttaac ccacagcaga atttctttga aaattggact cagtcctctc aaactgtgct 4920
gctgctttat caactaagtt tttgtaattt tctgaatcct ttgttgtcat ttcagcagtt 4980
tacagcatct tcattggaag tatattccat ctcaaacatt ctttgttcat ccataagaag 5040
caacttctta tcaagttttt tcatgacatt gcagtaactc agccccatct tcaggctcta 5100
cttctaattc tggttctctt gctacatctc cctcatctgc agtgacctct ccacggaagt 5160
cttgaactcc tcaaagtaat ccatgagggt tggaatcaac ttctaaactc ctgttaatgt 5220
tgatatattg accccctccc atgaattatg aatgttctta ataacttcta aatggtgata 5280
cctttccaga aggctttcaa tgtactttgc ccggatccat cagaagacta tcttggcagc 5340
tgtagactaa caatatattt cttaaatgat aagacttgaa agtcaaaagt actccttaat 5400
ccataggctg cagaatcaat gttgtattaa caggcacgaa aacagcatta atcttgtgca 5460
tctccatcgg agctcttggg tgactaggtg ccttgagcag taatattttg aaaggaggtt 5520
ttggttttgt tttttgtttt ttttttttgt tttttagcag taagtctcaa cactgggctt 5580
aaaatattca gtaaactatg ttgtaaaaag atgtgttatc atccagactt tgttgttcca 5640
ttactctaca caagcagggt acacttagca taattcttaa gggccttgga attttcagaa 5700
tggtaaatga gtatgggctt caacttaaaa tcatcaactg cattagcctg taacaagaga 5760
gtcagcctgt cctttgaagc aaggcattga cttctatcta tgaaagtctt agatggcacc 5820
ttgtttcaat agtaggctgt ttagtacagc caccttcatc agtgatctta gctagatctt 5880
ctgcataact tgctgcagct tctacatcag cacttgctgc ctcaccttgt ccttttatgt 5940
tatagagaca gctgcgcttc ttaaacttta taaaccaact tctgctagct tccaacttct 6000
cttctgcagc ttcctcattc tcttcataga actgaaggga gtcaaggcct tgctctggat 6060
taagctttgg cttaaggaat gttgtggctg acgtgatctt ctatccagac cactaaagcg 6120
ctctccatat cagcaataag gccgttttgc tttcttacct ttcatgtgtt cactggagta 6180
atttccttca agaatttttc ctttacattc acaacttggc taactggcat gcaaggccta 6240
gctttcagcc tgtcttggct tttgacatgc cttcctcact tagctcgtca tatctagctt 6300
ttgatttaaa gtggcaggca tacaactctt cctttcactt gaacacttag aggccactgt 6360
agggttatta attggcctaa tttcaatatt gttgtgtttt agggaataga gaggcccagg 6420
gagagggaga gagcccaaac ggctggttga tagagcaggc agaatgcaca caacatttat 6480
cagattatgt ttgcaccatt taccagatta tgggtacggt ttgtggcacc ccccaaaaat 6540
tagaatagta acatcaaaga tcactgatca cagatcgcca taacataaat aataataaac 6600
tttaaaatac tgtgagaatt accaaaatgt gatacagaga catgaagtga gcacatgctg 6660
ttgaaaaaaa tgacactgat agacatactt aacacgtggg attgccacaa accttcagtt 6720
tgtaaaagtc acagtaactg tgactcacaa aagaacaaag cacaataaaa cgaggtatgc 6780
ctgtattttt aaaaaaagct ttttgttaaa attcaggata tgtaataggt ctgtaggaat 6840
agtgaaatat ttttgctgat ggatgtagat atatacgtgg atagagatga agatcttaat 6900
tatagctatg cagcatagat ttagtcaaag acatttgaaa agacaaatgt taaattagtg 6960
tggctaatga cctacccgtg ccatgttttc cctcttgcaa tgagataccc cacactgtgt 7020
agaaggatgg agggaggact cctactgtcc ctctttgcgt gtggttatta agttgcctca 7080
ctgggctaaa acaccacaca tctcatagat aatatttggt aagttgtaat cgtcttcact 7140
cttctcttat cacccacccc tatcttccca cttttccatc tttgttggtt tgcaacagcc 7200
ccttcttttt gcctgactct ccaggatttt ctctcatcat aaattgttct aaagtacata 7260
ctaatatggg tctggattga ctattcttat ttgcaaaaca gcaattaaat gttataggga 7320
agtaggaaga aaaaggggta tccttgacaa taaaccaagc aatattctgg gggtgggata 7380
gagcaggaaa ttttattttt aatcttttaa aatccaagta ataggtaggc ttccagttag 7440
ctttaaatgt tttttttttc cagctcaaaa aattggattg tagttgatac tacatataat 7500
acattctaat tccctcactg tattctttgt ttagtttcat ttatttggtt taaaataatt 7560
ttttatccca tatctgaaat gtaatatatt tttatccaac aaccagcatg tacatatact 7620
taattatgtg gcacattttc taatagatca gtccatcaat ctactcattt taaagaaaaa 7680
aaaattttaa agtcactttt agagccctta atgtgtagtt gggggttaag ctttgtggat 7740
gtagccttta tatttagtat aattgaggtc taaaataata atcttctatt atctcaacag 7800
agcaaattat tgaaaaagat gaaggtcctt tttataccca tctaggagca ggtcctaatg 7860
tggcagctat tagagaaatc atggaagaaa ggtaattaac gcaaaggcac agggcagatt 7920
aacgtttatc cttttgtata tgtcagaatt tttccagcct tcacacacaa agcagtaaac 7980
aattgtaaat tgagtaatta ttagtaggct tagctattct agggttgcca acactacaca 8040
ctgtgctatt caccagagag tcacaatatt tgacaggact aatagtctgc tagctggcac 8100
aggctgccca ctttgcgatg gatgccagaa aacccaggca tgaacaggaa tcggccagcc 8160
aggctgccag ccacaaggta ctggcacagg ctccaacgag aggtcccact ctggctttcc 8220
cacctgataa taaagtgtca aagcagaaag actggtaaag tgtggtataa gaaaagaacc 8280
actgaattaa attcacctag tgttgcaaat gagtacttat ctctaagttt tcttttacca 8340
taaaaagaga gcaagtgtga tatgttgaat agaaagagaa acatactatt tacagctgcc 8400
tttttttttt tttttcgcta tcaatcacag gtatacaagt acttgccttt actcctgcat 8460
gtagaagact cttatgagcg agataatgca gagaaggcct ttcatataaa tttatacagc 8520
tctgagctgt tcttcttcta gggtgccttt tcattaagag gtaggcagta ttattattaa 8580
agtacttagg atacattggg gcagctagga catattcagt atcattcttg ctccatttcc 8640
aaattattca tttctaaatt agcatgtaga agttcactaa ataatcatct agtggcctgg 8700
cagaaatagt gaatttccct aagtgccttt tttttgttgt ttttttgttt tgttttttaa 8760
acaagcagta ggtggtgctt tggtcataag ggaagatata gtctatttct aggactattc 8820
catattttcc atgtggctgg atactaacta tttgccagcc tccttttcta aattgtgaga 8880
cattcttgga ggaacagttc taactaaaat ctattatgac tccccaagtt ttaaaatagc 8940
taaatttagt aagggaaaaa atagtttatg ttttagaaga ctgaacttag caaactaacc 9000
tgaattttgt gctttgtgaa attttatatc gaaatgagct ttcccatttt cacccacatg 9060
taatttacaa aatagttcat tacaattatc tgtacatttt gatattgagg aaaaacaagg 9120
cttaaaaacc attatccagt ttgcttggcg tagacctgtt taaaaaataa taaaccgttc 9180
atttctcagg atgtggtcat agaataaagt tatgctcaaa tgttcaaata tttaaa 9236
<210> 40
<211> 1165
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 40
Met Glu Gln Asp Arg Thr Asn His Val Glu Gly Asn Arg Leu Ser Pro
1 5 10 15
Phe Leu Ile Pro Ser Pro Pro Ile Cys Gln Thr Glu Pro Leu Ala Thr
20 25 30
Lys Leu Gln Asn Gly Ser Pro Leu Pro Glu Arg Ala His Pro Glu Val
35 40 45
Asn Gly Asp Thr Lys Trp His Ser Phe Lys Ser Tyr Tyr Gly Ile Pro
50 55 60
Cys Met Lys Gly Ser Gln Asn Ser Arg Val Ser Pro Asp Phe Thr Gln
65 70 75 80
Glu Ser Arg Gly Tyr Ser Lys Cys Leu Gln Asn Gly Gly Ile Lys Arg
85 90 95
Thr Val Ser Glu Pro Ser Leu Ser Gly Leu Leu Gln Ile Lys Lys Leu
100 105 110
Lys Gln Asp Gln Lys Ala Asn Gly Glu Arg Arg Asn Phe Gly Val Ser
115 120 125
Gln Glu Arg Asn Pro Gly Glu Ser Ser Gln Pro Asn Val Ser Asp Leu
130 135 140
Ser Asp Lys Lys Glu Ser Val Ser Ser Val Ala Gln Glu Asn Ala Val
145 150 155 160
Lys Asp Phe Thr Ser Phe Ser Thr His Asn Cys Ser Gly Pro Glu Asn
165 170 175
Pro Glu Leu Gln Ile Leu Asn Glu Gln Glu Gly Lys Ser Ala Asn Tyr
180 185 190
His Asp Lys Asn Ile Val Leu Leu Lys Asn Lys Ala Val Leu Met Pro
195 200 205
Asn Gly Ala Thr Val Ser Ala Ser Ser Val Glu His Thr His Gly Glu
210 215 220
Leu Leu Glu Lys Thr Leu Ser Gln Tyr Tyr Pro Asp Cys Val Ser Ile
225 230 235 240
Ala Val Gln Lys Thr Thr Ser His Ile Asn Ala Ile Asn Ser Gln Ala
245 250 255
Thr Asn Glu Leu Ser Cys Glu Ile Thr His Pro Ser His Thr Ser Gly
260 265 270
Gln Ile Asn Ser Ala Gln Thr Ser Asn Ser Glu Leu Pro Pro Lys Pro
275 280 285
Ala Ala Val Val Ser Glu Ala Cys Asp Ala Asp Asp Ala Asp Asn Ala
290 295 300
Ser Lys Leu Ala Ala Met Leu Asn Thr Cys Ser Phe Gln Lys Pro Glu
305 310 315 320
Gln Leu Gln Gln Gln Lys Ser Val Phe Glu Ile Cys Pro Ser Pro Ala
325 330 335
Glu Asn Asn Ile Gln Gly Thr Thr Lys Leu Ala Ser Gly Glu Glu Phe
340 345 350
Cys Ser Gly Ser Ser Ser Asn Leu Gln Ala Pro Gly Gly Ser Ser Glu
355 360 365
Arg Tyr Leu Lys Gln Asn Glu Met Asn Gly Ala Tyr Phe Lys Gln Ser
370 375 380
Ser Val Phe Thr Lys Asp Ser Phe Ser Ala Thr Thr Thr Pro Pro Pro
385 390 395 400
Pro Ser Gln Leu Leu Leu Ser Pro Pro Pro Pro Leu Pro Gln Val Pro
405 410 415
Gln Leu Pro Ser Glu Gly Lys Ser Thr Leu Asn Gly Gly Val Leu Glu
420 425 430
Glu His His His Tyr Pro Asn Gln Ser Asn Thr Thr Leu Leu Arg Glu
435 440 445
Val Lys Ile Glu Gly Lys Pro Glu Ala Pro Pro Ser Gln Ser Pro Asn
450 455 460
Pro Ser Thr His Val Cys Ser Pro Ser Pro Met Leu Ser Glu Arg Pro
465 470 475 480
Gln Asn Asn Cys Val Asn Arg Asn Asp Ile Gln Thr Ala Gly Thr Met
485 490 495
Thr Val Pro Leu Cys Ser Glu Lys Thr Arg Pro Met Ser Glu His Leu
500 505 510
Lys His Asn Pro Pro Ile Phe Gly Ser Ser Gly Glu Leu Gln Asp Asn
515 520 525
Cys Gln Gln Leu Met Arg Asn Lys Glu Gln Glu Ile Leu Lys Gly Arg
530 535 540
Asp Lys Glu Gln Thr Arg Asp Leu Val Pro Pro Thr Gln His Tyr Leu
545 550 555 560
Lys Pro Gly Trp Ile Glu Leu Lys Ala Pro Arg Phe His Gln Ala Glu
565 570 575
Ser His Leu Lys Arg Asn Glu Ala Ser Leu Pro Ser Ile Leu Gln Tyr
580 585 590
Gln Pro Asn Leu Ser Asn Gln Met Thr Ser Lys Gln Tyr Thr Gly Asn
595 600 605
Ser Asn Met Pro Gly Gly Leu Pro Arg Gln Ala Tyr Thr Gln Lys Thr
610 615 620
Thr Gln Leu Glu His Lys Ser Gln Met Tyr Gln Val Glu Met Asn Gln
625 630 635 640
Gly Gln Ser Gln Gly Thr Val Asp Gln His Leu Gln Phe Gln Lys Pro
645 650 655
Ser His Gln Val His Phe Ser Lys Thr Asp His Leu Pro Lys Ala His
660 665 670
Val Gln Ser Leu Cys Gly Thr Arg Phe His Phe Gln Gln Arg Ala Asp
675 680 685
Ser Gln Thr Glu Lys Leu Met Ser Pro Val Leu Lys Gln His Leu Asn
690 695 700
Gln Gln Ala Ser Glu Thr Glu Pro Phe Ser Asn Ser His Leu Leu Gln
705 710 715 720
His Lys Pro His Lys Gln Ala Ala Gln Thr Gln Pro Ser Gln Ser Ser
725 730 735
His Leu Pro Gln Asn Gln Gln Gln Gln Gln Lys Leu Gln Ile Lys Asn
740 745 750
Lys Glu Glu Ile Leu Gln Thr Phe Pro His Pro Gln Ser Asn Asn Asp
755 760 765
Gln Gln Arg Glu Gly Ser Phe Phe Gly Gln Thr Lys Val Glu Glu Cys
770 775 780
Phe His Gly Glu Asn Gln Tyr Ser Lys Ser Ser Glu Phe Glu Thr His
785 790 795 800
Asn Val Gln Met Gly Leu Glu Glu Val Gln Asn Ile Asn Arg Arg Asn
805 810 815
Ser Pro Tyr Ser Gln Thr Met Lys Ser Ser Ala Cys Lys Ile Gln Val
820 825 830
Ser Cys Ser Asn Asn Thr His Leu Val Ser Glu Asn Lys Glu Gln Thr
835 840 845
Thr His Pro Glu Leu Phe Ala Gly Asn Lys Thr Gln Asn Leu His His
850 855 860
Met Gln Tyr Phe Pro Asn Asn Val Ile Pro Lys Gln Asp Leu Leu His
865 870 875 880
Arg Cys Phe Gln Glu Gln Glu Gln Lys Ser Gln Gln Ala Ser Val Leu
885 890 895
Gln Gly Tyr Lys Asn Arg Asn Gln Asp Met Ser Gly Gln Gln Ala Ala
900 905 910
Gln Leu Ala Gln Gln Arg Tyr Leu Ile His Asn His Ala Asn Val Phe
915 920 925
Pro Val Pro Asp Gln Gly Gly Ser His Thr Gln Thr Pro Pro Gln Lys
930 935 940
Asp Thr Gln Lys His Ala Ala Leu Arg Trp His Leu Leu Gln Lys Gln
945 950 955 960
Glu Gln Gln Gln Thr Gln Gln Pro Gln Thr Glu Ser Cys His Ser Gln
965 970 975
Met His Arg Pro Ile Lys Val Glu Pro Gly Cys Lys Pro His Ala Cys
980 985 990
Met His Thr Ala Pro Pro Glu Asn Lys Thr Trp Lys Lys Val Thr Lys
995 1000 1005
Gln Glu Asn Pro Pro Ala Ser Cys Asp Asn Val Gln Gln Lys Ser
1010 1015 1020
Ile Ile Glu Thr Met Glu Gln His Leu Lys Gln Phe His Ala Lys
1025 1030 1035
Ser Leu Phe Asp His Lys Ala Leu Thr Leu Lys Ser Gln Lys Gln
1040 1045 1050
Val Lys Val Glu Met Ser Gly Pro Val Thr Val Leu Thr Arg Gln
1055 1060 1065
Thr Thr Ala Ala Glu Leu Asp Ser His Thr Pro Ala Leu Glu Gln
1070 1075 1080
Gln Thr Thr Ser Ser Glu Lys Thr Pro Thr Lys Arg Thr Ala Ala
1085 1090 1095
Ser Val Leu Asn Asn Phe Ile Glu Ser Pro Ser Lys Leu Leu Asp
1100 1105 1110
Thr Pro Ile Lys Asn Leu Leu Asp Thr Pro Val Lys Thr Gln Tyr
1115 1120 1125
Asp Phe Pro Ser Cys Arg Cys Val Gly Lys Cys Gln Lys Cys Thr
1130 1135 1140
Glu Thr His Gly Val Tyr Pro Glu Leu Ala Asn Leu Ser Ser Asp
1145 1150 1155
Met Gly Phe Ser Phe Phe Phe
1160 1165
<210> 41
<211> 4049
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 41
agcgcgtacc actctggcgc tcccgaggcg gcctcttgtg cgatccaggg cgcacaaggc 60
tgggagagcg ccccggggcc cctgctatcc gcgccggagg ttggaagagg gtgggttgcc 120
gccgcccgag ggcgagagcg ccagaggagc gggaagaagg agcgctcgcc cgcccgcctg 180
cctcctcgct gcctccccgg cgttggctct ctggactcct aggcttgctg gctgctcctc 240
ccacccgcgc ccgcctcctc actcgccttt tcgttcgccg gggctgcttt ccaagccctg 300
cggtgcgccc gggcgagtgc ggggcgaggg gcccggggcc agcaccgagc agggggcggg 360
ggtccgggca gagcgcggcc ggccggggag gggccatgtc tggcgcgggc gcagcggggc 420
ccgtctgcag caagtgaccg agcggcgcgg acggccgcct gccccctctg ccacctgggg 480
cggtgcgggc ccggagcccg gagcccgggt agcgcgtaga gccggcgcga tgcacgtgcg 540
ctcactgcga gctgcggcgc cgcacagctt cgtggcgctc tgggcacccc tgttcctgct 600
gcgctccgcc ctggccgact tcagcctgga caacgaggtg cactcgagct tcatccaccg 660
gcgcctccgc agccaggagc ggcgggagat gcagcgcgag atcctctcca ttttgggctt 720
gccccaccgc ccgcgcccgc acctccaggg caagcacaac tcggcaccca tgttcatgct 780
ggacctgtac aacgccatgg cggtggagga gggcggcggg cccggcggcc agggcttctc 840
ctacccctac aaggccgtct tcagtaccca gggcccccct ctggccagcc tgcaagatag 900
ccatttcctc accgacgccg acatggtcat gagcttcgtc aacctcgtgg aacatgacaa 960
ggaattcttc cacccacgct accaccatcg agagttccgg tttgatcttt ccaagatccc 1020
agaaggggaa gctgtcacgg cagccgaatt ccggatctac aaggactaca tccgggaacg 1080
cttcgacaat gagacgttcc ggatcagcgt ttatcaggtg ctccaggagc acttgggcag 1140
ggaatcggat ctcttcctgc tcgacagccg taccctctgg gcctcggagg agggctggct 1200
ggtgtttgac atcacagcca ccagcaacca ctgggtggtc aatccgcggc acaacctggg 1260
cctgcagctc tcggtggaga cgctggatgg gcagagcatc aaccccaagt tggcgggcct 1320
gattgggcgg cacgggcccc agaacaagca gcccttcatg gtggctttct tcaaggccac 1380
ggaggtccac ttccgcagca tccggtccac ggggagcaaa cagcgcagcc agaaccgctc 1440
caagacgccc aagaaccagg aagccctgcg gatggccaac gtggcagaga acagcagcag 1500
cgaccagagg caggcctgta agaagcacga gctgtatgtc agcttccgag acctgggctg 1560
gcaggactgg atcatcgcgc ctgaaggcta cgccgcctac tactgtgagg gggagtgtgc 1620
cttccctctg aactcctaca tgaacgccac caaccacgcc atcgtgcaga cgctggtcca 1680
cttcatcaac ccggaaacgg tgcccaagcc ctgctgtgcg cccacgcagc tcaatgccat 1740
ctccgtcctc tacttcgatg acagctccaa cgtcatcctg aagaaataca gaaacatggt 1800
ggtccgggcc tgtggctgcc actagctcct ccgagaattc agaccctttg gggccaagtt 1860
tttctggatc ctccattgct cgccttggcc aggaaccagc agaccaactg ccttttgtga 1920
gaccttcccc tccctatccc caactttaaa ggtgtgagag tattaggaaa catgagcagc 1980
atatggcttt tgatcagttt ttcagtggca gcatccaatg aacaagatcc tacaagctgt 2040
gcaggcaaaa cctagcagga aaaaaaaaca acgcataaag aaaaatggcc gggccaggtc 2100
attggctggg aagtctcagc catgcacgga ctcgtttcca gaggtaatta tgagcgccta 2160
ccagccaggc cacccagccg tgggaggaag ggggcgtggc aaggggtggg cacattggtg 2220
tctgtgcgaa aggaaaattg acccggaagt tcctgtaata aatgtcacaa taaaacgaat 2280
gaatgaaaat ggttaggacg ttacagatat attttcctaa acaatttatc cccatttctc 2340
ggtttatcct gatgcgtaaa cagaagctgt gtcaagtgga gggcggggag gtccctctcc 2400
attccctaca gttttcatcc tgaggcttgc agaggcccag tgtttaccga ggtttgccca 2460
aatccaagat ctagtgggag gggaaagagc aaatgtctgc tccgaggagg gcggtgtgtt 2520
gatctttgga ggaaaaatat gttctgttgt tcagctggat ttgccgtggc agaaatgaaa 2580
ctaggtgtgt gaaatacccg cagacatttg ggattggctt ttcacctcgc cccagtggta 2640
gtaaatccat gtgaaattgc agaggggaca aggacagcaa gtaggatgga acttgcaact 2700
caaccctgtt gttaagaagc accaatgggc cgggcacagt agctcccacc tgtaatccca 2760
gcactttggg aggctgaggt gggcggatca tttgaggtca ggagttcgag accagcctgg 2820
ccaacatggt gaaaccccat ctctactaaa aatacaaaaa ttagccgggc atggtggcac 2880
gcacctgtaa tcccagctac tctggaggct gaggcaggag aattgcttga accccagagg 2940
tggaggttgc agtgagccaa gatcgtccca ctgcactcca gcttgggtga caaaacaaga 3000
ctccatctca aaagaaaaaa aaaacagcac caatgaagcc tagttctcca cgggagtggg 3060
gtgagcagga gcactgcaca tcgccccagt ggaccctctg gtctttgtct gcagtggcat 3120
tccaaggctg ggccctggca agggcacccg tggctgtctc ttcatttgca gaccctgatc 3180
agaagtctct gcaaacaaat ttgctccttg aattaagggg gagatggcat aataggaggt 3240
ctgatgggtg caggatgtgc tggacttaca ttgcaaatag aagccttgtt gagggtgaca 3300
tcctaaccaa gtgtcccgat ttggaggtgg catttctgac gtggctcttg gtgtaagcct 3360
gccttgcctt ggctggtgag tcccataaat agtatgcact cagcctccgg ccacaaacac 3420
aaggcctagg ggagggctag actgtctgca aacgttttct gcatctgtaa agaaaacaag 3480
gtgatcgaaa actgtggcca tgtggaaccc ggtcttgtgg gggactgttt ctccatcttg 3540
actcagacag ttcctggaaa caccggggct ctgtttttat tttctttgat gtttttcttc 3600
tttagtagct tgggctgcag cctccactct ctagtcactg gggaggagta ttttttgtta 3660
tgtttggttt catttgctgg cagagctggg gctttttgtg tgatccctct tggtgtgagt 3720
tttctgaccc aaccagcctc tggttagcat catttgtaca tttaaacctg taaatagttg 3780
ttacaaagca aagagattat ttatttccat ccaaagctct tttgaacacc cccccccctt 3840
taatccctcg ttcaggacga tgagcttgct ttccttcaac ctgtttgttt tcttatttaa 3900
gactatttat taatggttgg accaatgtac tcacagctgt tgcgtcgagc agtccttagt 3960
gaaaattctg tataaataga caaaatgaaa agggtttgac cttgcaataa aaggagacgt 4020
ttggttctgg caaaaaaaaa aaaaaaaaa 4049
<210> 42
<211> 431
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 42
Met His Val Arg Ser Leu Arg Ala Ala Ala Pro His Ser Phe Val Ala
1 5 10 15
Leu Trp Ala Pro Leu Phe Leu Leu Arg Ser Ala Leu Ala Asp Phe Ser
20 25 30
Leu Asp Asn Glu Val His Ser Ser Phe Ile His Arg Arg Leu Arg Ser
35 40 45
Gln Glu Arg Arg Glu Met Gln Arg Glu Ile Leu Ser Ile Leu Gly Leu
50 55 60
Pro His Arg Pro Arg Pro His Leu Gln Gly Lys His Asn Ser Ala Pro
65 70 75 80
Met Phe Met Leu Asp Leu Tyr Asn Ala Met Ala Val Glu Glu Gly Gly
85 90 95
Gly Pro Gly Gly Gln Gly Phe Ser Tyr Pro Tyr Lys Ala Val Phe Ser
100 105 110
Thr Gln Gly Pro Pro Leu Ala Ser Leu Gln Asp Ser His Phe Leu Thr
115 120 125
Asp Ala Asp Met Val Met Ser Phe Val Asn Leu Val Glu His Asp Lys
130 135 140
Glu Phe Phe His Pro Arg Tyr His His Arg Glu Phe Arg Phe Asp Leu
145 150 155 160
Ser Lys Ile Pro Glu Gly Glu Ala Val Thr Ala Ala Glu Phe Arg Ile
165 170 175
Tyr Lys Asp Tyr Ile Arg Glu Arg Phe Asp Asn Glu Thr Phe Arg Ile
180 185 190
Ser Val Tyr Gln Val Leu Gln Glu His Leu Gly Arg Glu Ser Asp Leu
195 200 205
Phe Leu Leu Asp Ser Arg Thr Leu Trp Ala Ser Glu Glu Gly Trp Leu
210 215 220
Val Phe Asp Ile Thr Ala Thr Ser Asn His Trp Val Val Asn Pro Arg
225 230 235 240
His Asn Leu Gly Leu Gln Leu Ser Val Glu Thr Leu Asp Gly Gln Ser
245 250 255
Ile Asn Pro Lys Leu Ala Gly Leu Ile Gly Arg His Gly Pro Gln Asn
260 265 270
Lys Gln Pro Phe Met Val Ala Phe Phe Lys Ala Thr Glu Val His Phe
275 280 285
Arg Ser Ile Arg Ser Thr Gly Ser Lys Gln Arg Ser Gln Asn Arg Ser
290 295 300
Lys Thr Pro Lys Asn Gln Glu Ala Leu Arg Met Ala Asn Val Ala Glu
305 310 315 320
Asn Ser Ser Ser Asp Gln Arg Gln Ala Cys Lys Lys His Glu Leu Tyr
325 330 335
Val Ser Phe Arg Asp Leu Gly Trp Gln Asp Trp Ile Ile Ala Pro Glu
340 345 350
Gly Tyr Ala Ala Tyr Tyr Cys Glu Gly Glu Cys Ala Phe Pro Leu Asn
355 360 365
Ser Tyr Met Asn Ala Thr Asn His Ala Ile Val Gln Thr Leu Val His
370 375 380
Phe Ile Asn Pro Glu Thr Val Pro Lys Pro Cys Cys Ala Pro Thr Gln
385 390 395 400
Leu Asn Ala Ile Ser Val Leu Tyr Phe Asp Asp Ser Ser Asn Val Ile
405 410 415
Leu Lys Lys Tyr Arg Asn Met Val Val Arg Ala Cys Gly Cys His
420 425 430
<210> 43
<211> 4110
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 43
gtcgagcggg agcagaggag gcgagggagg agggccagag aggcagttgg aagatggcgg 60
acgaggcggc cctcgccctt cagcccggcg gctccccctc ggcggcgggg gccgacaggg 120
aggccgcgtc gtcccccgcc ggggagccgc tccgcaagag gccgcggaga gatggtcccg 180
gcctcgagcg gagcccgggc gagcccggtg gggcggcccc agagcgtgag gtgccggcgg 240
cggccagggg ctgcccgggt gcggcggcgg cggcgctgtg gcgggaggcg gaggcagagg 300
cggcggcggc aggcggggag caagaggccc aggcgactgc ggcggctggg gaaggagaca 360
atgggccggg cctgcagggc ccatctcggg agccaccgct ggccgacaac ttgtacgacg 420
aagacgacga cgacgagggc gaggaggagg aagaggcggc ggcggcggcg attgggtacc 480
gagataacct tctgttcggt gatgaaatta tcactaatgg ttttcattcc tgtgaaagtg 540
atgaggagga tagagcctca catgcaagct ctagtgactg gactccaagg ccacggatag 600
gtccatatac ttttgttcag caacatctta tgattggcac agatcctcga acaattctta 660
aagatttatt gccggaaaca atacctccac ctgagttgga tgatatgaca ctgtggcaga 720
ttgttattaa tatcctttca gaaccaccaa aaaggaaaaa aagaaaagat attaatacaa 780
ttgaagatgc tgtgaaatta ctgcaagagt gcaaaaaaat tatagttcta actggagctg 840
gggtgtctgt ttcatgtgga atacctgact tcaggtcaag ggatggtatt tatgctcgcc 900
ttgctgtaga cttcccagat cttccagatc ctcaagcgat gtttgatatt gaatatttca 960
gaaaagatcc aagaccattc ttcaagtttg caaaggaaat atatcctgga caattccagc 1020
catctctctg tcacaaattc atagccttgt cagataagga aggaaaacta cttcgcaact 1080
atacccagaa catagacacg ctggaacagg ttgcgggaat ccaaaggata attcagtgtc 1140
atggttcctt tgcaacagca tcttgcctga tttgtaaata caaagttgac tgtgaagctg 1200
tacgaggaga tatttttaat caggtagttc ctcgatgtcc taggtgccca gctgatgaac 1260
cgcttgctat catgaaacca gagattgtgt tttttggtga aaatttacca gaacagtttc 1320
atagagccat gaagtatgac aaagatgaag ttgacctcct cattgttatt gggtcttccc 1380
tcaaagtaag accagtagca ctaattccaa gttccatacc ccatgaagtg cctcagatat 1440
taattaatag agaacctttg cctcatctgc attttgatgt agagcttctt ggagactgtg 1500
atgtcataat taatgaattg tgtcataggt taggtggtga atatgccaaa ctttgctgta 1560
accctgtaaa gctttcagaa attactgaaa aacctccacg aacacaaaaa gaattggctt 1620
atttgtcaga gttgccaccc acacctcttc atgtttcaga agactcaagt tcaccagaaa 1680
gaacttcacc accagattct tcagtgattg tcacactttt agaccaagca gctaagagta 1740
atgatgattt agatgtgtct gaatcaaaag gttgtatgga agaaaaacca caggaagtac 1800
aaacttctag gaatgttgaa agtattgctg aacagatgga aaatccggat ttgaagaatg 1860
ttggttctag tactggggag aaaaatgaaa gaacttcagt ggctggaaca gtgagaaaat 1920
gctggcctaa tagagtggca aaggagcaga ttagtaggcg gcttgatggt aatcagtatc 1980
tgtttttgcc accaaatcgt tacattttcc atggcgctga ggtatattca gactctgaag 2040
atgacgtctt atcctctagt tcttgtggca gtaacagtga tagtgggaca tgccagagtc 2100
caagtttaga agaacccatg gaggatgaaa gtgaaattga agaattctac aatggcttag 2160
aagatgagcc tgatgttcca gagagagctg gaggagctgg atttgggact gatggagatg 2220
atcaagaggc aattaatgaa gctatatctg tgaaacagga agtaacagac atgaactatc 2280
catcaaacaa atcatagtgt aataattgtg caggtacagg aattgttcca ccagcattag 2340
gaactttagc atgtcaaaat gaatgtttac ttgtgaactc gatagagcaa ggaaaccaga 2400
aaggtgtaat atttataggt tggtaaaata gattgttttt catggataat ttttaacttc 2460
attatttctg tacttgtaca aactcaacac taactttttt ttttttaaaa aaaaaaaggt 2520
actaagtatc ttcaatcagc tgttggtcaa gactaacttt cttttaaagg ttcatttgta 2580
tgataaattc atatgtgtat atataatttt ttttgttttg tctagtgagt ttcaacattt 2640
ttaaagtttt caaaaagcca tcggaatgtt aaattaatgt aaagggaaca gctaatctag 2700
accaaagaat ggtattttca cttttctttg taacattgaa tggtttgaag tactcaaaat 2760
ctgttacgct aaacttttga ttctttaaca caattatttt taaacactgg cattttccaa 2820
aactgtggca gctaactttt taaaatctca aatgacatgc agtgtgagta gaaggaagtc 2880
aacaatatgt ggggagagca ctcggttgtc tttactttta aaagtaatac ttggtgctaa 2940
gaatttcagg attattgtat ttacgttcaa atgaagatgg cttttgtact tcctgtggac 3000
atgtagtaat gtctatattg gctcataaaa ctaacctgaa aaacaaataa atgctttgga 3060
aatgtttcag ttgctttaga aacattagtg cctgcctgga tccccttagt tttgaaatat 3120
ttgccattgt tgtttaaata cctatcactg tggtagagct tgcattgatc ttttccacaa 3180
gtattaaact gccaaaatgt gaatatgcaa agcctttctg aatctataat aatggtactt 3240
ctactgggga gagtgtaata ttttggactg ctgttttcca ttaatgagga gagcaacagg 3300
cccctgatta tacagttcca aagtaataag atgttaattg taattcagcc agaaagtaca 3360
tgtctcccat tgggaggatt tggtgttaaa taccaaactg ctagccctag tattatggag 3420
atgaacatga tgatgtaact tgtaatagca gaatagttaa tgaatgaaac tagttcttat 3480
aatttatctt tatttaaaag cttagcctgc cttaaaacta gagatcaact ttctcagctg 3540
caaaagcttc tagtctttca agaagttcat actttatgaa attgcacagt aagcatttat 3600
ttttcagacc atttttgaac atcactccta aattaataaa gtattcctct gttgctttag 3660
tatttattac aataaaaagg gtttgaaata tagctgttct ttatgcataa aacacccagc 3720
taggaccatt actgccagag aaaaaaatcg tattgaatgg ccatttccct acttataaga 3780
tgtctcaatc tgaatttatt tggctacact aaagaatgca gtatatttag ttttccattt 3840
gcatgatgtt tgtgtgctat agatgatatt ttaaattgaa aagtttgttt taaattattt 3900
ttacagtgaa gactgttttc agctcttttt atattgtaca tagtctttta tgtaatttac 3960
tggcatatgt tttgtagact gtttaatgac tggatatctt ccttcaactt ttgaaataca 4020
aaaccagtgt tttttacttg tacactgttt taaagtctat taaaattgtc atttgacttt 4080
tttctgttaa cttaaaaaaa aaaaaaaaaa 4110
<210> 44
<211> 747
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 44
Met Ala Asp Glu Ala Ala Leu Ala Leu Gln Pro Gly Gly Ser Pro Ser
1 5 10 15
Ala Ala Gly Ala Asp Arg Glu Ala Ala Ser Ser Pro Ala Gly Glu Pro
20 25 30
Leu Arg Lys Arg Pro Arg Arg Asp Gly Pro Gly Leu Glu Arg Ser Pro
35 40 45
Gly Glu Pro Gly Gly Ala Ala Pro Glu Arg Glu Val Pro Ala Ala Ala
50 55 60
Arg Gly Cys Pro Gly Ala Ala Ala Ala Ala Leu Trp Arg Glu Ala Glu
65 70 75 80
Ala Glu Ala Ala Ala Ala Gly Gly Glu Gln Glu Ala Gln Ala Thr Ala
85 90 95
Ala Ala Gly Glu Gly Asp Asn Gly Pro Gly Leu Gln Gly Pro Ser Arg
100 105 110
Glu Pro Pro Leu Ala Asp Asn Leu Tyr Asp Glu Asp Asp Asp Asp Glu
115 120 125
Gly Glu Glu Glu Glu Glu Ala Ala Ala Ala Ala Ile Gly Tyr Arg Asp
130 135 140
Asn Leu Leu Phe Gly Asp Glu Ile Ile Thr Asn Gly Phe His Ser Cys
145 150 155 160
Glu Ser Asp Glu Glu Asp Arg Ala Ser His Ala Ser Ser Ser Asp Trp
165 170 175
Thr Pro Arg Pro Arg Ile Gly Pro Tyr Thr Phe Val Gln Gln His Leu
180 185 190
Met Ile Gly Thr Asp Pro Arg Thr Ile Leu Lys Asp Leu Leu Pro Glu
195 200 205
Thr Ile Pro Pro Pro Glu Leu Asp Asp Met Thr Leu Trp Gln Ile Val
210 215 220
Ile Asn Ile Leu Ser Glu Pro Pro Lys Arg Lys Lys Arg Lys Asp Ile
225 230 235 240
Asn Thr Ile Glu Asp Ala Val Lys Leu Leu Gln Glu Cys Lys Lys Ile
245 250 255
Ile Val Leu Thr Gly Ala Gly Val Ser Val Ser Cys Gly Ile Pro Asp
260 265 270
Phe Arg Ser Arg Asp Gly Ile Tyr Ala Arg Leu Ala Val Asp Phe Pro
275 280 285
Asp Leu Pro Asp Pro Gln Ala Met Phe Asp Ile Glu Tyr Phe Arg Lys
290 295 300
Asp Pro Arg Pro Phe Phe Lys Phe Ala Lys Glu Ile Tyr Pro Gly Gln
305 310 315 320
Phe Gln Pro Ser Leu Cys His Lys Phe Ile Ala Leu Ser Asp Lys Glu
325 330 335
Gly Lys Leu Leu Arg Asn Tyr Thr Gln Asn Ile Asp Thr Leu Glu Gln
340 345 350
Val Ala Gly Ile Gln Arg Ile Ile Gln Cys His Gly Ser Phe Ala Thr
355 360 365
Ala Ser Cys Leu Ile Cys Lys Tyr Lys Val Asp Cys Glu Ala Val Arg
370 375 380
Gly Asp Ile Phe Asn Gln Val Val Pro Arg Cys Pro Arg Cys Pro Ala
385 390 395 400
Asp Glu Pro Leu Ala Ile Met Lys Pro Glu Ile Val Phe Phe Gly Glu
405 410 415
Asn Leu Pro Glu Gln Phe His Arg Ala Met Lys Tyr Asp Lys Asp Glu
420 425 430
Val Asp Leu Leu Ile Val Ile Gly Ser Ser Leu Lys Val Arg Pro Val
435 440 445
Ala Leu Ile Pro Ser Ser Ile Pro His Glu Val Pro Gln Ile Leu Ile
450 455 460
Asn Arg Glu Pro Leu Pro His Leu His Phe Asp Val Glu Leu Leu Gly
465 470 475 480
Asp Cys Asp Val Ile Ile Asn Glu Leu Cys His Arg Leu Gly Gly Glu
485 490 495
Tyr Ala Lys Leu Cys Cys Asn Pro Val Lys Leu Ser Glu Ile Thr Glu
500 505 510
Lys Pro Pro Arg Thr Gln Lys Glu Leu Ala Tyr Leu Ser Glu Leu Pro
515 520 525
Pro Thr Pro Leu His Val Ser Glu Asp Ser Ser Ser Pro Glu Arg Thr
530 535 540
Ser Pro Pro Asp Ser Ser Val Ile Val Thr Leu Leu Asp Gln Ala Ala
545 550 555 560
Lys Ser Asn Asp Asp Leu Asp Val Ser Glu Ser Lys Gly Cys Met Glu
565 570 575
Glu Lys Pro Gln Glu Val Gln Thr Ser Arg Asn Val Glu Ser Ile Ala
580 585 590
Glu Gln Met Glu Asn Pro Asp Leu Lys Asn Val Gly Ser Ser Thr Gly
595 600 605
Glu Lys Asn Glu Arg Thr Ser Val Ala Gly Thr Val Arg Lys Cys Trp
610 615 620
Pro Asn Arg Val Ala Lys Glu Gln Ile Ser Arg Arg Leu Asp Gly Asn
625 630 635 640
Gln Tyr Leu Phe Leu Pro Pro Asn Arg Tyr Ile Phe His Gly Ala Glu
645 650 655
Val Tyr Ser Asp Ser Glu Asp Asp Val Leu Ser Ser Ser Ser Cys Gly
660 665 670
Ser Asn Ser Asp Ser Gly Thr Cys Gln Ser Pro Ser Leu Glu Glu Pro
675 680 685
Met Glu Asp Glu Ser Glu Ile Glu Glu Phe Tyr Asn Gly Leu Glu Asp
690 695 700
Glu Pro Asp Val Pro Glu Arg Ala Gly Gly Ala Gly Phe Gly Thr Asp
705 710 715 720
Gly Asp Asp Gln Glu Ala Ile Asn Glu Ala Ile Ser Val Lys Gln Glu
725 730 735
Val Thr Asp Met Asn Tyr Pro Ser Asn Lys Ser
740 745
<210> 45
<211> 3604
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 45
gcatctcctc ctccctctcc ccgggctcct actggcctga ggttgagggc ggctgggggc 60
tcggggcagg ctccgcggcg ttcccctccc caccccggcc ctccgttcag ccgcgctcct 120
ccggggctgc ggttcctact gcgcgagctg ccagtggatt cgctcttttc ctccgtccgt 180
ggcccgcctg ggcggccttg ttctttccgc agcagccaga taaccttctg ttcggtgatg 240
aaattatcac taatggtttt cattcctgtg aaagtgatga ggaggataga gcctcacatg 300
caagctctag tgactggact ccaaggccac ggataggtgt ctgtttcatg tggaatacct 360
gacttcaggt caagggatgg tatttatgct cgccttgctg tagacttccc agatcttcca 420
gatcctcaag cgatgtttga tattgaatat ttcagaaaag atccaagacc attcttcaag 480
tttgcaaagg aaatatatcc tggacaattc cagccatctc tctgtcacaa attcatagcc 540
ttgtcagata aggaaggaaa actacttcgc aactataccc agaacataga cacgctggaa 600
caggttgcgg gaatccaaag gataattcag tgtcatggtt cctttgcaac agcatcttgc 660
ctgatttgta aatacaaagt tgactgtgaa gctgtacgag gagatatttt taatcaggta 720
gttcctcgat gtcctaggtg cccagctgat gaaccgcttg ctatcatgaa accagagatt 780
gtgttttttg gtgaaaattt accagaacag tttcatagag ccatgaagta tgacaaagat 840
gaagttgacc tcctcattgt tattgggtct tccctcaaag taagaccagt agcactaatt 900
ccaagttcca taccccatga agtgcctcag atattaatta atagagaacc tttgcctcat 960
ctgcattttg atgtagagct tcttggagac tgtgatgtca taattaatga attgtgtcat 1020
aggttaggtg gtgaatatgc caaactttgc tgtaaccctg taaagctttc agaaattact 1080
gaaaaacctc cacgaacaca aaaagaattg gcttatttgt cagagttgcc acccacacct 1140
cttcatgttt cagaagactc aagttcacca gaaagaactt caccaccaga ttcttcagtg 1200
attgtcacac ttttagacca agcagctaag agtaatgatg atttagatgt gtctgaatca 1260
aaaggttgta tggaagaaaa accacaggaa gtacaaactt ctaggaatgt tgaaagtatt 1320
gctgaacaga tggaaaatcc ggatttgaag aatgttggtt ctagtactgg ggagaaaaat 1380
gaaagaactt cagtggctgg aacagtgaga aaatgctggc ctaatagagt ggcaaaggag 1440
cagattagta ggcggcttga tggtaatcag tatctgtttt tgccaccaaa tcgttacatt 1500
ttccatggcg ctgaggtata ttcagactct gaagatgacg tcttatcctc tagttcttgt 1560
ggcagtaaca gtgatagtgg gacatgccag agtccaagtt tagaagaacc catggaggat 1620
gaaagtgaaa ttgaagaatt ctacaatggc ttagaagatg agcctgatgt tccagagaga 1680
gctggaggag ctggatttgg gactgatgga gatgatcaag aggcaattaa tgaagctata 1740
tctgtgaaac aggaagtaac agacatgaac tatccatcaa acaaatcata gtgtaataat 1800
tgtgcaggta caggaattgt tccaccagca ttaggaactt tagcatgtca aaatgaatgt 1860
ttacttgtga actcgataga gcaaggaaac cagaaaggtg taatatttat aggttggtaa 1920
aatagattgt ttttcatgga taatttttaa cttcattatt tctgtacttg tacaaactca 1980
acactaactt tttttttttt aaaaaaaaaa aggtactaag tatcttcaat cagctgttgg 2040
tcaagactaa ctttctttta aaggttcatt tgtatgataa attcatatgt gtatatataa 2100
ttttttttgt tttgtctagt gagtttcaac atttttaaag ttttcaaaaa gccatcggaa 2160
tgttaaatta atgtaaaggg aacagctaat ctagaccaaa gaatggtatt ttcacttttc 2220
tttgtaacat tgaatggttt gaagtactca aaatctgtta cgctaaactt ttgattcttt 2280
aacacaatta tttttaaaca ctggcatttt ccaaaactgt ggcagctaac tttttaaaat 2340
ctcaaatgac atgcagtgtg agtagaagga agtcaacaat atgtggggag agcactcggt 2400
tgtctttact tttaaaagta atacttggtg ctaagaattt caggattatt gtatttacgt 2460
tcaaatgaag atggcttttg tacttcctgt ggacatgtag taatgtctat attggctcat 2520
aaaactaacc tgaaaaacaa ataaatgctt tggaaatgtt tcagttgctt tagaaacatt 2580
agtgcctgcc tggatcccct tagttttgaa atatttgcca ttgttgttta aatacctatc 2640
actgtggtag agcttgcatt gatcttttcc acaagtatta aactgccaaa atgtgaatat 2700
gcaaagcctt tctgaatcta taataatggt acttctactg gggagagtgt aatattttgg 2760
actgctgttt tccattaatg aggagagcaa caggcccctg attatacagt tccaaagtaa 2820
taagatgtta attgtaattc agccagaaag tacatgtctc ccattgggag gatttggtgt 2880
taaataccaa actgctagcc ctagtattat ggagatgaac atgatgatgt aacttgtaat 2940
agcagaatag ttaatgaatg aaactagttc ttataattta tctttattta aaagcttagc 3000
ctgccttaaa actagagatc aactttctca gctgcaaaag cttctagtct ttcaagaagt 3060
tcatacttta tgaaattgca cagtaagcat ttatttttca gaccattttt gaacatcact 3120
cctaaattaa taaagtattc ctctgttgct ttagtattta ttacaataaa aagggtttga 3180
aatatagctg ttctttatgc ataaaacacc cagctaggac cattactgcc agagaaaaaa 3240
atcgtattga atggccattt ccctacttat aagatgtctc aatctgaatt tatttggcta 3300
cactaaagaa tgcagtatat ttagttttcc atttgcatga tgtttgtgtg ctatagatga 3360
tattttaaat tgaaaagttt gttttaaatt atttttacag tgaagactgt tttcagctct 3420
ttttatattg tacatagtct tttatgtaat ttactggcat atgttttgta gactgtttaa 3480
tgactggata tcttccttca acttttgaaa tacaaaacca gtgtttttta cttgtacact 3540
gttttaaagt ctattaaaat tgtcatttga cttttttctg ttaacttaaa aaaaaaaaaa 3600
aaaa 3604
<210> 46
<211> 452
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 46
Met Phe Asp Ile Glu Tyr Phe Arg Lys Asp Pro Arg Pro Phe Phe Lys
1 5 10 15
Phe Ala Lys Glu Ile Tyr Pro Gly Gln Phe Gln Pro Ser Leu Cys His
20 25 30
Lys Phe Ile Ala Leu Ser Asp Lys Glu Gly Lys Leu Leu Arg Asn Tyr
35 40 45
Thr Gln Asn Ile Asp Thr Leu Glu Gln Val Ala Gly Ile Gln Arg Ile
50 55 60
Ile Gln Cys His Gly Ser Phe Ala Thr Ala Ser Cys Leu Ile Cys Lys
65 70 75 80
Tyr Lys Val Asp Cys Glu Ala Val Arg Gly Asp Ile Phe Asn Gln Val
85 90 95
Val Pro Arg Cys Pro Arg Cys Pro Ala Asp Glu Pro Leu Ala Ile Met
100 105 110
Lys Pro Glu Ile Val Phe Phe Gly Glu Asn Leu Pro Glu Gln Phe His
115 120 125
Arg Ala Met Lys Tyr Asp Lys Asp Glu Val Asp Leu Leu Ile Val Ile
130 135 140
Gly Ser Ser Leu Lys Val Arg Pro Val Ala Leu Ile Pro Ser Ser Ile
145 150 155 160
Pro His Glu Val Pro Gln Ile Leu Ile Asn Arg Glu Pro Leu Pro His
165 170 175
Leu His Phe Asp Val Glu Leu Leu Gly Asp Cys Asp Val Ile Ile Asn
180 185 190
Glu Leu Cys His Arg Leu Gly Gly Glu Tyr Ala Lys Leu Cys Cys Asn
195 200 205
Pro Val Lys Leu Ser Glu Ile Thr Glu Lys Pro Pro Arg Thr Gln Lys
210 215 220
Glu Leu Ala Tyr Leu Ser Glu Leu Pro Pro Thr Pro Leu His Val Ser
225 230 235 240
Glu Asp Ser Ser Ser Pro Glu Arg Thr Ser Pro Pro Asp Ser Ser Val
245 250 255
Ile Val Thr Leu Leu Asp Gln Ala Ala Lys Ser Asn Asp Asp Leu Asp
260 265 270
Val Ser Glu Ser Lys Gly Cys Met Glu Glu Lys Pro Gln Glu Val Gln
275 280 285
Thr Ser Arg Asn Val Glu Ser Ile Ala Glu Gln Met Glu Asn Pro Asp
290 295 300
Leu Lys Asn Val Gly Ser Ser Thr Gly Glu Lys Asn Glu Arg Thr Ser
305 310 315 320
Val Ala Gly Thr Val Arg Lys Cys Trp Pro Asn Arg Val Ala Lys Glu
325 330 335
Gln Ile Ser Arg Arg Leu Asp Gly Asn Gln Tyr Leu Phe Leu Pro Pro
340 345 350
Asn Arg Tyr Ile Phe His Gly Ala Glu Val Tyr Ser Asp Ser Glu Asp
355 360 365
Asp Val Leu Ser Ser Ser Ser Cys Gly Ser Asn Ser Asp Ser Gly Thr
370 375 380
Cys Gln Ser Pro Ser Leu Glu Glu Pro Met Glu Asp Glu Ser Glu Ile
385 390 395 400
Glu Glu Phe Tyr Asn Gly Leu Glu Asp Glu Pro Asp Val Pro Glu Arg
405 410 415
Ala Gly Gly Ala Gly Phe Gly Thr Asp Gly Asp Asp Gln Glu Ala Ile
420 425 430
Asn Glu Ala Ile Ser Val Lys Gln Glu Val Thr Asp Met Asn Tyr Pro
435 440 445
Ser Asn Lys Ser
450
<210> 47
<211> 3393
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 47
gtgtctgttt catgtggaat acctgacttc aggtcaaggg atggtattta tgctcgcctt 60
gctgtagact tcccagatct tccagatcct caagcgatgt ttgatattga atatttcaga 120
aaagatccaa gaccattctt caagtttgca aagaagaaac agcattgaag cattatttgg 180
ggggaaaaac acacacacaa aatccagcaa ctcagcattc atgagcaact ctatactata 240
ccagtatgtg cctgtgcagt ggaaggaaaa caattttgga aatatatcct ggacaattcc 300
agccatctct ctgtcacaaa ttcatagcct tgtcagataa ggaaggaaaa ctacttcgca 360
actataccca gaacatagac acgctggaac aggttgcggg aatccaaagg ataattcagt 420
gtcatggttc ctttgcaaca gcatcttgcc tgatttgtaa atacaaagtt gactgtgaag 480
ctgtacgagg agatattttt aatcaggtag ttcctcgatg tcctaggtgc ccagctgatg 540
aaccgcttgc tatcatgaaa ccagagattg tgttttttgg tgaaaattta ccagaacagt 600
ttcatagagc catgaagtat gacaaagatg aagttgacct cctcattgtt attgggtctt 660
ccctcaaagt aagaccagta gcactaattc caagttccat accccatgaa gtgcctcaga 720
tattaattaa tagagaacct ttgcctcatc tgcattttga tgtagagctt cttggagact 780
gtgatgtcat aattaatgaa ttgtgtcata ggttaggtgg tgaatatgcc aaactttgct 840
gtaaccctgt aaagctttca gaaattactg aaaaacctcc acgaacacaa aaagaattgg 900
cttatttgtc agagttgcca cccacacctc ttcatgtttc agaagactca agttcaccag 960
aaagaacttc accaccagat tcttcagtga ttgtcacact tttagaccaa gcagctaaga 1020
gtaatgatga tttagatgtg tctgaatcaa aaggttgtat ggaagaaaaa ccacaggaag 1080
tacaaacttc taggaatgtt gaaagtattg ctgaacagat ggaaaatccg gatttgaaga 1140
atgttggttc tagtactggg gagaaaaatg aaagaacttc agtggctgga acagtgagaa 1200
aatgctggcc taatagagtg gcaaaggagc agattagtag gcggcttgat ggtaatcagt 1260
atctgttttt gccaccaaat cgttacattt tccatggcgc tgaggtatat tcagactctg 1320
aagatgacgt cttatcctct agttcttgtg gcagtaacag tgatagtggg acatgccaga 1380
gtccaagttt agaagaaccc atggaggatg aaagtgaaat tgaagaattc tacaatggct 1440
tagaagatga gcctgatgtt ccagagagag ctggaggagc tggatttggg actgatggag 1500
atgatcaaga ggcaattaat gaagctatat ctgtgaaaca ggaagtaaca gacatgaact 1560
atccatcaaa caaatcatag tgtaataatt gtgcaggtac aggaattgtt ccaccagcat 1620
taggaacttt agcatgtcaa aatgaatgtt tacttgtgaa ctcgatagag caaggaaacc 1680
agaaaggtgt aatatttata ggttggtaaa atagattgtt tttcatggat aatttttaac 1740
ttcattattt ctgtacttgt acaaactcaa cactaacttt ttttttttta aaaaaaaaaa 1800
ggtactaagt atcttcaatc agctgttggt caagactaac tttcttttaa aggttcattt 1860
gtatgataaa ttcatatgtg tatatataat tttttttgtt ttgtctagtg agtttcaaca 1920
tttttaaagt tttcaaaaag ccatcggaat gttaaattaa tgtaaaggga acagctaatc 1980
tagaccaaag aatggtattt tcacttttct ttgtaacatt gaatggtttg aagtactcaa 2040
aatctgttac gctaaacttt tgattcttta acacaattat ttttaaacac tggcattttc 2100
caaaactgtg gcagctaact ttttaaaatc tcaaatgaca tgcagtgtga gtagaaggaa 2160
gtcaacaata tgtggggaga gcactcggtt gtctttactt ttaaaagtaa tacttggtgc 2220
taagaatttc aggattattg tatttacgtt caaatgaaga tggcttttgt acttcctgtg 2280
gacatgtagt aatgtctata ttggctcata aaactaacct gaaaaacaaa taaatgcttt 2340
ggaaatgttt cagttgcttt agaaacatta gtgcctgcct ggatcccctt agttttgaaa 2400
tatttgccat tgttgtttaa atacctatca ctgtggtaga gcttgcattg atcttttcca 2460
caagtattaa actgccaaaa tgtgaatatg caaagccttt ctgaatctat aataatggta 2520
cttctactgg ggagagtgta atattttgga ctgctgtttt ccattaatga ggagagcaac 2580
aggcccctga ttatacagtt ccaaagtaat aagatgttaa ttgtaattca gccagaaagt 2640
acatgtctcc cattgggagg atttggtgtt aaataccaaa ctgctagccc tagtattatg 2700
gagatgaaca tgatgatgta acttgtaata gcagaatagt taatgaatga aactagttct 2760
tataatttat ctttatttaa aagcttagcc tgccttaaaa ctagagatca actttctcag 2820
ctgcaaaagc ttctagtctt tcaagaagtt catactttat gaaattgcac agtaagcatt 2880
tatttttcag accatttttg aacatcactc ctaaattaat aaagtattcc tctgttgctt 2940
tagtatttat tacaataaaa agggtttgaa atatagctgt tctttatgca taaaacaccc 3000
agctaggacc attactgcca gagaaaaaaa tcgtattgaa tggccatttc cctacttata 3060
agatgtctca atctgaattt atttggctac actaaagaat gcagtatatt tagttttcca 3120
tttgcatgat gtttgtgtgc tatagatgat attttaaatt gaaaagtttg ttttaaatta 3180
tttttacagt gaagactgtt ttcagctctt tttatattgt acatagtctt ttatgtaatt 3240
tactggcata tgttttgtag actgtttaat gactggatat cttccttcaa cttttgaaat 3300
acaaaaccag tgttttttac ttgtacactg ttttaaagtc tattaaaatt gtcatttgac 3360
ttttttctgt taacttaaaa aaaaaaaaaa aaa 3393
<210> 48
<211> 444
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 48
Met Cys Leu Cys Ser Gly Arg Lys Thr Ile Leu Glu Ile Tyr Pro Gly
1 5 10 15
Gln Phe Gln Pro Ser Leu Cys His Lys Phe Ile Ala Leu Ser Asp Lys
20 25 30
Glu Gly Lys Leu Leu Arg Asn Tyr Thr Gln Asn Ile Asp Thr Leu Glu
35 40 45
Gln Val Ala Gly Ile Gln Arg Ile Ile Gln Cys His Gly Ser Phe Ala
50 55 60
Thr Ala Ser Cys Leu Ile Cys Lys Tyr Lys Val Asp Cys Glu Ala Val
65 70 75 80
Arg Gly Asp Ile Phe Asn Gln Val Val Pro Arg Cys Pro Arg Cys Pro
85 90 95
Ala Asp Glu Pro Leu Ala Ile Met Lys Pro Glu Ile Val Phe Phe Gly
100 105 110
Glu Asn Leu Pro Glu Gln Phe His Arg Ala Met Lys Tyr Asp Lys Asp
115 120 125
Glu Val Asp Leu Leu Ile Val Ile Gly Ser Ser Leu Lys Val Arg Pro
130 135 140
Val Ala Leu Ile Pro Ser Ser Ile Pro His Glu Val Pro Gln Ile Leu
145 150 155 160
Ile Asn Arg Glu Pro Leu Pro His Leu His Phe Asp Val Glu Leu Leu
165 170 175
Gly Asp Cys Asp Val Ile Ile Asn Glu Leu Cys His Arg Leu Gly Gly
180 185 190
Glu Tyr Ala Lys Leu Cys Cys Asn Pro Val Lys Leu Ser Glu Ile Thr
195 200 205
Glu Lys Pro Pro Arg Thr Gln Lys Glu Leu Ala Tyr Leu Ser Glu Leu
210 215 220
Pro Pro Thr Pro Leu His Val Ser Glu Asp Ser Ser Ser Pro Glu Arg
225 230 235 240
Thr Ser Pro Pro Asp Ser Ser Val Ile Val Thr Leu Leu Asp Gln Ala
245 250 255
Ala Lys Ser Asn Asp Asp Leu Asp Val Ser Glu Ser Lys Gly Cys Met
260 265 270
Glu Glu Lys Pro Gln Glu Val Gln Thr Ser Arg Asn Val Glu Ser Ile
275 280 285
Ala Glu Gln Met Glu Asn Pro Asp Leu Lys Asn Val Gly Ser Ser Thr
290 295 300
Gly Glu Lys Asn Glu Arg Thr Ser Val Ala Gly Thr Val Arg Lys Cys
305 310 315 320
Trp Pro Asn Arg Val Ala Lys Glu Gln Ile Ser Arg Arg Leu Asp Gly
325 330 335
Asn Gln Tyr Leu Phe Leu Pro Pro Asn Arg Tyr Ile Phe His Gly Ala
340 345 350
Glu Val Tyr Ser Asp Ser Glu Asp Asp Val Leu Ser Ser Ser Ser Cys
355 360 365
Gly Ser Asn Ser Asp Ser Gly Thr Cys Gln Ser Pro Ser Leu Glu Glu
370 375 380
Pro Met Glu Asp Glu Ser Glu Ile Glu Glu Phe Tyr Asn Gly Leu Glu
385 390 395 400
Asp Glu Pro Asp Val Pro Glu Arg Ala Gly Gly Ala Gly Phe Gly Thr
405 410 415
Asp Gly Asp Asp Gln Glu Ala Ile Asn Glu Ala Ile Ser Val Lys Gln
420 425 430
Glu Val Thr Asp Met Asn Tyr Pro Ser Asn Lys Ser
435 440
<210> 49
<211> 6849
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 49
gcggtctctc gctctgcgcg cacacaccac acacacgcac acgcacacac acgcgcgcac 60
acacgcagcc ggcacaggcg gcggcggcgg ctgcccaagt caggacgaac ctatctaggt 120
accgtcttga gaaggcggca gcggcggcgg cggcggcggc ggcggcagcc cgagcatccc 180
tcctctcccg gagagggagc accgccgaga gtttccgttc cctttgccat tcccttcccc 240
ctccttttct tttattttcg agagaatttc ttcttggctt attggtttaa tttgattttt 300
aaaattttgg gttgcttttg tgtatgtgtg cttttttttt ctttcctcat tttatttgca 360
tccagagcat ggcgggctgc gggctgtcgg aagacaccct cttctcttcc ttcttttaca 420
actacggctc ctcctgggaa accccttcca accaggtttt ttgcgaaaat cagtgaacta 480
atattggtaa aattggagcc ccatggatga agggtacttt tctgcccctg gactgccctg 540
gctgctgctt tggtaaaagc ttgcaaggag agagagtaac agccgctggc gaatccagtt 600
tgtgcaagca gcatcagcaa tggatgagac ctccccaagg ctggaagaag actggaaaaa 660
agtacttcag cgagaagcag gctggcagtg tgctgctctg gttggtgaag accagcctct 720
ttgcccagat cttcctgaac ttgatctttc tgaactagat gtgaacgact tggatacaga 780
cagctttctg ggtggactca agtggtgcag tgaccaatca gaaataatat ccaatcagta 840
caacaatgag ccttcaaaca tatttgagaa gatagatgaa gagaatgagg caaacttgct 900
agcagtcctc acagagacac tagacagtct ccctgtggat gaagacggat tgccctcatt 960
tgatgcgctg acagatggag acgtgaccac tgacaatgag gctagtcctt cctccatgcc 1020
tgacggcacc cctccacccc aggaggcaga agagccgtct ctacttaaga agctcttact 1080
ggcaccagcc aacactcagc taagttataa tgaatgcagt ggtctcagta cccagaacca 1140
tgcaaatcac aatcacagga tcagaacaaa ccctgcaatt gttaagactg agaattcatg 1200
gagcaataaa gcgaagagta tttgtcaaca gcaaaagcca caaagacgtc cctgctcgga 1260
gcttctcaaa tatctgacca caaacgatga ccctcctcac accaaaccca cagagaacag 1320
aaacagcagc agagacaaat gcacctccaa aaagaagtcc cacacacagt cgcagtcaca 1380
acacttacaa gccaaaccaa caactttatc tcttcctctg accccagagt caccaaatga 1440
ccccaagggt tccccatttg agaacaagac tattgaacgc accttaagtg tggaactctc 1500
tggaactgca ggcctaactc cacccaccac tcctcctcat aaagccaacc aagataaccc 1560
ttttagggct tctccaaagc tgaagtcctc ttgcaagact gtggtgccac caccatcaaa 1620
gaagcccagg tacagtgagt cttctggtac acaaggcaat aactccacca agaaagggcc 1680
ggagcaatcc gagttgtatg cacaactcag caagtcctca gtcctcactg gtggacacga 1740
ggaaaggaag accaagcggc ccagtctgcg gctgtttggt gaccatgact attgccagtc 1800
aattaattcc aaaacagaaa tactcattaa tatatcacag gagctccaag actctagaca 1860
actagaaaat aaagatgtct cctctgattg gcaggggcag atttgttctt ccacagattc 1920
agaccagtgc tacctgagag agactttgga ggcaagcaag caggtctctc cttgcagcac 1980
aagaaaacag ctccaagacc aggaaatccg agccgagctg aacaagcact tcggtcatcc 2040
cagtcaagct gtttttgacg acgaagcaga caagaccggt gaactgaggg acagtgattt 2100
cagtaatgaa caattctcca aactacctat gtttataaat tcaggactag ccatggatgg 2160
cctgtttgat gacagcgaag atgaaagtga taaactgagc tacccttggg atggcacgca 2220
atcctattca ttgttcaatg tgtctccttc ttgttcttct tttaactctc catgtagaga 2280
ttctgtgtca ccacccaaat ccttattttc tcaaagaccc caaaggatgc gctctcgttc 2340
aaggtccttt tctcgacaca ggtcgtgttc ccgatcacca tattccaggt caagatcaag 2400
gtctccaggc agtagatcct cttcaagatc ctgctattac tatgagtcaa gccactacag 2460
acaccgcacg caccgaaatt ctcccttgta tgtgagatca cgttcaagat cgccctacag 2520
ccgtcggccc aggtatgaca gctacgagga atatcagcac gagaggctga agagggaaga 2580
atatcgcaga gagtatgaga agcgagagtc tgagagggcc aagcaaaggg agaggcagag 2640
gcagaaggca attgaagagc gccgtgtgat ttatgtcggt aaaatcagac ctgacacaac 2700
acggacagaa ctgagggacc gttttgaagt ttttggtgaa attgaggagt gcacagtaaa 2760
tctgcgggat gatggagaca gctatggttt cattacctac cgttatacct gtgatgcttt 2820
tgctgctctt gaaaatggat acactttgcg caggtcaaac gaaactgact ttgagctgta 2880
cttttgtgga cgcaagcaat ttttcaagtc taactatgca gacctagatt caaactcaga 2940
tgactttgac cctgcttcca ccaagagcaa gtatgactct ctggattttg atagtttact 3000
gaaagaagct cagagaagct tgcgcaggta acatgttccc tagctgagga tgacagaggg 3060
atggcgaata cctcatggga cagcgcgtcc ttccctaaag actattgcaa gtcatactta 3120
ggaatttctc ctactttaca ctctctgtac aaaaacaaaa caaaacaaca acaatacaac 3180
aagaacaaca acaacaataa caacaatggt ttacatgaac acagctgctg aagaggcaag 3240
agacagaatg atatccagta agcacatgtt tattcatggg tgtcagcttt gcttttcctg 3300
gagtctcttg gtgatggagt gtgcgtgtgt gcatgtatgt gtgtgtgtat gtatgtgtgt 3360
ggtgtgtgtg cttggtttag gggaagtatg tgtgggtaca tgtgaggact gggggcacct 3420
gaccagaatg cgcaagggca aaccatttca aatggcagca gttccatgaa gacacgctta 3480
aaacctagaa cttcaaaatg ttcgtattct attcaaaagg aaatatatat atatatatat 3540
atatatatat atatatatat aaattaaaaa ggaaagaaaa ctaacaacca accaaccaac 3600
caaccaacca caaaccaccc taaaatgaca gccgctgatg tctgggcatc agcctttgta 3660
ctctgttttt ttaagaaagt gcagaatcaa cttgaagcaa gctttctctc ataacgtaat 3720
gattatatga caatcctgaa gaaaccacag gttccataga actaatatcc tgtctctctc 3780
tctctctctc tctctctctt ttttttttct ttttcctttt gccatggaat ctgggtggga 3840
gaggatactg cgggcaccag aatgctaaag tttcctaaca ttttgaagtt tctgtagttc 3900
atccttaatc ctgacaccca tgtaaatgtc caaaatgttg atcttccact gcaaatttca 3960
aaagccttgt caatggtcaa gcgtgcagct tgttcagcgg ttctttctga ggagcggaca 4020
ccgggttaca ttactaatga gagttgggta gaactctctg agatgtgttc agatagtgta 4080
attgctacat tctctgatgt agttaagtat ttacagatgt taaatggagt atttttattt 4140
tatgtatata ctatacaaca atgttctttt ttgttacagc tatgcactgt aaatgcagcc 4200
ttcttttcaa aactgctaaa tttttcttaa tcaagaatat tcaaatgtaa ttatgaggtg 4260
aaacaattat tgtacactaa catatttaga agctgaactt actgcttata tatatttgat 4320
tgtaaaaaca aaaagacagt gtgtgtgtct gttgagtgca acaagagcaa aatgatgctt 4380
tccgcacatc catcccttag gtgagcttca atctaagcat cttgtcaaga aatatcctag 4440
tcccctaaag gtattaacca cttctgcgat atttttccac attttcttgt cgcttgtttt 4500
tctttgaagt tttatacact ggatttgtta ggggaatgaa attttctcat ctaaaatttt 4560
tctagaagat atcatgattt tatgtaaagt ctctcaatgg gtaaccatta agaaatgttt 4620
ttattttctc tatcaacagt agttttgaaa ctagaagtca aaaatctttt taaaatgctg 4680
ttttgtttta atttttgtga ttttaatttg atacaaaatg ctgaggtaat aattatagta 4740
tgatttttac aataattaat gtgtgtctga agactatctt tgaagccagt atttctttcc 4800
cttggcagag tatgacgatg gtatttatct gtatttttta cagttatgca tcctgtataa 4860
atactgatat ttcattcctt tgtttactaa agagacatat ttatcagttg cagatagcct 4920
atttattata aattatgaga tgatgaaaat aataaagcca gtggaaattt tctacctagg 4980
atgcatgaca attgtcaggt tggagtgtaa gtgcttcatt tgggaaattc agcttttgca 5040
gaagcagtgt ttctacttgc actagcatgg cctctgacgt gaccatggtg ttgttcttga 5100
tgacattgct tctgctaaat ttaataaaaa cttcagaaaa acctccattt tgatcatcag 5160
gatttcatct gagtgtggag tccctggaat ggaattcagt aacatttgga gtgtgtattc 5220
aagtttctaa attgagattc gattactgtt tggctgacat gacttttctg gaagacatga 5280
tacacctact actcaattgt tcttttcctt tctctcgccc aacacgatct tgtaagatgg 5340
atttcacccc caggccaatg cagctaattt tgatagctgc attcatttat caccagcata 5400
ttgtgttctg agtgaatcca ctgtttgtcc tgtcggatgc ttgcttgatt ttttggcttc 5460
ttatttctaa gtagatagaa agcaataaaa atactatgaa atgaaagaac ttgttcacag 5520
gttctgcgtt acaacagtaa cacatcttta atccgcctaa ttcttgttgt tctgtaggtt 5580
aaatgcaggt attttaactg tgtgaacgcc aaactaaagt ttacagtctt tctttctgaa 5640
ttttgagtat cttctgttgt agaataataa taaaaagact attaagagca ataaattatt 5700
tttaagaaat cgagatttag taaatcctat tatgtgttca aggaccacat gtgttctcta 5760
ttttgccttt aaatttttgt gaaccaattt taaatacatt ctcctttttg ccctggattg 5820
ttgacatgag tggaatactt ggtttctttt cttacttatc aaaagacagc actacagata 5880
tcatattgag gattaattta tcccccctac ccccagcctg acaaatattg ttaccatgaa 5940
gatagttttc ctcaatggac ttcaaattgc atctagaatt agtggagctt ttgtatcttc 6000
tgcagacact gtgggtagcc catcaaaatg taagctgtgc tcctctcatt tttattttta 6060
tttttttggg agagaatatt tcaaatgaac acgtgcaccc catcatcact ggaggcaaat 6120
ttcagcatag atctgtagga tttttagaag accgtgggcc attgccttca tgccgtggta 6180
agtaccacat ctacaatttt ggtaaccgaa ctggtgcttt agtaatgtgg atttttttct 6240
tttttaaaag agatgtagca gaataattct tccagtgcaa caaaatcaat tttttgctaa 6300
acgactccga gaacaacagt tgggctgtca acattcaaag cagcagagag ggaactttgc 6360
actattgggg tatgatgttt gggtcagttg ataaaaggaa accttttcat gcctttagat 6420
gtgagcttcc agtaggtaat gattatgtgt cctttcttga tggctgtaat gagaacttca 6480
atcactgtag tctaagacct gatctataga tgacctagaa tagccatgta ctataatgtg 6540
atgattctaa atttgtacct atgtgacaga cattttcaat aatgtgaact gctgatttga 6600
tggagctact ttaagatttg taggtgaaag tgtaatactg ttggttgaac tatgctgaag 6660
agggaaagtg agcgattagt tgagcccttg ccgggccttt tttccacctg ccaattctac 6720
atgtattgtt gtggttttat tcattgtatg aaaattcctg tgattttttt taaatgtgca 6780
gtacacatca gcctcactga gctaataaag ggaaacgaat gtttcaaatc taaaaaaaaa 6840
aaaaaaaaa 6849
<210> 50
<211> 803
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 50
Met Asp Glu Thr Ser Pro Arg Leu Glu Glu Asp Trp Lys Lys Val Leu
1 5 10 15
Gln Arg Glu Ala Gly Trp Gln Cys Ala Ala Leu Val Gly Glu Asp Gln
20 25 30
Pro Leu Cys Pro Asp Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val
35 40 45
Asn Asp Leu Asp Thr Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser
50 55 60
Asp Gln Ser Glu Ile Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn
65 70 75 80
Ile Phe Glu Lys Ile Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val
85 90 95
Leu Thr Glu Thr Leu Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro
100 105 110
Ser Phe Asp Ala Leu Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala
115 120 125
Ser Pro Ser Ser Met Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu
130 135 140
Glu Pro Ser Leu Leu Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln
145 150 155 160
Leu Ser Tyr Asn Glu Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn
165 170 175
His Asn His Arg Ile Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn
180 185 190
Ser Trp Ser Asn Lys Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln
195 200 205
Arg Arg Pro Cys Ser Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp
210 215 220
Pro Pro His Thr Lys Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys
225 230 235 240
Cys Thr Ser Lys Lys Lys Ser His Thr Gln Ser Gln Ser Gln His Leu
245 250 255
Gln Ala Lys Pro Thr Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro
260 265 270
Asn Asp Pro Lys Gly Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr
275 280 285
Leu Ser Val Glu Leu Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr
290 295 300
Pro Pro His Lys Ala Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys
305 310 315 320
Leu Lys Ser Ser Cys Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro
325 330 335
Arg Tyr Ser Glu Ser Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys
340 345 350
Gly Pro Glu Gln Ser Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val
355 360 365
Leu Thr Gly Gly His Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg
370 375 380
Leu Phe Gly Asp His Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu
385 390 395 400
Ile Leu Ile Asn Ile Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu
405 410 415
Asn Lys Asp Val Ser Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr
420 425 430
Asp Ser Asp Gln Cys Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln
435 440 445
Val Ser Pro Cys Ser Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg
450 455 460
Ala Glu Leu Asn Lys His Phe Gly His Pro Ser Gln Ala Val Phe Asp
465 470 475 480
Asp Glu Ala Asp Lys Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn
485 490 495
Glu Gln Phe Ser Lys Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met
500 505 510
Asp Gly Leu Phe Asp Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr
515 520 525
Pro Trp Asp Gly Thr Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser
530 535 540
Cys Ser Ser Phe Asn Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys
545 550 555 560
Ser Leu Phe Ser Gln Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser
565 570 575
Phe Ser Arg His Arg Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg
580 585 590
Ser Arg Ser Pro Gly Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr
595 600 605
Glu Ser Ser His Tyr Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr
610 615 620
Val Arg Ser Arg Ser Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp
625 630 635 640
Ser Tyr Glu Glu Tyr Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg
645 650 655
Arg Glu Tyr Glu Lys Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg
660 665 670
Gln Arg Gln Lys Ala Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys
675 680 685
Ile Arg Pro Asp Thr Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val
690 695 700
Phe Gly Glu Ile Glu Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp
705 710 715 720
Ser Tyr Gly Phe Ile Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala
725 730 735
Leu Glu Asn Gly Tyr Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu
740 745 750
Leu Tyr Phe Cys Gly Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp
755 760 765
Leu Asp Ser Asn Ser Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys
770 775 780
Tyr Asp Ser Leu Asp Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser
785 790 795 800
Leu Arg Arg
<210> 51
<211> 6335
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 51
tagtaagaca ggtgccttca gttcactctc agtaaggggc tggttgcctg catgagtgtg 60
tgctctgtgt cactgtggat tggagttgaa aaagcttgac tggcgtcatt caggagctgg 120
atggcgtggg acatgtgcaa ccaggactct gagtctgtat ggagtgacat cgagtgtgct 180
gctctggttg gtgaagacca gcctctttgc ccagatcttc ctgaacttga tctttctgaa 240
ctagatgtga acgacttgga tacagacagc tttctgggtg gactcaagtg gtgcagtgac 300
caatcagaaa taatatccaa tcagtacaac aatgagcctt caaacatatt tgagaagata 360
gatgaagaga atgaggcaaa cttgctagca gtcctcacag agacactaga cagtctccct 420
gtggatgaag acggattgcc ctcatttgat gcgctgacag atggagacgt gaccactgac 480
aatgaggcta gtccttcctc catgcctgac ggcacccctc caccccagga ggcagaagag 540
ccgtctctac ttaagaagct cttactggca ccagccaaca ctcagctaag ttataatgaa 600
tgcagtggtc tcagtaccca gaaccatgca aatcacaatc acaggatcag aacaaaccct 660
gcaattgtta agactgagaa ttcatggagc aataaagcga agagtatttg tcaacagcaa 720
aagccacaaa gacgtccctg ctcggagctt ctcaaatatc tgaccacaaa cgatgaccct 780
cctcacacca aacccacaga gaacagaaac agcagcagag acaaatgcac ctccaaaaag 840
aagtcccaca cacagtcgca gtcacaacac ttacaagcca aaccaacaac tttatctctt 900
cctctgaccc cagagtcacc aaatgacccc aagggttccc catttgagaa caagactatt 960
gaacgcacct taagtgtgga actctctgga actgcaggcc taactccacc caccactcct 1020
cctcataaag ccaaccaaga taaccctttt agggcttctc caaagctgaa gtcctcttgc 1080
aagactgtgg tgccaccacc atcaaagaag cccaggtaca gtgagtcttc tggtacacaa 1140
ggcaataact ccaccaagaa agggccggag caatccgagt tgtatgcaca actcagcaag 1200
tcctcagtcc tcactggtgg acacgaggaa aggaagacca agcggcccag tctgcggctg 1260
tttggtgacc atgactattg ccagtcaatt aattccaaaa cagaaatact cattaatata 1320
tcacaggagc tccaagactc tagacaacta gaaaataaag atgtctcctc tgattggcag 1380
gggcagattt gttcttccac agattcagac cagtgctacc tgagagagac tttggaggca 1440
agcaagcagg tctctccttg cagcacaaga aaacagctcc aagaccagga aatccgagcc 1500
gagctgaaca agcacttcgg tcatcccagt caagctgttt ttgacgacga agcagacaag 1560
accggtgaac tgagggacag tgatttcagt aatgaacaat tctccaaact acctatgttt 1620
ataaattcag gactagccat ggatggcctg tttgatgaca gcgaagatga aagtgataaa 1680
ctgagctacc cttgggatgg cacgcaatcc tattcattgt tcaatgtgtc tccttcttgt 1740
tcttctttta actctccatg tagagattct gtgtcaccac ccaaatcctt attttctcaa 1800
agaccccaaa ggatgcgctc tcgttcaagg tccttttctc gacacaggtc gtgttcccga 1860
tcaccatatt ccaggtcaag atcaaggtct ccaggcagta gatcctcttc aagatcctgc 1920
tattactatg agtcaagcca ctacagacac cgcacgcacc gaaattctcc cttgtatgtg 1980
agatcacgtt caagatcgcc ctacagccgt cggcccaggt atgacagcta cgaggaatat 2040
cagcacgaga ggctgaagag ggaagaatat cgcagagagt atgagaagcg agagtctgag 2100
agggccaagc aaagggagag gcagaggcag aaggcaattg aagagcgccg tgtgatttat 2160
gtcggtaaaa tcagacctga cacaacacgg acagaactga gggaccgttt tgaagttttt 2220
ggtgaaattg aggagtgcac agtaaatctg cgggatgatg gagacagcta tggtttcatt 2280
acctaccgtt atacctgtga tgcttttgct gctcttgaaa atggatacac tttgcgcagg 2340
tcaaacgaaa ctgactttga gctgtacttt tgtggacgca agcaattttt caagtctaac 2400
tatgcagacc tagattcaaa ctcagatgac tttgaccctg cttccaccaa gagcaagtat 2460
gactctctgg attttgatag tttactgaaa gaagctcaga gaagcttgcg caggtaacat 2520
gttccctagc tgaggatgac agagggatgg cgaatacctc atgggacagc gcgtccttcc 2580
ctaaagacta ttgcaagtca tacttaggaa tttctcctac tttacactct ctgtacaaaa 2640
acaaaacaaa acaacaacaa tacaacaaga acaacaacaa caataacaac aatggtttac 2700
atgaacacag ctgctgaaga ggcaagagac agaatgatat ccagtaagca catgtttatt 2760
catgggtgtc agctttgctt ttcctggagt ctcttggtga tggagtgtgc gtgtgtgcat 2820
gtatgtgtgt gtgtatgtat gtgtgtggtg tgtgtgcttg gtttagggga agtatgtgtg 2880
ggtacatgtg aggactgggg gcacctgacc agaatgcgca agggcaaacc atttcaaatg 2940
gcagcagttc catgaagaca cgcttaaaac ctagaacttc aaaatgttcg tattctattc 3000
aaaaggaaat atatatatat atatatatat atatatatat atatataaat taaaaaggaa 3060
agaaaactaa caaccaacca accaaccaac caaccacaaa ccaccctaaa atgacagccg 3120
ctgatgtctg ggcatcagcc tttgtactct gtttttttaa gaaagtgcag aatcaacttg 3180
aagcaagctt tctctcataa cgtaatgatt atatgacaat cctgaagaaa ccacaggttc 3240
catagaacta atatcctgtc tctctctctc tctctctctc tctctttttt ttttcttttt 3300
ccttttgcca tggaatctgg gtgggagagg atactgcggg caccagaatg ctaaagtttc 3360
ctaacatttt gaagtttctg tagttcatcc ttaatcctga cacccatgta aatgtccaaa 3420
atgttgatct tccactgcaa atttcaaaag ccttgtcaat ggtcaagcgt gcagcttgtt 3480
cagcggttct ttctgaggag cggacaccgg gttacattac taatgagagt tgggtagaac 3540
tctctgagat gtgttcagat agtgtaattg ctacattctc tgatgtagtt aagtatttac 3600
agatgttaaa tggagtattt ttattttatg tatatactat acaacaatgt tcttttttgt 3660
tacagctatg cactgtaaat gcagccttct tttcaaaact gctaaatttt tcttaatcaa 3720
gaatattcaa atgtaattat gaggtgaaac aattattgta cactaacata tttagaagct 3780
gaacttactg cttatatata tttgattgta aaaacaaaaa gacagtgtgt gtgtctgttg 3840
agtgcaacaa gagcaaaatg atgctttccg cacatccatc ccttaggtga gcttcaatct 3900
aagcatcttg tcaagaaata tcctagtccc ctaaaggtat taaccacttc tgcgatattt 3960
ttccacattt tcttgtcgct tgtttttctt tgaagtttta tacactggat ttgttagggg 4020
aatgaaattt tctcatctaa aatttttcta gaagatatca tgattttatg taaagtctct 4080
caatgggtaa ccattaagaa atgtttttat tttctctatc aacagtagtt ttgaaactag 4140
aagtcaaaaa tctttttaaa atgctgtttt gttttaattt ttgtgatttt aatttgatac 4200
aaaatgctga ggtaataatt atagtatgat ttttacaata attaatgtgt gtctgaagac 4260
tatctttgaa gccagtattt ctttcccttg gcagagtatg acgatggtat ttatctgtat 4320
tttttacagt tatgcatcct gtataaatac tgatatttca ttcctttgtt tactaaagag 4380
acatatttat cagttgcaga tagcctattt attataaatt atgagatgat gaaaataata 4440
aagccagtgg aaattttcta cctaggatgc atgacaattg tcaggttgga gtgtaagtgc 4500
ttcatttggg aaattcagct tttgcagaag cagtgtttct acttgcacta gcatggcctc 4560
tgacgtgacc atggtgttgt tcttgatgac attgcttctg ctaaatttaa taaaaacttc 4620
agaaaaacct ccattttgat catcaggatt tcatctgagt gtggagtccc tggaatggaa 4680
ttcagtaaca tttggagtgt gtattcaagt ttctaaattg agattcgatt actgtttggc 4740
tgacatgact tttctggaag acatgataca cctactactc aattgttctt ttcctttctc 4800
tcgcccaaca cgatcttgta agatggattt cacccccagg ccaatgcagc taattttgat 4860
agctgcattc atttatcacc agcatattgt gttctgagtg aatccactgt ttgtcctgtc 4920
ggatgcttgc ttgatttttt ggcttcttat ttctaagtag atagaaagca ataaaaatac 4980
tatgaaatga aagaacttgt tcacaggttc tgcgttacaa cagtaacaca tctttaatcc 5040
gcctaattct tgttgttctg taggttaaat gcaggtattt taactgtgtg aacgccaaac 5100
taaagtttac agtctttctt tctgaatttt gagtatcttc tgttgtagaa taataataaa 5160
aagactatta agagcaataa attattttta agaaatcgag atttagtaaa tcctattatg 5220
tgttcaagga ccacatgtgt tctctatttt gcctttaaat ttttgtgaac caattttaaa 5280
tacattctcc tttttgccct ggattgttga catgagtgga atacttggtt tcttttctta 5340
cttatcaaaa gacagcacta cagatatcat attgaggatt aatttatccc ccctaccccc 5400
agcctgacaa atattgttac catgaagata gttttcctca atggacttca aattgcatct 5460
agaattagtg gagcttttgt atcttctgca gacactgtgg gtagcccatc aaaatgtaag 5520
ctgtgctcct ctcattttta tttttatttt tttgggagag aatatttcaa atgaacacgt 5580
gcaccccatc atcactggag gcaaatttca gcatagatct gtaggatttt tagaagaccg 5640
tgggccattg ccttcatgcc gtggtaagta ccacatctac aattttggta accgaactgg 5700
tgctttagta atgtggattt ttttcttttt taaaagagat gtagcagaat aattcttcca 5760
gtgcaacaaa atcaattttt tgctaaacga ctccgagaac aacagttggg ctgtcaacat 5820
tcaaagcagc agagagggaa ctttgcacta ttggggtatg atgtttgggt cagttgataa 5880
aaggaaacct tttcatgcct ttagatgtga gcttccagta ggtaatgatt atgtgtcctt 5940
tcttgatggc tgtaatgaga acttcaatca ctgtagtcta agacctgatc tatagatgac 6000
ctagaatagc catgtactat aatgtgatga ttctaaattt gtacctatgt gacagacatt 6060
ttcaataatg tgaactgctg atttgatgga gctactttaa gatttgtagg tgaaagtgta 6120
atactgttgg ttgaactatg ctgaagaggg aaagtgagcg attagttgag cccttgccgg 6180
gccttttttc cacctgccaa ttctacatgt attgttgtgg ttttattcat tgtatgaaaa 6240
ttcctgtgat tttttttaaa tgtgcagtac acatcagcct cactgagcta ataaagggaa 6300
acgaatgttt caaatctaaa aaaaaaaaaa aaaaa 6335
<210> 52
<211> 798
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 52
Met Ala Trp Asp Met Cys Asn Gln Asp Ser Glu Ser Val Trp Ser Asp
1 5 10 15
Ile Glu Cys Ala Ala Leu Val Gly Glu Asp Gln Pro Leu Cys Pro Asp
20 25 30
Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val Asn Asp Leu Asp Thr
35 40 45
Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser Asp Gln Ser Glu Ile
50 55 60
Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn Ile Phe Glu Lys Ile
65 70 75 80
Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val Leu Thr Glu Thr Leu
85 90 95
Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro Ser Phe Asp Ala Leu
100 105 110
Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala Ser Pro Ser Ser Met
115 120 125
Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu Glu Pro Ser Leu Leu
130 135 140
Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln Leu Ser Tyr Asn Glu
145 150 155 160
Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn His Asn His Arg Ile
165 170 175
Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn Ser Trp Ser Asn Lys
180 185 190
Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln Arg Arg Pro Cys Ser
195 200 205
Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp Pro Pro His Thr Lys
210 215 220
Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys Cys Thr Ser Lys Lys
225 230 235 240
Lys Ser His Thr Gln Ser Gln Ser Gln His Leu Gln Ala Lys Pro Thr
245 250 255
Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro Asn Asp Pro Lys Gly
260 265 270
Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr Leu Ser Val Glu Leu
275 280 285
Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr Pro Pro His Lys Ala
290 295 300
Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys Leu Lys Ser Ser Cys
305 310 315 320
Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro Arg Tyr Ser Glu Ser
325 330 335
Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys Gly Pro Glu Gln Ser
340 345 350
Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val Leu Thr Gly Gly His
355 360 365
Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg Leu Phe Gly Asp His
370 375 380
Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu Ile Leu Ile Asn Ile
385 390 395 400
Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu Asn Lys Asp Val Ser
405 410 415
Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr Asp Ser Asp Gln Cys
420 425 430
Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln Val Ser Pro Cys Ser
435 440 445
Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg Ala Glu Leu Asn Lys
450 455 460
His Phe Gly His Pro Ser Gln Ala Val Phe Asp Asp Glu Ala Asp Lys
465 470 475 480
Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn Glu Gln Phe Ser Lys
485 490 495
Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met Asp Gly Leu Phe Asp
500 505 510
Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr Pro Trp Asp Gly Thr
515 520 525
Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser Cys Ser Ser Phe Asn
530 535 540
Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys Ser Leu Phe Ser Gln
545 550 555 560
Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser Phe Ser Arg His Arg
565 570 575
Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg Ser Arg Ser Pro Gly
580 585 590
Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr Glu Ser Ser His Tyr
595 600 605
Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr Val Arg Ser Arg Ser
610 615 620
Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp Ser Tyr Glu Glu Tyr
625 630 635 640
Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg Arg Glu Tyr Glu Lys
645 650 655
Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg Gln Arg Gln Lys Ala
660 665 670
Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys Ile Arg Pro Asp Thr
675 680 685
Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val Phe Gly Glu Ile Glu
690 695 700
Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp Ser Tyr Gly Phe Ile
705 710 715 720
Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala Leu Glu Asn Gly Tyr
725 730 735
Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu Leu Tyr Phe Cys Gly
740 745 750
Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp Leu Asp Ser Asn Ser
755 760 765
Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys Tyr Asp Ser Leu Asp
770 775 780
Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser Leu Arg Arg
785 790 795
<210> 53
<211> 6681
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 53
gcggtctctc gctctgcgcg cacacaccac acacacgcac acgcacacac acgcgcgcac 60
acacgcagcc ggcacaggcg gcggcggcgg ctgcccaagt caggacgaac ctatctaggt 120
accgtcttga gaaggcggca gcggcggcgg cggcggcggc ggcggcagcc cgagcatccc 180
tcctctcccg gagagggagc accgccgaga gtttccgttc cctttgccat tcccttcccc 240
ctccttttct tttattttcg agagaatttc ttcttggctt attggtttaa tttgattttt 300
aaaattttgg gttgcttttg tgtatgtgtg cttttttttt ctttcctcat tttatttgca 360
tccagagcat ggcgggctgc gggctgtcgg aagacaccct cttctcttcc ttcttttaca 420
actacggctc ctcctgggaa accccttcca accaggtttt ttgcgaaaat cagtgaacta 480
atattggtaa aattggagcc ccatggatga agggtacttt tgtgctgctc tggttggtga 540
agaccagcct ctttgcccag atcttcctga acttgatctt tctgaactag atgtgaacga 600
cttggataca gacagctttc tgggtggact caagtggtgc agtgaccaat cagaaataat 660
atccaatcag tacaacaatg agccttcaaa catatttgag aagatagatg aagagaatga 720
ggcaaacttg ctagcagtcc tcacagagac actagacagt ctccctgtgg atgaagacgg 780
attgccctca tttgatgcgc tgacagatgg agacgtgacc actgacaatg aggctagtcc 840
ttcctccatg cctgacggca cccctccacc ccaggaggca gaagagccgt ctctacttaa 900
gaagctctta ctggcaccag ccaacactca gctaagttat aatgaatgca gtggtctcag 960
tacccagaac catgcaaatc acaatcacag gatcagaaca aaccctgcaa ttgttaagac 1020
tgagaattca tggagcaata aagcgaagag tatttgtcaa cagcaaaagc cacaaagacg 1080
tccctgctcg gagcttctca aatatctgac cacaaacgat gaccctcctc acaccaaacc 1140
cacagagaac agaaacagca gcagagacaa atgcacctcc aaaaagaagt cccacacaca 1200
gtcgcagtca caacacttac aagccaaacc aacaacttta tctcttcctc tgaccccaga 1260
gtcaccaaat gaccccaagg gttccccatt tgagaacaag actattgaac gcaccttaag 1320
tgtggaactc tctggaactg caggcctaac tccacccacc actcctcctc ataaagccaa 1380
ccaagataac ccttttaggg cttctccaaa gctgaagtcc tcttgcaaga ctgtggtgcc 1440
accaccatca aagaagccca ggtacagtga gtcttctggt acacaaggca ataactccac 1500
caagaaaggg ccggagcaat ccgagttgta tgcacaactc agcaagtcct cagtcctcac 1560
tggtggacac gaggaaagga agaccaagcg gcccagtctg cggctgtttg gtgaccatga 1620
ctattgccag tcaattaatt ccaaaacaga aatactcatt aatatatcac aggagctcca 1680
agactctaga caactagaaa ataaagatgt ctcctctgat tggcaggggc agatttgttc 1740
ttccacagat tcagaccagt gctacctgag agagactttg gaggcaagca agcaggtctc 1800
tccttgcagc acaagaaaac agctccaaga ccaggaaatc cgagccgagc tgaacaagca 1860
cttcggtcat cccagtcaag ctgtttttga cgacgaagca gacaagaccg gtgaactgag 1920
ggacagtgat ttcagtaatg aacaattctc caaactacct atgtttataa attcaggact 1980
agccatggat ggcctgtttg atgacagcga agatgaaagt gataaactga gctacccttg 2040
ggatggcacg caatcctatt cattgttcaa tgtgtctcct tcttgttctt cttttaactc 2100
tccatgtaga gattctgtgt caccacccaa atccttattt tctcaaagac cccaaaggat 2160
gcgctctcgt tcaaggtcct tttctcgaca caggtcgtgt tcccgatcac catattccag 2220
gtcaagatca aggtctccag gcagtagatc ctcttcaaga tcctgctatt actatgagtc 2280
aagccactac agacaccgca cgcaccgaaa ttctcccttg tatgtgagat cacgttcaag 2340
atcgccctac agccgtcggc ccaggtatga cagctacgag gaatatcagc acgagaggct 2400
gaagagggaa gaatatcgca gagagtatga gaagcgagag tctgagaggg ccaagcaaag 2460
ggagaggcag aggcagaagg caattgaaga gcgccgtgtg atttatgtcg gtaaaatcag 2520
acctgacaca acacggacag aactgaggga ccgttttgaa gtttttggtg aaattgagga 2580
gtgcacagta aatctgcggg atgatggaga cagctatggt ttcattacct accgttatac 2640
ctgtgatgct tttgctgctc ttgaaaatgg atacactttg cgcaggtcaa acgaaactga 2700
ctttgagctg tacttttgtg gacgcaagca atttttcaag tctaactatg cagacctaga 2760
ttcaaactca gatgactttg accctgcttc caccaagagc aagtatgact ctctggattt 2820
tgatagttta ctgaaagaag ctcagagaag cttgcgcagg taacatgttc cctagctgag 2880
gatgacagag ggatggcgaa tacctcatgg gacagcgcgt ccttccctaa agactattgc 2940
aagtcatact taggaatttc tcctacttta cactctctgt acaaaaacaa aacaaaacaa 3000
caacaataca acaagaacaa caacaacaat aacaacaatg gtttacatga acacagctgc 3060
tgaagaggca agagacagaa tgatatccag taagcacatg tttattcatg ggtgtcagct 3120
ttgcttttcc tggagtctct tggtgatgga gtgtgcgtgt gtgcatgtat gtgtgtgtgt 3180
atgtatgtgt gtggtgtgtg tgcttggttt aggggaagta tgtgtgggta catgtgagga 3240
ctgggggcac ctgaccagaa tgcgcaaggg caaaccattt caaatggcag cagttccatg 3300
aagacacgct taaaacctag aacttcaaaa tgttcgtatt ctattcaaaa ggaaatatat 3360
atatatatat atatatatat atatatatat ataaattaaa aaggaaagaa aactaacaac 3420
caaccaacca accaaccaac cacaaaccac cctaaaatga cagccgctga tgtctgggca 3480
tcagcctttg tactctgttt ttttaagaaa gtgcagaatc aacttgaagc aagctttctc 3540
tcataacgta atgattatat gacaatcctg aagaaaccac aggttccata gaactaatat 3600
cctgtctctc tctctctctc tctctctctc tttttttttt ctttttcctt ttgccatgga 3660
atctgggtgg gagaggatac tgcgggcacc agaatgctaa agtttcctaa cattttgaag 3720
tttctgtagt tcatccttaa tcctgacacc catgtaaatg tccaaaatgt tgatcttcca 3780
ctgcaaattt caaaagcctt gtcaatggtc aagcgtgcag cttgttcagc ggttctttct 3840
gaggagcgga caccgggtta cattactaat gagagttggg tagaactctc tgagatgtgt 3900
tcagatagtg taattgctac attctctgat gtagttaagt atttacagat gttaaatgga 3960
gtatttttat tttatgtata tactatacaa caatgttctt ttttgttaca gctatgcact 4020
gtaaatgcag ccttcttttc aaaactgcta aatttttctt aatcaagaat attcaaatgt 4080
aattatgagg tgaaacaatt attgtacact aacatattta gaagctgaac ttactgctta 4140
tatatatttg attgtaaaaa caaaaagaca gtgtgtgtgt ctgttgagtg caacaagagc 4200
aaaatgatgc tttccgcaca tccatccctt aggtgagctt caatctaagc atcttgtcaa 4260
gaaatatcct agtcccctaa aggtattaac cacttctgcg atatttttcc acattttctt 4320
gtcgcttgtt tttctttgaa gttttataca ctggatttgt taggggaatg aaattttctc 4380
atctaaaatt tttctagaag atatcatgat tttatgtaaa gtctctcaat gggtaaccat 4440
taagaaatgt ttttattttc tctatcaaca gtagttttga aactagaagt caaaaatctt 4500
tttaaaatgc tgttttgttt taatttttgt gattttaatt tgatacaaaa tgctgaggta 4560
ataattatag tatgattttt acaataatta atgtgtgtct gaagactatc tttgaagcca 4620
gtatttcttt cccttggcag agtatgacga tggtatttat ctgtattttt tacagttatg 4680
catcctgtat aaatactgat atttcattcc tttgtttact aaagagacat atttatcagt 4740
tgcagatagc ctatttatta taaattatga gatgatgaaa ataataaagc cagtggaaat 4800
tttctaccta ggatgcatga caattgtcag gttggagtgt aagtgcttca tttgggaaat 4860
tcagcttttg cagaagcagt gtttctactt gcactagcat ggcctctgac gtgaccatgg 4920
tgttgttctt gatgacattg cttctgctaa atttaataaa aacttcagaa aaacctccat 4980
tttgatcatc aggatttcat ctgagtgtgg agtccctgga atggaattca gtaacatttg 5040
gagtgtgtat tcaagtttct aaattgagat tcgattactg tttggctgac atgacttttc 5100
tggaagacat gatacaccta ctactcaatt gttcttttcc tttctctcgc ccaacacgat 5160
cttgtaagat ggatttcacc cccaggccaa tgcagctaat tttgatagct gcattcattt 5220
atcaccagca tattgtgttc tgagtgaatc cactgtttgt cctgtcggat gcttgcttga 5280
ttttttggct tcttatttct aagtagatag aaagcaataa aaatactatg aaatgaaaga 5340
acttgttcac aggttctgcg ttacaacagt aacacatctt taatccgcct aattcttgtt 5400
gttctgtagg ttaaatgcag gtattttaac tgtgtgaacg ccaaactaaa gtttacagtc 5460
tttctttctg aattttgagt atcttctgtt gtagaataat aataaaaaga ctattaagag 5520
caataaatta tttttaagaa atcgagattt agtaaatcct attatgtgtt caaggaccac 5580
atgtgttctc tattttgcct ttaaattttt gtgaaccaat tttaaataca ttctcctttt 5640
tgccctggat tgttgacatg agtggaatac ttggtttctt ttcttactta tcaaaagaca 5700
gcactacaga tatcatattg aggattaatt tatcccccct acccccagcc tgacaaatat 5760
tgttaccatg aagatagttt tcctcaatgg acttcaaatt gcatctagaa ttagtggagc 5820
ttttgtatct tctgcagaca ctgtgggtag cccatcaaaa tgtaagctgt gctcctctca 5880
tttttatttt tatttttttg ggagagaata tttcaaatga acacgtgcac cccatcatca 5940
ctggaggcaa atttcagcat agatctgtag gatttttaga agaccgtggg ccattgcctt 6000
catgccgtgg taagtaccac atctacaatt ttggtaaccg aactggtgct ttagtaatgt 6060
ggattttttt cttttttaaa agagatgtag cagaataatt cttccagtgc aacaaaatca 6120
attttttgct aaacgactcc gagaacaaca gttgggctgt caacattcaa agcagcagag 6180
agggaacttt gcactattgg ggtatgatgt ttgggtcagt tgataaaagg aaaccttttc 6240
atgcctttag atgtgagctt ccagtaggta atgattatgt gtcctttctt gatggctgta 6300
atgagaactt caatcactgt agtctaagac ctgatctata gatgacctag aatagccatg 6360
tactataatg tgatgattct aaatttgtac ctatgtgaca gacattttca ataatgtgaa 6420
ctgctgattt gatggagcta ctttaagatt tgtaggtgaa agtgtaatac tgttggttga 6480
actatgctga agagggaaag tgagcgatta gttgagccct tgccgggcct tttttccacc 6540
tgccaattct acatgtattg ttgtggtttt attcattgta tgaaaattcc tgtgattttt 6600
tttaaatgtg cagtacacat cagcctcact gagctaataa agggaaacga atgtttcaaa 6660
tctaaaaaaa aaaaaaaaaa a 6681
<210> 54
<211> 786
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 54
Met Asp Glu Gly Tyr Phe Cys Ala Ala Leu Val Gly Glu Asp Gln Pro
1 5 10 15
Leu Cys Pro Asp Leu Pro Glu Leu Asp Leu Ser Glu Leu Asp Val Asn
20 25 30
Asp Leu Asp Thr Asp Ser Phe Leu Gly Gly Leu Lys Trp Cys Ser Asp
35 40 45
Gln Ser Glu Ile Ile Ser Asn Gln Tyr Asn Asn Glu Pro Ser Asn Ile
50 55 60
Phe Glu Lys Ile Asp Glu Glu Asn Glu Ala Asn Leu Leu Ala Val Leu
65 70 75 80
Thr Glu Thr Leu Asp Ser Leu Pro Val Asp Glu Asp Gly Leu Pro Ser
85 90 95
Phe Asp Ala Leu Thr Asp Gly Asp Val Thr Thr Asp Asn Glu Ala Ser
100 105 110
Pro Ser Ser Met Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu Glu
115 120 125
Pro Ser Leu Leu Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln Leu
130 135 140
Ser Tyr Asn Glu Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn His
145 150 155 160
Asn His Arg Ile Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn Ser
165 170 175
Trp Ser Asn Lys Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln Arg
180 185 190
Arg Pro Cys Ser Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp Pro
195 200 205
Pro His Thr Lys Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys Cys
210 215 220
Thr Ser Lys Lys Lys Ser His Thr Gln Ser Gln Ser Gln His Leu Gln
225 230 235 240
Ala Lys Pro Thr Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro Asn
245 250 255
Asp Pro Lys Gly Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr Leu
260 265 270
Ser Val Glu Leu Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr Pro
275 280 285
Pro His Lys Ala Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys Leu
290 295 300
Lys Ser Ser Cys Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro Arg
305 310 315 320
Tyr Ser Glu Ser Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys Gly
325 330 335
Pro Glu Gln Ser Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val Leu
340 345 350
Thr Gly Gly His Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg Leu
355 360 365
Phe Gly Asp His Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu Ile
370 375 380
Leu Ile Asn Ile Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu Asn
385 390 395 400
Lys Asp Val Ser Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr Asp
405 410 415
Ser Asp Gln Cys Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln Val
420 425 430
Ser Pro Cys Ser Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg Ala
435 440 445
Glu Leu Asn Lys His Phe Gly His Pro Ser Gln Ala Val Phe Asp Asp
450 455 460
Glu Ala Asp Lys Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn Glu
465 470 475 480
Gln Phe Ser Lys Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met Asp
485 490 495
Gly Leu Phe Asp Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr Pro
500 505 510
Trp Asp Gly Thr Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser Cys
515 520 525
Ser Ser Phe Asn Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys Ser
530 535 540
Leu Phe Ser Gln Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser Phe
545 550 555 560
Ser Arg His Arg Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg Ser
565 570 575
Arg Ser Pro Gly Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr Glu
580 585 590
Ser Ser His Tyr Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr Val
595 600 605
Arg Ser Arg Ser Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp Ser
610 615 620
Tyr Glu Glu Tyr Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg Arg
625 630 635 640
Glu Tyr Glu Lys Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg Gln
645 650 655
Arg Gln Lys Ala Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys Ile
660 665 670
Arg Pro Asp Thr Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val Phe
675 680 685
Gly Glu Ile Glu Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp Ser
690 695 700
Tyr Gly Phe Ile Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala Leu
705 710 715 720
Glu Asn Gly Tyr Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu Leu
725 730 735
Tyr Phe Cys Gly Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp Leu
740 745 750
Asp Ser Asn Ser Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys Tyr
755 760 765
Asp Ser Leu Asp Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser Leu
770 775 780
Arg Arg
785
<210> 55
<211> 6545
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 55
agaagccact ttaaaaaaca aagcaaaagg ctcagaggta acagcctcca gtgaatctga 60
tccatgtgta aggaaaacag gatgcgtccc tggaccggct ggtagcaaga tttatgtttc 120
agaatattgc aacataactt ccttccctct gttgcctttg tgcattgttt gaaggaggag 180
aataaaggac tacttttgca gcacagcagt ctgtaaagat ggatggcatg gggttagttt 240
aaatagcata ttggcctttc tgggtcactg tgggcaacct tgtccctggt ttattttaac 300
acctgcttta atgcctccat gatacaactg aatgggcatc tttcattcat tcgtctgtta 360
cttctgaatg aagctacttg gggttcgtta gaatgatggc aagtgagaat gcagtcgtct 420
ctaggtcatt acttgtaata cgttctgagg actgcctttg ctgatggggg gagaaggact 480
ctcacagctg tagccagcgt tcatgtttgg tcattgctgg aactctcagg aagcctgaaa 540
ctgtgaactt tgtagcagaa aaggaagata gatgaagaga atgaggcaaa cttgctagca 600
gtcctcacag agacactaga cagtctccct gtggatgaag acggattgcc ctcatttgat 660
gcgctgacag atggagacgt gaccactgac aatgaggcta gtccttcctc catgcctgac 720
ggcacccctc caccccagga ggcagaagag ccgtctctac ttaagaagct cttactggca 780
ccagccaaca ctcagctaag ttataatgaa tgcagtggtc tcagtaccca gaaccatgca 840
aatcacaatc acaggatcag aacaaaccct gcaattgtta agactgagaa ttcatggagc 900
aataaagcga agagtatttg tcaacagcaa aagccacaaa gacgtccctg ctcggagctt 960
ctcaaatatc tgaccacaaa cgatgaccct cctcacacca aacccacaga gaacagaaac 1020
agcagcagag acaaatgcac ctccaaaaag aagtcccaca cacagtcgca gtcacaacac 1080
ttacaagcca aaccaacaac tttatctctt cctctgaccc cagagtcacc aaatgacccc 1140
aagggttccc catttgagaa caagactatt gaacgcacct taagtgtgga actctctgga 1200
actgcaggcc taactccacc caccactcct cctcataaag ccaaccaaga taaccctttt 1260
agggcttctc caaagctgaa gtcctcttgc aagactgtgg tgccaccacc atcaaagaag 1320
cccaggtaca gtgagtcttc tggtacacaa ggcaataact ccaccaagaa agggccggag 1380
caatccgagt tgtatgcaca actcagcaag tcctcagtcc tcactggtgg acacgaggaa 1440
aggaagacca agcggcccag tctgcggctg tttggtgacc atgactattg ccagtcaatt 1500
aattccaaaa cagaaatact cattaatata tcacaggagc tccaagactc tagacaacta 1560
gaaaataaag atgtctcctc tgattggcag gggcagattt gttcttccac agattcagac 1620
cagtgctacc tgagagagac tttggaggca agcaagcagg tctctccttg cagcacaaga 1680
aaacagctcc aagaccagga aatccgagcc gagctgaaca agcacttcgg tcatcccagt 1740
caagctgttt ttgacgacga agcagacaag accggtgaac tgagggacag tgatttcagt 1800
aatgaacaat tctccaaact acctatgttt ataaattcag gactagccat ggatggcctg 1860
tttgatgaca gcgaagatga aagtgataaa ctgagctacc cttgggatgg cacgcaatcc 1920
tattcattgt tcaatgtgtc tccttcttgt tcttctttta actctccatg tagagattct 1980
gtgtcaccac ccaaatcctt attttctcaa agaccccaaa ggatgcgctc tcgttcaagg 2040
tccttttctc gacacaggtc gtgttcccga tcaccatatt ccaggtcaag atcaaggtct 2100
ccaggcagta gatcctcttc aagatcctgc tattactatg agtcaagcca ctacagacac 2160
cgcacgcacc gaaattctcc cttgtatgtg agatcacgtt caagatcgcc ctacagccgt 2220
cggcccaggt atgacagcta cgaggaatat cagcacgaga ggctgaagag ggaagaatat 2280
cgcagagagt atgagaagcg agagtctgag agggccaagc aaagggagag gcagaggcag 2340
aaggcaattg aagagcgccg tgtgatttat gtcggtaaaa tcagacctga cacaacacgg 2400
acagaactga gggaccgttt tgaagttttt ggtgaaattg aggagtgcac agtaaatctg 2460
cgggatgatg gagacagcta tggtttcatt acctaccgtt atacctgtga tgcttttgct 2520
gctcttgaaa atggatacac tttgcgcagg tcaaacgaaa ctgactttga gctgtacttt 2580
tgtggacgca agcaattttt caagtctaac tatgcagacc tagattcaaa ctcagatgac 2640
tttgaccctg cttccaccaa gagcaagtat gactctctgg attttgatag tttactgaaa 2700
gaagctcaga gaagcttgcg caggtaacat gttccctagc tgaggatgac agagggatgg 2760
cgaatacctc atgggacagc gcgtccttcc ctaaagacta ttgcaagtca tacttaggaa 2820
tttctcctac tttacactct ctgtacaaaa acaaaacaaa acaacaacaa tacaacaaga 2880
acaacaacaa caataacaac aatggtttac atgaacacag ctgctgaaga ggcaagagac 2940
agaatgatat ccagtaagca catgtttatt catgggtgtc agctttgctt ttcctggagt 3000
ctcttggtga tggagtgtgc gtgtgtgcat gtatgtgtgt gtgtatgtat gtgtgtggtg 3060
tgtgtgcttg gtttagggga agtatgtgtg ggtacatgtg aggactgggg gcacctgacc 3120
agaatgcgca agggcaaacc atttcaaatg gcagcagttc catgaagaca cgcttaaaac 3180
ctagaacttc aaaatgttcg tattctattc aaaaggaaat atatatatat atatatatat 3240
atatatatat atatataaat taaaaaggaa agaaaactaa caaccaacca accaaccaac 3300
caaccacaaa ccaccctaaa atgacagccg ctgatgtctg ggcatcagcc tttgtactct 3360
gtttttttaa gaaagtgcag aatcaacttg aagcaagctt tctctcataa cgtaatgatt 3420
atatgacaat cctgaagaaa ccacaggttc catagaacta atatcctgtc tctctctctc 3480
tctctctctc tctctttttt ttttcttttt ccttttgcca tggaatctgg gtgggagagg 3540
atactgcggg caccagaatg ctaaagtttc ctaacatttt gaagtttctg tagttcatcc 3600
ttaatcctga cacccatgta aatgtccaaa atgttgatct tccactgcaa atttcaaaag 3660
ccttgtcaat ggtcaagcgt gcagcttgtt cagcggttct ttctgaggag cggacaccgg 3720
gttacattac taatgagagt tgggtagaac tctctgagat gtgttcagat agtgtaattg 3780
ctacattctc tgatgtagtt aagtatttac agatgttaaa tggagtattt ttattttatg 3840
tatatactat acaacaatgt tcttttttgt tacagctatg cactgtaaat gcagccttct 3900
tttcaaaact gctaaatttt tcttaatcaa gaatattcaa atgtaattat gaggtgaaac 3960
aattattgta cactaacata tttagaagct gaacttactg cttatatata tttgattgta 4020
aaaacaaaaa gacagtgtgt gtgtctgttg agtgcaacaa gagcaaaatg atgctttccg 4080
cacatccatc ccttaggtga gcttcaatct aagcatcttg tcaagaaata tcctagtccc 4140
ctaaaggtat taaccacttc tgcgatattt ttccacattt tcttgtcgct tgtttttctt 4200
tgaagtttta tacactggat ttgttagggg aatgaaattt tctcatctaa aatttttcta 4260
gaagatatca tgattttatg taaagtctct caatgggtaa ccattaagaa atgtttttat 4320
tttctctatc aacagtagtt ttgaaactag aagtcaaaaa tctttttaaa atgctgtttt 4380
gttttaattt ttgtgatttt aatttgatac aaaatgctga ggtaataatt atagtatgat 4440
ttttacaata attaatgtgt gtctgaagac tatctttgaa gccagtattt ctttcccttg 4500
gcagagtatg acgatggtat ttatctgtat tttttacagt tatgcatcct gtataaatac 4560
tgatatttca ttcctttgtt tactaaagag acatatttat cagttgcaga tagcctattt 4620
attataaatt atgagatgat gaaaataata aagccagtgg aaattttcta cctaggatgc 4680
atgacaattg tcaggttgga gtgtaagtgc ttcatttggg aaattcagct tttgcagaag 4740
cagtgtttct acttgcacta gcatggcctc tgacgtgacc atggtgttgt tcttgatgac 4800
attgcttctg ctaaatttaa taaaaacttc agaaaaacct ccattttgat catcaggatt 4860
tcatctgagt gtggagtccc tggaatggaa ttcagtaaca tttggagtgt gtattcaagt 4920
ttctaaattg agattcgatt actgtttggc tgacatgact tttctggaag acatgataca 4980
cctactactc aattgttctt ttcctttctc tcgcccaaca cgatcttgta agatggattt 5040
cacccccagg ccaatgcagc taattttgat agctgcattc atttatcacc agcatattgt 5100
gttctgagtg aatccactgt ttgtcctgtc ggatgcttgc ttgatttttt ggcttcttat 5160
ttctaagtag atagaaagca ataaaaatac tatgaaatga aagaacttgt tcacaggttc 5220
tgcgttacaa cagtaacaca tctttaatcc gcctaattct tgttgttctg taggttaaat 5280
gcaggtattt taactgtgtg aacgccaaac taaagtttac agtctttctt tctgaatttt 5340
gagtatcttc tgttgtagaa taataataaa aagactatta agagcaataa attattttta 5400
agaaatcgag atttagtaaa tcctattatg tgttcaagga ccacatgtgt tctctatttt 5460
gcctttaaat ttttgtgaac caattttaaa tacattctcc tttttgccct ggattgttga 5520
catgagtgga atacttggtt tcttttctta cttatcaaaa gacagcacta cagatatcat 5580
attgaggatt aatttatccc ccctaccccc agcctgacaa atattgttac catgaagata 5640
gttttcctca atggacttca aattgcatct agaattagtg gagcttttgt atcttctgca 5700
gacactgtgg gtagcccatc aaaatgtaag ctgtgctcct ctcattttta tttttatttt 5760
tttgggagag aatatttcaa atgaacacgt gcaccccatc atcactggag gcaaatttca 5820
gcatagatct gtaggatttt tagaagaccg tgggccattg ccttcatgcc gtggtaagta 5880
ccacatctac aattttggta accgaactgg tgctttagta atgtggattt ttttcttttt 5940
taaaagagat gtagcagaat aattcttcca gtgcaacaaa atcaattttt tgctaaacga 6000
ctccgagaac aacagttggg ctgtcaacat tcaaagcagc agagagggaa ctttgcacta 6060
ttggggtatg atgtttgggt cagttgataa aaggaaacct tttcatgcct ttagatgtga 6120
gcttccagta ggtaatgatt atgtgtcctt tcttgatggc tgtaatgaga acttcaatca 6180
ctgtagtcta agacctgatc tatagatgac ctagaatagc catgtactat aatgtgatga 6240
ttctaaattt gtacctatgt gacagacatt ttcaataatg tgaactgctg atttgatgga 6300
gctactttaa gatttgtagg tgaaagtgta atactgttgg ttgaactatg ctgaagaggg 6360
aaagtgagcg attagttgag cccttgccgg gccttttttc cacctgccaa ttctacatgt 6420
attgttgtgg ttttattcat tgtatgaaaa ttcctgtgat tttttttaaa tgtgcagtac 6480
acatcagcct cactgagcta ataaagggaa acgaatgttt caaatctaaa aaaaaaaaaa 6540
aaaaa 6545
<210> 56
<211> 671
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 56
Met Pro Asp Gly Thr Pro Pro Pro Gln Glu Ala Glu Glu Pro Ser Leu
1 5 10 15
Leu Lys Lys Leu Leu Leu Ala Pro Ala Asn Thr Gln Leu Ser Tyr Asn
20 25 30
Glu Cys Ser Gly Leu Ser Thr Gln Asn His Ala Asn His Asn His Arg
35 40 45
Ile Arg Thr Asn Pro Ala Ile Val Lys Thr Glu Asn Ser Trp Ser Asn
50 55 60
Lys Ala Lys Ser Ile Cys Gln Gln Gln Lys Pro Gln Arg Arg Pro Cys
65 70 75 80
Ser Glu Leu Leu Lys Tyr Leu Thr Thr Asn Asp Asp Pro Pro His Thr
85 90 95
Lys Pro Thr Glu Asn Arg Asn Ser Ser Arg Asp Lys Cys Thr Ser Lys
100 105 110
Lys Lys Ser His Thr Gln Ser Gln Ser Gln His Leu Gln Ala Lys Pro
115 120 125
Thr Thr Leu Ser Leu Pro Leu Thr Pro Glu Ser Pro Asn Asp Pro Lys
130 135 140
Gly Ser Pro Phe Glu Asn Lys Thr Ile Glu Arg Thr Leu Ser Val Glu
145 150 155 160
Leu Ser Gly Thr Ala Gly Leu Thr Pro Pro Thr Thr Pro Pro His Lys
165 170 175
Ala Asn Gln Asp Asn Pro Phe Arg Ala Ser Pro Lys Leu Lys Ser Ser
180 185 190
Cys Lys Thr Val Val Pro Pro Pro Ser Lys Lys Pro Arg Tyr Ser Glu
195 200 205
Ser Ser Gly Thr Gln Gly Asn Asn Ser Thr Lys Lys Gly Pro Glu Gln
210 215 220
Ser Glu Leu Tyr Ala Gln Leu Ser Lys Ser Ser Val Leu Thr Gly Gly
225 230 235 240
His Glu Glu Arg Lys Thr Lys Arg Pro Ser Leu Arg Leu Phe Gly Asp
245 250 255
His Asp Tyr Cys Gln Ser Ile Asn Ser Lys Thr Glu Ile Leu Ile Asn
260 265 270
Ile Ser Gln Glu Leu Gln Asp Ser Arg Gln Leu Glu Asn Lys Asp Val
275 280 285
Ser Ser Asp Trp Gln Gly Gln Ile Cys Ser Ser Thr Asp Ser Asp Gln
290 295 300
Cys Tyr Leu Arg Glu Thr Leu Glu Ala Ser Lys Gln Val Ser Pro Cys
305 310 315 320
Ser Thr Arg Lys Gln Leu Gln Asp Gln Glu Ile Arg Ala Glu Leu Asn
325 330 335
Lys His Phe Gly His Pro Ser Gln Ala Val Phe Asp Asp Glu Ala Asp
340 345 350
Lys Thr Gly Glu Leu Arg Asp Ser Asp Phe Ser Asn Glu Gln Phe Ser
355 360 365
Lys Leu Pro Met Phe Ile Asn Ser Gly Leu Ala Met Asp Gly Leu Phe
370 375 380
Asp Asp Ser Glu Asp Glu Ser Asp Lys Leu Ser Tyr Pro Trp Asp Gly
385 390 395 400
Thr Gln Ser Tyr Ser Leu Phe Asn Val Ser Pro Ser Cys Ser Ser Phe
405 410 415
Asn Ser Pro Cys Arg Asp Ser Val Ser Pro Pro Lys Ser Leu Phe Ser
420 425 430
Gln Arg Pro Gln Arg Met Arg Ser Arg Ser Arg Ser Phe Ser Arg His
435 440 445
Arg Ser Cys Ser Arg Ser Pro Tyr Ser Arg Ser Arg Ser Arg Ser Pro
450 455 460
Gly Ser Arg Ser Ser Ser Arg Ser Cys Tyr Tyr Tyr Glu Ser Ser His
465 470 475 480
Tyr Arg His Arg Thr His Arg Asn Ser Pro Leu Tyr Val Arg Ser Arg
485 490 495
Ser Arg Ser Pro Tyr Ser Arg Arg Pro Arg Tyr Asp Ser Tyr Glu Glu
500 505 510
Tyr Gln His Glu Arg Leu Lys Arg Glu Glu Tyr Arg Arg Glu Tyr Glu
515 520 525
Lys Arg Glu Ser Glu Arg Ala Lys Gln Arg Glu Arg Gln Arg Gln Lys
530 535 540
Ala Ile Glu Glu Arg Arg Val Ile Tyr Val Gly Lys Ile Arg Pro Asp
545 550 555 560
Thr Thr Arg Thr Glu Leu Arg Asp Arg Phe Glu Val Phe Gly Glu Ile
565 570 575
Glu Glu Cys Thr Val Asn Leu Arg Asp Asp Gly Asp Ser Tyr Gly Phe
580 585 590
Ile Thr Tyr Arg Tyr Thr Cys Asp Ala Phe Ala Ala Leu Glu Asn Gly
595 600 605
Tyr Thr Leu Arg Arg Ser Asn Glu Thr Asp Phe Glu Leu Tyr Phe Cys
610 615 620
Gly Arg Lys Gln Phe Phe Lys Ser Asn Tyr Ala Asp Leu Asp Ser Asn
625 630 635 640
Ser Asp Asp Phe Asp Pro Ala Ser Thr Lys Ser Lys Tyr Asp Ser Leu
645 650 655
Asp Phe Asp Ser Leu Leu Lys Glu Ala Gln Arg Ser Leu Arg Arg
660 665 670
<210> 57
<211> 7667
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 57
gtccgggttc gcttgcctcg tcagcgtccg cgtttttccc ggcccccccc aacccccccg 60
gacaggaccc ccttgagctt gtccctcagc tgccaccatg agcgaccaag atcactccat 120
ggatgaaatg acagctgtgg tgaaaattga aaaaggagtt ggtggcaata atgggggcaa 180
tggtaatggt ggtggtgcct tttcacaggc tcgaagtagc agcacaggca gtagcagcag 240
cactggagga ggagggcagg agtcccagcc atcccctttg gctctgctgg cagcaacttg 300
cagcagaatt gagtcaccca atgagaacag caacaactcc cagggcccga gtcagtcagg 360
gggaacaggt gagcttgacc tcacagccac acaactttca cagggtgcca atggctggca 420
gatcatctct tcctcctctg gggctacccc tacctcaaag gaacagagtg gcagcagtac 480
caatggcagc aatggcagtg agtcttccaa gaatcgcaca gtctctggtg ggcagtatgt 540
tgtggctgcc gctcccaact tacagaacca gcaagttctg acaggactac ctggagtgat 600
gcctaatatt cagtatcaag taatcccaca gttccagacc gttgatgggc aacagctgca 660
gtttgctgcc actggggccc aagtgcagca ggatggttct ggtcaaatac agatcatacc 720
aggtgcaaac caacagatta tcacaaatcg aggaagtgga ggcaacatca ttgctgctat 780
gccaaaccta ctccagcagg ctgtccccct ccaaggcctg gctaataatg tactctcagg 840
acagactcag tatgtgacca atgtaccagt ggccctgaat gggaacatca ccttgctacc 900
tgtcaacagc gtttctgcag ctaccttgac tcccagctct caggcagtca cgatcagcag 960
ctctgggtcc caggagagtg gctcacagcc tgtcacctca gggactacca tcagttctgc 1020
cagcttggta tcatcacaag ccagttccag ctcctttttc accaatgcca atagctactc 1080
aactactact accaccagca acatgggaat tatgaacttt actaccagtg gatcatcagg 1140
gaccaactct caaggccaga caccccagag ggtcagtggg ctacaggggt ctgatgctct 1200
gaacatccag caaaaccaga catctggagg ctcattgcaa gcaggccagc aaaaagaagg 1260
agagcaaaac cagcagacac agcagcaaca aattcttatc cagcctcagc tagttcaagg 1320
gggacaggcc ctccaggccc tccaagcagc accattgtca gggcagacct ttacaactca 1380
agccatctcc caggaaaccc tccagaacct ccagcttcag gctgttccaa actctggtcc 1440
catcatcatc cggacaccaa cagtggggcc caatggacag gtcagttggc agactctaca 1500
gctgcagaac ctccaagttc agaacccaca agcccaaaca atcaccttag ccccaatgca 1560
gggtgtttcc ttggggcaga ccagcagcag caacaccact ctcacaccca ttgcctcagc 1620
tgcttccatt cctgctggca cagtcactgt gaatgctgct caactctcct ccatgccagg 1680
cctccagacc attaacctca gtgcattggg tacttcagga atccaggtgc acccaattca 1740
aggcctgccg ttggctatag caaatgcccc aggtgatcat ggagctcagc ttggtctcca 1800
tggggctggt ggtgatggaa tacatgatga cacagcaggt ggagaggaag gagaaaacag 1860
cccagatgcc caaccccaag ccggtcggag gacccggcgg gaagcatgca cctgccccta 1920
ctgtaaagac agtgaaggaa ggggctcggg ggatcctggc aaaaagaaac agcatatttg 1980
ccacatccaa ggctgtggga aagtgtatgg caagacctct cacctgcggg cacacttgcg 2040
ctggcataca ggcgagaggc catttatgtg tacctggtca tactgtggga aacgcttcac 2100
acgttcggat gagctacaga ggcacaaacg tacacacaca ggtgagaaga aatttgcctg 2160
ccctgagtgt cctaagcgct tcatgaggag tgaccacctg tcaaaacata tcaagaccca 2220
ccagaataag aagggaggcc caggtgtagc tctgagtgtg ggcactttgc ccctggacag 2280
tggggcaggt tcagaaggca gtggcactgc cactccttca gcccttatta ccaccaatat 2340
ggtagccatg gaggccatct gtccagaggg cattgcccgt cttgccaaca gtggcatcaa 2400
cgtcatgcag gtggcagatc tgcagtccat taatatcagt ggcaatggct tctgagatca 2460
ggcacccggg gccagagaca tatgggccat accccttaac cccgggatgc aaggtagcat 2520
gggtccaaga gacatggaag agagagccat gaagcattaa aatgcatggt gttgagaaga 2580
atcaggagag ggatacaaga gaggagatgg ggtcccggca cccatctgta tcatcagtgc 2640
ctctttgaag gtgggaaaca ttagtgaaaa ttctgttggt gccacgcttt gatgagcatt 2700
tgtttgaccc cagtttcttc ttacacttct taccccagcc tacccttcct gcatttctct 2760
tctcagctct tccatgatgg attccccccc ctttcctaaa gccatcatgc cttgataaat 2820
atatatgatc attgaaatac tttttaacaa aaaacagatt ctatattatt atatatatat 2880
atatatatat aaagatatat agagatgcat tcacaggggt tggctgggag gaggaagacc 2940
attctgtgac caaaatacct tggtcatttt ttttatattg ccttatttcc ctatggctga 3000
gccttgttgt gacacatcaa gcttttctgt agatgttgtc ttggcttccc accagcttaa 3060
gcgttcatat gctctgcttt tagttcatat atacatacat aatgtttttc ctttcttaat 3120
tttgtctttt tgtttgggat cagcttcttg cactccttcc ctaactcaac tgttgccgtc 3180
tcatcttctc tcatctgatc acttcatgtt ttgtttttgt tactgcctgg atgaggcact 3240
tctgtcaatt ttttcaggac cttagttcca gcagcagaat ggaaaaatcc ttgaagccca 3300
ggctgatgct tgaagtaact gtggagggag tgttcaaaat actactgacg caggcacctt 3360
cttggcgctg gagagtcaaa ggcatctccc ttcattagct gctctgagca tcaagaatta 3420
gaagtctttc agtggaattg tacaagagtc cctttgaaga taataatctt ggctcagttt 3480
gtataaactg tcaaattttc aaataatagg tagggggctt tcactaggaa aatcatgtgc 3540
tcagaagagg aaatgactcg tagtcaggtt caggagttag tggagtattt ggactttggt 3600
actgctgtct tccaaggtag ctctaagttt tgatgtgtgg gcttctgagt ttatattctg 3660
aaaggaaata cacttctttt gaacatcccc actaggttct tttccattgt caataaggag 3720
catcagccag tgaatctgtt tcaggtttcc attctgcaga actcctccaa agcatgtgct 3780
agtggcaaga cagtggttct tatgatgttt tcccttaact tttccttgta tgttcttggg 3840
tggttcctaa gggaaaggga agcacatgat catgggaatg atagcccaga acaaaaagaa 3900
atcttgtctt accacagtgt tttataggag agattgggag aaatcatcct gttttctctg 3960
tgacctgatt tcagaagaga ctgatccaaa aattataacg gcagggaacc tagtgcattt 4020
ggcactgaga tttaaatgca accagaattg tcctcaaggc ccagccataa aagcattgtc 4080
tctctcgacc ttctggtatc ttgttagaga gcttttcact gtgaggaagt gtggaaaaat 4140
agctctgtgt gtgtgtgtgt gtgtgtgtgt gtgtgtgtgt gtaatctgtt aggttgggga 4200
taggttttct gctagccaat attaaaagag acctgcaata aaaaaattac cctgatctga 4260
tagaaagcaa gtgtttttgt atgtgtgggt gaatgtgtgt tcatgcccgt atatgtctac 4320
acacagatga caaattatat ttgaaatcgt tggaaaataa attcagatca aaatgccttt 4380
caggcccatt acctagaaat ctatcttaaa acctgggtat gttcctaagg tcatttcttt 4440
gcttatgcta aattaattac aattatgaat ggaggatatt ctactgtact tttttaaaaa 4500
gaaactattt ttgtgtttga aagtgaaacc aacatccaga tctatagcag agtccttatt 4560
cttctcataa atctttttac tttggctaca aatagatgat ggtatgattc tattatatat 4620
tttatataaa atccatccaa attaagtttt gggtaagtgt gttgtttaat ctgaactata 4680
gtaacttaat actctaaaca atagttcact ccatttggtc ctttctccac agatgtaatt 4740
atgttttcaa ctcaggaact atggcaagga actttcccca gatcaaattc tattaacgct 4800
gagatacaag tcatccatgc acagccacta tcataccctt tattctcact gaaaggcaga 4860
actcagaacc tgttatttta tgtctgtaat catgtacttt ggcatctttt ggaggaaagg 4920
ggcaggataa ctcactggaa tgtacagtat tttgctagtg catttcaagg aatggaatct 4980
tctccagtat gaaattacca gatataaaat aatgtaatga tgctgaggat ataagctttt 5040
agaaggtaat ttgatggtat ttctttctcg aatgaaaagc tgctggttta ccctcaaccc 5100
tattcattag cattaccatg agtgaattta tatctaatta tttccacttg ccctgttctc 5160
ttcacaccaa ggaagctcca gatccagtat cttgtttggc ctcaaaacag aagcagcttc 5220
ttttgtctcc cagcagtagt gagccactca gtctcttcca caggaagttt ggagcctaca 5280
ttccttgagt caggagctta ttacagaaaa accccgtttc cctgaacttt tggctaacag 5340
aaattaattt aactgacatg catattgatt ctgaaatttt tttcctaagt ttttttcatt 5400
tttttgaatg agttttttaa attttttaga tgaccaaaac ttgcagggca ggggatgccc 5460
agaagagtgg tgagatagta aaacacttat tccctcatcc tttcaggttt tcaggttgcc 5520
catttatatt catttacatg tcatttgact gtctcacttt ttacccagaa cagtaacaac 5580
ccacaccgtc ttccttcagg gatttccaac tggcactctg tgggtgctac acagaatgca 5640
atttaatgga tatttctcag cctggttcag aataaattga tcctttgatc ccagaaagta 5700
tatactgaag tgtgggataa agattatgat taggggaggg ttggagacaa aagctgtaaa 5760
ttactatggc tgatttattt ctactatata catatatatt ttttgctttt gtatatccta 5820
tataggaaac taagcattgt atttttttta acaaatctaa aaaagcacta tgaactacag 5880
gtgtttgact ttcaaaatat attttgtatt gttaatatct tcacattgtg tgaatactgg 5940
aagctgcaga tctttgctag gacgcaataa atttatatac tttttgaggg gttcttctgg 6000
ggtgctaatc aggcccctgt tatgcttagg gggagccctg gtgctacttg cttgaagttt 6060
tcagtgtaag taccctgatg ccttttggac cttgggatca gatcaagagt tttggagatc 6120
aggtaccaag gaaataagga cagtctagct gcctcaagtg aggggccctt tgcatagctc 6180
tccttccccc tcactgaagc tgggtagcct attggggttg agagggaaaa tgtgaaatct 6240
cagaatttat ctcccttaga agagagccag taacttatgt acaaggatga aagaaaggtc 6300
gcagcagtag ctttggggaa agggaggaag atatggcact tctccaaccc cggaaaacat 6360
tgcttttgaa aactgctgat aaaatatgag ccggttatta cttctgtttg ggagactgtg 6420
ctctctgtgg tgcctctctt ggctctactc cacagatacc agacctcttc taagaggatg 6480
agcagaccag ctttgaggtt gacctgtttc tctttgtctg ccttcccaaa acaccagccc 6540
ccaggaagac attaagcagc cttaagctta aattcctact ccctcttcca aatttggctc 6600
acttgcctta gatccaaggc agggaaagga aaagaagggg ggtctctggc tttattactc 6660
ccctaagtct ttactctgac ttccccaaac ccagaaagat tttctccaca gtgttcattt 6720
gaaagaggag tattttgtcc cattttcccc ttcctcatta tcaaacagcc ccagtcttcc 6780
ttgtctctgc taagaaagta gaggcatgat gatctgcctc tcaactgccc taagtcctag 6840
ctaagtatca ggggaaaaaa aaaaaaaaaa agcctaacaa atgggattag actagggctg 6900
caagtagtga ggattttgtt gatacctctg ctgggatgtg tgctttccca tatcttgcct 6960
tcaggaatta cactgtgcct tttccccagg gatatgggct ctgtctaccc agtgctccag 7020
tttcccggta actgctcttg aacattgtgg acaagggcag gtcttcatat ttttgatcat 7080
ccctttctcc cagtgaaatc ccatagccct tacctagagt ctagggcaca aagacttcgg 7140
ggaagataca ctgagattga cctgaggaga catctacaca caccagtggc agctgcccca 7200
gggcctgctt ccccttccta agtctgtcat cctctggaag ggatgggtgg tgctccaatc 7260
tctggtgcct aaaaacccaa gtttatttct ctcttaacac tggcaataac cagtccacac 7320
cactgttgcc ttttaaaacc tcttaataat ctcatgctgt gtttgttttg attccaatcc 7380
aattatcacc agggctgtgt gggtaaatgc ttttaaatgc tctctcatct tgttcttccc 7440
cctcaccccc cactcttagg tatgtatgat gctaatcttg tccctaagta agtttcttcc 7500
tgctcctttt gtatcttcct ttcttgtctt tcctcctacc ttttgtctct tggtgttttg 7560
ggactttttt tttttttttt ttggcctttt gtacaaagat tagtttcaat gtagtctgta 7620
gcctcctttg taaaccaatt aaaaagtttt ttaataaaaa aaaaaaa 7667
<210> 58
<211> 785
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 58
Met Ser Asp Gln Asp His Ser Met Asp Glu Met Thr Ala Val Val Lys
1 5 10 15
Ile Glu Lys Gly Val Gly Gly Asn Asn Gly Gly Asn Gly Asn Gly Gly
20 25 30
Gly Ala Phe Ser Gln Ala Arg Ser Ser Ser Thr Gly Ser Ser Ser Ser
35 40 45
Thr Gly Gly Gly Gly Gln Glu Ser Gln Pro Ser Pro Leu Ala Leu Leu
50 55 60
Ala Ala Thr Cys Ser Arg Ile Glu Ser Pro Asn Glu Asn Ser Asn Asn
65 70 75 80
Ser Gln Gly Pro Ser Gln Ser Gly Gly Thr Gly Glu Leu Asp Leu Thr
85 90 95
Ala Thr Gln Leu Ser Gln Gly Ala Asn Gly Trp Gln Ile Ile Ser Ser
100 105 110
Ser Ser Gly Ala Thr Pro Thr Ser Lys Glu Gln Ser Gly Ser Ser Thr
115 120 125
Asn Gly Ser Asn Gly Ser Glu Ser Ser Lys Asn Arg Thr Val Ser Gly
130 135 140
Gly Gln Tyr Val Val Ala Ala Ala Pro Asn Leu Gln Asn Gln Gln Val
145 150 155 160
Leu Thr Gly Leu Pro Gly Val Met Pro Asn Ile Gln Tyr Gln Val Ile
165 170 175
Pro Gln Phe Gln Thr Val Asp Gly Gln Gln Leu Gln Phe Ala Ala Thr
180 185 190
Gly Ala Gln Val Gln Gln Asp Gly Ser Gly Gln Ile Gln Ile Ile Pro
195 200 205
Gly Ala Asn Gln Gln Ile Ile Thr Asn Arg Gly Ser Gly Gly Asn Ile
210 215 220
Ile Ala Ala Met Pro Asn Leu Leu Gln Gln Ala Val Pro Leu Gln Gly
225 230 235 240
Leu Ala Asn Asn Val Leu Ser Gly Gln Thr Gln Tyr Val Thr Asn Val
245 250 255
Pro Val Ala Leu Asn Gly Asn Ile Thr Leu Leu Pro Val Asn Ser Val
260 265 270
Ser Ala Ala Thr Leu Thr Pro Ser Ser Gln Ala Val Thr Ile Ser Ser
275 280 285
Ser Gly Ser Gln Glu Ser Gly Ser Gln Pro Val Thr Ser Gly Thr Thr
290 295 300
Ile Ser Ser Ala Ser Leu Val Ser Ser Gln Ala Ser Ser Ser Ser Phe
305 310 315 320
Phe Thr Asn Ala Asn Ser Tyr Ser Thr Thr Thr Thr Thr Ser Asn Met
325 330 335
Gly Ile Met Asn Phe Thr Thr Ser Gly Ser Ser Gly Thr Asn Ser Gln
340 345 350
Gly Gln Thr Pro Gln Arg Val Ser Gly Leu Gln Gly Ser Asp Ala Leu
355 360 365
Asn Ile Gln Gln Asn Gln Thr Ser Gly Gly Ser Leu Gln Ala Gly Gln
370 375 380
Gln Lys Glu Gly Glu Gln Asn Gln Gln Thr Gln Gln Gln Gln Ile Leu
385 390 395 400
Ile Gln Pro Gln Leu Val Gln Gly Gly Gln Ala Leu Gln Ala Leu Gln
405 410 415
Ala Ala Pro Leu Ser Gly Gln Thr Phe Thr Thr Gln Ala Ile Ser Gln
420 425 430
Glu Thr Leu Gln Asn Leu Gln Leu Gln Ala Val Pro Asn Ser Gly Pro
435 440 445
Ile Ile Ile Arg Thr Pro Thr Val Gly Pro Asn Gly Gln Val Ser Trp
450 455 460
Gln Thr Leu Gln Leu Gln Asn Leu Gln Val Gln Asn Pro Gln Ala Gln
465 470 475 480
Thr Ile Thr Leu Ala Pro Met Gln Gly Val Ser Leu Gly Gln Thr Ser
485 490 495
Ser Ser Asn Thr Thr Leu Thr Pro Ile Ala Ser Ala Ala Ser Ile Pro
500 505 510
Ala Gly Thr Val Thr Val Asn Ala Ala Gln Leu Ser Ser Met Pro Gly
515 520 525
Leu Gln Thr Ile Asn Leu Ser Ala Leu Gly Thr Ser Gly Ile Gln Val
530 535 540
His Pro Ile Gln Gly Leu Pro Leu Ala Ile Ala Asn Ala Pro Gly Asp
545 550 555 560
His Gly Ala Gln Leu Gly Leu His Gly Ala Gly Gly Asp Gly Ile His
565 570 575
Asp Asp Thr Ala Gly Gly Glu Glu Gly Glu Asn Ser Pro Asp Ala Gln
580 585 590
Pro Gln Ala Gly Arg Arg Thr Arg Arg Glu Ala Cys Thr Cys Pro Tyr
595 600 605
Cys Lys Asp Ser Glu Gly Arg Gly Ser Gly Asp Pro Gly Lys Lys Lys
610 615 620
Gln His Ile Cys His Ile Gln Gly Cys Gly Lys Val Tyr Gly Lys Thr
625 630 635 640
Ser His Leu Arg Ala His Leu Arg Trp His Thr Gly Glu Arg Pro Phe
645 650 655
Met Cys Thr Trp Ser Tyr Cys Gly Lys Arg Phe Thr Arg Ser Asp Glu
660 665 670
Leu Gln Arg His Lys Arg Thr His Thr Gly Glu Lys Lys Phe Ala Cys
675 680 685
Pro Glu Cys Pro Lys Arg Phe Met Arg Ser Asp His Leu Ser Lys His
690 695 700
Ile Lys Thr His Gln Asn Lys Lys Gly Gly Pro Gly Val Ala Leu Ser
705 710 715 720
Val Gly Thr Leu Pro Leu Asp Ser Gly Ala Gly Ser Glu Gly Ser Gly
725 730 735
Thr Ala Thr Pro Ser Ala Leu Ile Thr Thr Asn Met Val Ala Met Glu
740 745 750
Ala Ile Cys Pro Glu Gly Ile Ala Arg Leu Ala Asn Ser Gly Ile Asn
755 760 765
Val Met Gln Val Ala Asp Leu Gln Ser Ile Asn Ile Ser Gly Asn Gly
770 775 780
Phe
785
<210> 59
<211> 1333
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 59
gaggcttcca aggcaggata cttgtgtctc agatgcggtc gcttctttca tacagcaatt 60
gccgccttgc tgaggatcaa ggaacctcag tgtcagatca cgccctcccc ccaaacttag 120
aaattcagat ggggcgcaga aatttctctt gttctgcgtg atctgcatag atggtccaag 180
aggtggtttt tccaggagcc cagcacccct cctccctccg actcagaccc aggagtctgg 240
ccctccattg aaaggacccc aggttacatc atccattcag gctgcccttg ccacgatgga 300
attctgtagc tcctgccaaa tgggtcaaat atcatggttc aggcgcaggg agggtgattg 360
ggcgggcctg tctgggtata aattctggag cttctgcatc tatcccaaaa aacaagggtg 420
ttctgtcagc tgaggatcca gccgaaagag gagccaggca ctcaggccac ctgagtctac 480
tcacctggac aactggaatc tggcaccaat tctaaaccac tcagcttctc cgagctcaca 540
ccccggagat cacctgagga cccgagccat tgatggactc ggacgagacc gggttcgagc 600
actcaggact gtgggtttct gtgctggctg gtcttctgct gggagcctgc caggcacacc 660
ccatccctga ctccagtcct ctcctgcaat tcgggggcca agtccggcag cggtacctct 720
acacagatga tgcccagcag acagaagccc acctggagat cagggaggat gggacggtgg 780
ggggcgctgc tgaccagagc cccgaaagtc tcctgcagct gaaagccttg aagccgggag 840
ttattcaaat cttgggagtc aagacatcca ggttcctgtg ccagcggcca gatggggccc 900
tgtatggatc gctccacttt gaccctgagg cctgcagctt ccgggagctg cttcttgagg 960
acggatacaa tgtttaccag tccgaagccc acggcctccc gctgcacctg ccagggaaca 1020
agtccccaca ccgggaccct gcaccccgag gaccagctcg cttcctgcca ctaccaggcc 1080
tgccccccgc actcccggag ccacccggaa tcctggcccc ccagcccccc gatgtgggct 1140
cctcggaccc tctgagcatg gtgggacctt cccagggccg aagccccagc tacgcttcct 1200
gaagccagag gctgtttact atgacatctc ctctttattt attaggttat ttatcttatt 1260
tattttttta tttttcttac ttgagataat aaagagttcc agaggaggat aaaaaaaaaa 1320
aaaaaaaaaa aaa 1333
<210> 60
<211> 209
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 60
Met Asp Ser Asp Glu Thr Gly Phe Glu His Ser Gly Leu Trp Val Ser
1 5 10 15
Val Leu Ala Gly Leu Leu Leu Gly Ala Cys Gln Ala His Pro Ile Pro
20 25 30
Asp Ser Ser Pro Leu Leu Gln Phe Gly Gly Gln Val Arg Gln Arg Tyr
35 40 45
Leu Tyr Thr Asp Asp Ala Gln Gln Thr Glu Ala His Leu Glu Ile Arg
50 55 60
Glu Asp Gly Thr Val Gly Gly Ala Ala Asp Gln Ser Pro Glu Ser Leu
65 70 75 80
Leu Gln Leu Lys Ala Leu Lys Pro Gly Val Ile Gln Ile Leu Gly Val
85 90 95
Lys Thr Ser Arg Phe Leu Cys Gln Arg Pro Asp Gly Ala Leu Tyr Gly
100 105 110
Ser Leu His Phe Asp Pro Glu Ala Cys Ser Phe Arg Glu Leu Leu Leu
115 120 125
Glu Asp Gly Tyr Asn Val Tyr Gln Ser Glu Ala His Gly Leu Pro Leu
130 135 140
His Leu Pro Gly Asn Lys Ser Pro His Arg Asp Pro Ala Pro Arg Gly
145 150 155 160
Pro Ala Arg Phe Leu Pro Leu Pro Gly Leu Pro Pro Ala Leu Pro Glu
165 170 175
Pro Pro Gly Ile Leu Ala Pro Gln Pro Pro Asp Val Gly Ser Ser Asp
180 185 190
Pro Leu Ser Met Val Gly Pro Ser Gln Gly Arg Ser Pro Ser Tyr Ala
195 200 205
Ser
<210> 61
<211> 1000
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 61
agagcaaggg aaaggaactt cctccacctt cggggctgga gcccttttcc tctgcatctc 60
cagtctctga gtgaagatgg ggggcctgac agcctcggac gtacacccga ccctgggggt 120
ccagctcttc tcagctggaa tagcggcgtg cttggcggac gtgatcacct tcccgctgga 180
cacggccaaa gtccggctcc aggtccaagg tgaatgcccg acgtccagtg ttattaggta 240
taaaggtgtc ctgggaacaa tcaccgctgt ggtaaaaaca gaagggcgga tgaaactcta 300
cagcgggctg cctgcggggc ttcagcggca aatcagctcc gcctctctca ggatcggcct 360
ctacgacacg gtccaggagt tcctcaccgc agggaaagaa acagcaccta gtttaggaag 420
caagatttta gctggtctaa cgactggagg agtggcagta ttcattgggc aacccacaga 480
ggtcgtgaaa gtcagacttc aagcacagag ccatctccac ggaatcaaac ctcgctacac 540
ggggacttat aatgcgtaca gaataatagc aacaaccgaa ggcttgacgg gtctttggaa 600
agggactact cccaatctga tgagaagtgt catcatcaat tgtacagagc tagtaacata 660
tgatctaatg aaggaggcct ttgtgaaaaa caacatatta gcagatgacg tcccctgcca 720
cttggtgtcg gctcttatcg ctggattttg cgcaacagct atgtcctccc cggtggatgt 780
agtaaaaacc agatttatta attctccacc aggacagtac aaaagtgtgc ccaactgtgc 840
aatgaaagtg ttcactaacg aaggaccaac ggctttcttc aaggggttgg taccttcctt 900
cttgcgactt ggatcctgga acgtcattat gtttgtgtgc tttgaacaac tgaaacgaga 960
actgtcaaag tcaaggcaga ctatggactg tgccacataa 1000
<210> 62
<211> 307
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 62
Met Gly Gly Leu Thr Ala Ser Asp Val His Pro Thr Leu Gly Val Gln
1 5 10 15
Leu Phe Ser Ala Gly Ile Ala Ala Cys Leu Ala Asp Val Ile Thr Phe
20 25 30
Pro Leu Asp Thr Ala Lys Val Arg Leu Gln Val Gln Gly Glu Cys Pro
35 40 45
Thr Ser Ser Val Ile Arg Tyr Lys Gly Val Leu Gly Thr Ile Thr Ala
50 55 60
Val Val Lys Thr Glu Gly Arg Met Lys Leu Tyr Ser Gly Leu Pro Ala
65 70 75 80
Gly Leu Gln Arg Gln Ile Ser Ser Ala Ser Leu Arg Ile Gly Leu Tyr
85 90 95
Asp Thr Val Gln Glu Phe Leu Thr Ala Gly Lys Glu Thr Ala Pro Ser
100 105 110
Leu Gly Ser Lys Ile Leu Ala Gly Leu Thr Thr Gly Gly Val Ala Val
115 120 125
Phe Ile Gly Gln Pro Thr Glu Val Val Lys Val Arg Leu Gln Ala Gln
130 135 140
Ser His Leu His Gly Ile Lys Pro Arg Tyr Thr Gly Thr Tyr Asn Ala
145 150 155 160
Tyr Arg Ile Ile Ala Thr Thr Glu Gly Leu Thr Gly Leu Trp Lys Gly
165 170 175
Thr Thr Pro Asn Leu Met Arg Ser Val Ile Ile Asn Cys Thr Glu Leu
180 185 190
Val Thr Tyr Asp Leu Met Lys Glu Ala Phe Val Lys Asn Asn Ile Leu
195 200 205
Ala Asp Asp Val Pro Cys His Leu Val Ser Ala Leu Ile Ala Gly Phe
210 215 220
Cys Ala Thr Ala Met Ser Ser Pro Val Asp Val Val Lys Thr Arg Phe
225 230 235 240
Ile Asn Ser Pro Pro Gly Gln Tyr Lys Ser Val Pro Asn Cys Ala Met
245 250 255
Lys Val Phe Thr Asn Glu Gly Pro Thr Ala Phe Phe Lys Gly Leu Val
260 265 270
Pro Ser Phe Leu Arg Leu Gly Ser Trp Asn Val Ile Met Phe Val Cys
275 280 285
Phe Glu Gln Leu Lys Arg Glu Leu Ser Lys Ser Arg Gln Thr Met Asp
290 295 300
Cys Ala Thr
305
<210> 63
<211> 1766
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 63
agggcgcagc aggccaaggg ggaggtgcga gcgtggacct gggacgggtc tgggcggctc 60
tcggtggttg gcacgggttc gcacacccat tcaagcggca ggacgcactt gtcttagcag 120
ttctcgctga ccgcgctagc tgcggcttct acgctccggc actctgagtt catcagcaaa 180
cgccctggcg tctgtcctca ccatgcctag cctttgggac cgcttctcgt cgtcgtccac 240
ctcctcttcg ccctcgtcct tgccccgaac tcccacccca gatcggccgc cgcgctcagc 300
ctgggggtcg gcgacccggg aggaggggtt tgaccgctcc acgagcctgg agagctcgga 360
ctgcgagtcc ctggacagca gcaacagtgg cttcgggccg gaggaagaca cggcttacct 420
ggatggggtg tcgttgcccg acttcgagct gctcagtgac cctgaggatg aacacttgtg 480
tgccaacctg atgcagctgc tgcaggagag cctggcccag gcgcggctgg gctctcgacg 540
ccctgcgcgc ctgctgatgc ctagccagtt ggtaagccag gtgggcaaag aactactgcg 600
cctggcctac agcgagccgt gcggcctgcg gggggcgctg ctggacgtct gcgtggagca 660
gggcaagagc tgccacagcg tgggccagct ggcactcgac cccagcctgg tgcccacctt 720
ccagctgacc ctcgtgctgc gcctggactc acgactctgg cccaagatcc aggggctgtt 780
tagctccgcc aactctccct tcctccctgg cttcagccag tccctgacgc tgagcactgg 840
cttccgagtc atcaagaaga agctgtacag ctcggaacag ctgctcattg aggagtgttg 900
aacttcaacc tgagggggcc gacagtgccc tccaagacag agacgactga acttttgggg 960
tggagactag aggcaggagc tgagggactg attcctgtgg ttggaaaact gaggcagcca 1020
cctaaggtgg aggtggggga atagtgtttc ccaggaagct cattgagttg tgtgcgggtg 1080
gctgtgcatt ggggacacat acccctcagt actgtagcat gaaacaaagg cttaggggcc 1140
aacaaggctt ccagctggat gtgtgtgtag catgtacctt attatttttg ttactgacag 1200
ttaacagtgg tgtgacatcc agagagcagc tgggctgctc ccgccccagc ccggcccagg 1260
gtgaaggaag aggcacgtgc tcctcagagc agccggaggg aggggggagg tcggaggtcg 1320
tggaggtggt ttgtgtatct tactggtctg aagggaccaa gtgtgtttgt tgtttgtttt 1380
gtatcttgtt tttctgatcg gagcatcact actgacctgt tgtaggcagc tatcttacag 1440
acgcatgaat gtaagagtag gaaggggtgg gtgtcaggga tcacttggga tctttgacac 1500
ttgaaaaatt acacctggca gctgcgttta agccttcccc catcgtgtac tgcagagttg 1560
agctggcagg ggaggggctg agagggtggg ggctggaacc cctccccggg aggagtgcca 1620
tctgggtctt ccatctagaa ctgtttacat gaagataaga tactcactgt tcatgaatac 1680
acttgatgtt caagtattaa gacctatgca atatttttta cttttctaat aaacatgttt 1740
gttaaaacaa aaaaaaaaaa aaaaaa 1766
<210> 64
<211> 232
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 64
Met Pro Ser Leu Trp Asp Arg Phe Ser Ser Ser Ser Thr Ser Ser Ser
1 5 10 15
Pro Ser Ser Leu Pro Arg Thr Pro Thr Pro Asp Arg Pro Pro Arg Ser
20 25 30
Ala Trp Gly Ser Ala Thr Arg Glu Glu Gly Phe Asp Arg Ser Thr Ser
35 40 45
Leu Glu Ser Ser Asp Cys Glu Ser Leu Asp Ser Ser Asn Ser Gly Phe
50 55 60
Gly Pro Glu Glu Asp Thr Ala Tyr Leu Asp Gly Val Ser Leu Pro Asp
65 70 75 80
Phe Glu Leu Leu Ser Asp Pro Glu Asp Glu His Leu Cys Ala Asn Leu
85 90 95
Met Gln Leu Leu Gln Glu Ser Leu Ala Gln Ala Arg Leu Gly Ser Arg
100 105 110
Arg Pro Ala Arg Leu Leu Met Pro Ser Gln Leu Val Ser Gln Val Gly
115 120 125
Lys Glu Leu Leu Arg Leu Ala Tyr Ser Glu Pro Cys Gly Leu Arg Gly
130 135 140
Ala Leu Leu Asp Val Cys Val Glu Gln Gly Lys Ser Cys His Ser Val
145 150 155 160
Gly Gln Leu Ala Leu Asp Pro Ser Leu Val Pro Thr Phe Gln Leu Thr
165 170 175
Leu Val Leu Arg Leu Asp Ser Arg Leu Trp Pro Lys Ile Gln Gly Leu
180 185 190
Phe Ser Ser Ala Asn Ser Pro Phe Leu Pro Gly Phe Ser Gln Ser Leu
195 200 205
Thr Leu Ser Thr Gly Phe Arg Val Ile Lys Lys Lys Leu Tyr Ser Ser
210 215 220
Glu Gln Leu Leu Ile Glu Glu Cys
225 230
<210> 65
<211> 2037
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 65
aaatgacttt tctgtcttgc tcagctccag gggtcatttt ccggttagcc ttcggggtgt 60
ccgcgtgaga attggctata tcctggagcg agtgctggga ggtgctagtc cgccgcgcct 120
tattcgagag gtgtcagggc tgggagacta ggatgtcgga cacgtggagc tctatccagg 180
cccacaagaa gcagctggac tctctgcggg agaggctgca gcggaggcgg aagcaggact 240
cggggcactt ggatctacgg aatccagagg cagcattgtc tccaaccttc cgtagtgaca 300
gcccagtgcc tactgcaccc acctctggtg gccctaagcc cagcacagct tcagcagttc 360
ctgaattagc tacagatcct gagttagaga agaagttgct acaccacctc tctgatctgg 420
ccttaacatt gcccactgat gctgtgtcca tctgtcttgc catctccacg ccagatgctc 480
ctgccactca agatggggta gaaagcctcc tgcagaagtt tgcagctcag gagttgattg 540
aggtaaagcg aggtctccta caagatgatg cacatcctac tcttgtaacc tatgctgacc 600
attccaagct ctctgccatg atgggtgctg tggcagaaaa gaagggccct ggggaggtag 660
cagggactgt cacagggcag aagcggcgtg cagaacagga ctcgactaca gtagctgcct 720
ttgccagttc gttagtctct ggtctgaact cttcagcatc ggaaccagca aaggagccag 780
ccaagaaatc aaggaaacat gctgcctcag atgttgatct ggagatagag agccttctga 840
accaacagtc cactaaggaa caacagagca agaaggtcag tcaggagatc ctagagctat 900
taaatactac aacagccaag gaacaatcca ttgttgaaaa atttcgctct cgaggtcggg 960
cccaagtgca agaattctgt gactatggaa ccaaggagga gtgcatgaaa gccagtgatg 1020
ctgatcgacc ctgtcgcaag ctgcacttca gacgaattat caataaacac actgatgagt 1080
ctttaggtga ctgctctttc cttaatacat gtttccacat ggatacctgc aagtatgttc 1140
actatgaaat tgatgcttgc atggattctg aggcccctgg cagcaaagac cacacgccaa 1200
gccaggagct tgctcttaca cagagtgtcg gaggtgattc cagtgcagac cgactcttcc 1260
cacctcagtg gatctgttgt gatatccgct acctggacgt cagtatcttg ggcaagtttg 1320
cagttgtgat ggctgaccca ccctgggata ttcacatgga actgccctat gggaccctga 1380
cagatgatga gatgcgcagg ctcaacatac ccgtactaca ggatgatggc tttctcttcc 1440
tctgggtcac aggcagggcc atggagttgg ggagagaatg tctaaacctc tgggggtatg 1500
aacgggtaga tgaaattatt tgggtgaaga caaatcaact gcaacgcatc attcggacag 1560
gccgtacagg tcactggttg aaccatggga aggaacactg cttggttggt gtcaaaggaa 1620
atccccaagg cttcaaccag ggtctggatt gtgatgtgat cgtagctgag gttcgttcca 1680
ccagtcataa accagatgaa atctatggca tgattgaaag actatctcct ggcactcgca 1740
agattgagtt atttggacga ccacacaatg tgcaacccaa ctggatcacc cttggaaacc 1800
aactggatgg gatccaccta ctagacccag atgtggttgc acggttcaag caaaggtacc 1860
cagatggtat catctctaaa cctaagaatt tatagaagca cttccttaca gagctaagaa 1920
tccatagcca tggctctgta agctaaacct gaagagtgat atttgtacaa tagctttctt 1980
ctttatttaa ataaacattt gtattgtagt tgggattctg aaaaaaaaaa aaaaaaa 2037
<210> 66
<211> 580
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 66
Met Ser Asp Thr Trp Ser Ser Ile Gln Ala His Lys Lys Gln Leu Asp
1 5 10 15
Ser Leu Arg Glu Arg Leu Gln Arg Arg Arg Lys Gln Asp Ser Gly His
20 25 30
Leu Asp Leu Arg Asn Pro Glu Ala Ala Leu Ser Pro Thr Phe Arg Ser
35 40 45
Asp Ser Pro Val Pro Thr Ala Pro Thr Ser Gly Gly Pro Lys Pro Ser
50 55 60
Thr Ala Ser Ala Val Pro Glu Leu Ala Thr Asp Pro Glu Leu Glu Lys
65 70 75 80
Lys Leu Leu His His Leu Ser Asp Leu Ala Leu Thr Leu Pro Thr Asp
85 90 95
Ala Val Ser Ile Cys Leu Ala Ile Ser Thr Pro Asp Ala Pro Ala Thr
100 105 110
Gln Asp Gly Val Glu Ser Leu Leu Gln Lys Phe Ala Ala Gln Glu Leu
115 120 125
Ile Glu Val Lys Arg Gly Leu Leu Gln Asp Asp Ala His Pro Thr Leu
130 135 140
Val Thr Tyr Ala Asp His Ser Lys Leu Ser Ala Met Met Gly Ala Val
145 150 155 160
Ala Glu Lys Lys Gly Pro Gly Glu Val Ala Gly Thr Val Thr Gly Gln
165 170 175
Lys Arg Arg Ala Glu Gln Asp Ser Thr Thr Val Ala Ala Phe Ala Ser
180 185 190
Ser Leu Val Ser Gly Leu Asn Ser Ser Ala Ser Glu Pro Ala Lys Glu
195 200 205
Pro Ala Lys Lys Ser Arg Lys His Ala Ala Ser Asp Val Asp Leu Glu
210 215 220
Ile Glu Ser Leu Leu Asn Gln Gln Ser Thr Lys Glu Gln Gln Ser Lys
225 230 235 240
Lys Val Ser Gln Glu Ile Leu Glu Leu Leu Asn Thr Thr Thr Ala Lys
245 250 255
Glu Gln Ser Ile Val Glu Lys Phe Arg Ser Arg Gly Arg Ala Gln Val
260 265 270
Gln Glu Phe Cys Asp Tyr Gly Thr Lys Glu Glu Cys Met Lys Ala Ser
275 280 285
Asp Ala Asp Arg Pro Cys Arg Lys Leu His Phe Arg Arg Ile Ile Asn
290 295 300
Lys His Thr Asp Glu Ser Leu Gly Asp Cys Ser Phe Leu Asn Thr Cys
305 310 315 320
Phe His Met Asp Thr Cys Lys Tyr Val His Tyr Glu Ile Asp Ala Cys
325 330 335
Met Asp Ser Glu Ala Pro Gly Ser Lys Asp His Thr Pro Ser Gln Glu
340 345 350
Leu Ala Leu Thr Gln Ser Val Gly Gly Asp Ser Ser Ala Asp Arg Leu
355 360 365
Phe Pro Pro Gln Trp Ile Cys Cys Asp Ile Arg Tyr Leu Asp Val Ser
370 375 380
Ile Leu Gly Lys Phe Ala Val Val Met Ala Asp Pro Pro Trp Asp Ile
385 390 395 400
His Met Glu Leu Pro Tyr Gly Thr Leu Thr Asp Asp Glu Met Arg Arg
405 410 415
Leu Asn Ile Pro Val Leu Gln Asp Asp Gly Phe Leu Phe Leu Trp Val
420 425 430
Thr Gly Arg Ala Met Glu Leu Gly Arg Glu Cys Leu Asn Leu Trp Gly
435 440 445
Tyr Glu Arg Val Asp Glu Ile Ile Trp Val Lys Thr Asn Gln Leu Gln
450 455 460
Arg Ile Ile Arg Thr Gly Arg Thr Gly His Trp Leu Asn His Gly Lys
465 470 475 480
Glu His Cys Leu Val Gly Val Lys Gly Asn Pro Gln Gly Phe Asn Gln
485 490 495
Gly Leu Asp Cys Asp Val Ile Val Ala Glu Val Arg Ser Thr Ser His
500 505 510
Lys Pro Asp Glu Ile Tyr Gly Met Ile Glu Arg Leu Ser Pro Gly Thr
515 520 525
Arg Lys Ile Glu Leu Phe Gly Arg Pro His Asn Val Gln Pro Asn Trp
530 535 540
Ile Thr Leu Gly Asn Gln Leu Asp Gly Ile His Leu Leu Asp Pro Asp
545 550 555 560
Val Val Ala Arg Phe Lys Gln Arg Tyr Pro Asp Gly Ile Ile Ser Lys
565 570 575
Pro Lys Asn Leu
580
<210> 67
<211> 4162
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 67
agaagtccat tcggctcaca catttgcccc aagacaaacc acgttaaaat aacacccagg 60
gtagctgctg ccaccgtctt ctgtctctac ctccctcctg gctggccaat ggctctgtgt 120
tcctgggcct gctgctggct gtccagagta ggggttgctt agagctgtgt gcatccctgc 180
gggtggtgtg ggagtgggcg gttgtctaaa ggcaggtccc ctctactgat aaacaaggac 240
cggagataga cctagaggct gacattcttg gctcccccag cctacacccc ccccacctcg 300
atttcccaca gagccctagg gacgggtagc cagctctgtg gcatggtatc tggaggcagg 360
ccagcaacct gatgtgcatg ccacggcccg tccctctccc cactcagagc tgcagtagcc 420
tggaggttca gagagccggg ctactctgag aagaagacac caagtggatt ctgcttcccc 480
tgggacagca ctgagcgagt gtggagagag gtacagccct cggcctacaa gctctttagt 540
cttgaaagcg ccacaagcag cagctgctga gccatggctg aaggggaaat caccaccttc 600
acagccctga ccgagaagtt taatctgcct ccagggaatt acaagaagcc caaactcctc 660
tactgtagca acgggggcca cttcctgagg atccttccgg atggcacagt ggatgggaca 720
agggacagga gcgaccagca cattcagctg cagctcagtg cggaaagcgt gggggaggtg 780
tatataaaga gtaccgagac tggccagtac ttggccatgg acaccgacgg gcttttatac 840
ggctcacaga caccaaatga ggaatgtttg ttcctggaaa ggctggagga gaaccattac 900
aacacctata tatccaagaa gcatgcagag aagaattggt ttgttggcct caagaagaat 960
gggagctgca aacgcggtcc tcggactcac tatggccaga aagcaatctt gtttctcccc 1020
ctgccagtct cttctgatta aagagatctg ttctgggtgt tgaccactcc agagaagttt 1080
cgaggggtcc tcacctggtt gacccaaaaa tgttcccttg accattggct gcgctaaccc 1140
ccagcccaca gagcctgaat ttgtaagcaa cttgcttcta aatgcccagt tcacttcttt 1200
gcagagcctt ttacccctgc acagtttaga acagagggac caaattgctt ctaggagtca 1260
actggctggc cagtctgggt ctgggtttgg atctccaatt gcctcttgca ggctgagtcc 1320
ctccatgcaa aagtggggct aaatgaagtg tgttaagggg tcggctaagt gggacattag 1380
taactgcaca ctatttccct ctactgagta aaccctatct gtgattcccc caaacatctg 1440
gcatggctcc cttttgtcct tcctgtgccc tgcaaatatt agcaaagaag cttcatgcca 1500
ggttaggaag gcagcattcc atgaccagaa acagggacaa agaaatcccc ccttcagaac 1560
agaggcattt aaaatggaaa agagagattg gattttggtg ggtaacttag aaggatggca 1620
tctccatgta gaataaatga agaaagggag gcccagccgc aggaaggcag aataaatcct 1680
tgggagtcat taccacgcct tgaccttccc aaggttactc agcagcagag agccctgggt 1740
gacttcaggt ggagagcact agaagtggtt tcctgataac aagcaaggat atcagagctg 1800
ggaaattcat gtggatctgg ggactgagtg tgggagtgca gagaaagaaa gggaaactgg 1860
ctgaggggat accataaaaa gaggatgatt tcagaaggag aaggaaaaag aaagtaatgc 1920
cacacattgt gcttggcccc tggtaagcag aggctttggg gtcctagccc agtgcttctc 1980
caacactgaa gtgcttgcag atcatctggg gacctggttt gaatggagat tctgattcag 2040
tgggttgggg gcagagtttc tgcagttcca tcaggtcccc cccaggtgca ggtgctgaca 2100
atactgctgc cttacccgcc atacattaag gagcagggtc ctggtcctaa agagttattc 2160
aaatgaaggt ggttcgacgc cccgaacctc acctgacctc aactaaccct taaaaatgca 2220
cacctcatga gtctacctga gcattcaggc agcactgaca atagttatgc ctgtactaag 2280
gagcatgatt ttaagaggct ttggcccaat gcctataaaa tgcccatttc gaagatatac 2340
aaaaacatac ttcaaaaatg ttaaaccctt accaacagct tttcccagga gaccatttgt 2400
attaccatta cttgtataaa tacacttcct gcttaaactt gacccaggtg gctagcaaat 2460
tagaaacacc attcatctct aacatatgat actgatgcca tgtaaaggcc tttaataagt 2520
cattgaaatt tactgtgaga ctgtatgttt taattgcatt taaaaatata tagcttgaaa 2580
gcagttaaac tgattagtat tcaggcactg agaatgatag taataggata caatgtataa 2640
gctactcact tatctgatac ttatttacct ataaaatgag atttttgttt tccactgtgc 2700
tattacaaat tttcttttga aagtaggaac tcttaagcaa tggtaattgt gaataaaaat 2760
tgatgagagt gttagctcct gtttcatatg aaattgaagt aattgttaac taaaaacaat 2820
tccttagtaa ctgaactgtc atatttagaa tggaaggaaa atgacagttt gtgaaagttc 2880
aaagcaatag tgcaattgaa gaattgacct aagtaagctg acattatggt taataatagt 2940
attttagatt tgtgcagcaa aataatttca taactttttt gtttttgtta cttggataag 3000
atcaatctgt tttattttag taaatctttg caggcaagtt agagaaaatg cagtgtggct 3060
taacgtctct ttagtatgaa gatttggcca gaaaaagata cccagagagg aaatctaaga 3120
taattataat ggtccatact ttttattgta tgaatcaaac tcaagcataa cattggccaa 3180
ggaaaattaa ataccattgc taacttgtga aatggaagtc tgtgatttcg gagatgcaaa 3240
gcattgtagt aaaaacacca atgtgacctc gaccatctca gcccagatat cattcatata 3300
tctgttcaat gactattaag gtgcctactg tgtgctaggc actgtactgg atactgggga 3360
ccttgtctgt ctggtttgct gctgtatctt ctcccagggc attatattta tgatgaaaga 3420
tgctgtggat tcaattcttt cagtcaagaa taaacacaga ctttgtaggt tcctgctgaa 3480
taaagcaaat cccagaaacc cagattttgg aagaatcagc aaccccagca taaaataaac 3540
ccctatcaaa atgtcagagg acatggcaag gtaaacttag cattttcaac tttagaaccg 3600
ggtcagcttc agggggactg ctttcaaatc agccaaagag cctgtcagat cttcttagaa 3660
ggaagaggtt ggtagttccc tgctctgttt tgaacatgct ctagtttatt aacctgggga 3720
cattcccatt gctgtcttaa gtaagtctca tagccagctc ctgtcacgtg actctcatat 3780
ggattcattt tcgggccagc tctgaacaaa gcatcatgaa catatgtgct tttggtcgtt 3840
tgcaatgtga tggtggtgga ggtaggtatt ggtttccttg gaaggcatga taagaaagat 3900
tcacaatggc caacagtgtg tatgaacaaa aaactgattg gagcatcagc tagtactgaa 3960
ggtccttgct ttgtgtcaga ggcaaaggaa cccaaggcgc caagtcctca gccttgagtg 4020
tactgctgac aactaaactc acaggctgca aagcagacct ctgatgaaga tgcctgttat 4080
ttcacatcac tgtctttttg tgtatcatag tctgcacctt acaaatatta ataaatgttc 4140
caataatagg tgaaaaaaaa aa 4162
<210> 68
<211> 155
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 68
Met Ala Glu Gly Glu Ile Thr Thr Phe Thr Ala Leu Thr Glu Lys Phe
1 5 10 15
Asn Leu Pro Pro Gly Asn Tyr Lys Lys Pro Lys Leu Leu Tyr Cys Ser
20 25 30
Asn Gly Gly His Phe Leu Arg Ile Leu Pro Asp Gly Thr Val Asp Gly
35 40 45
Thr Arg Asp Arg Ser Asp Gln His Ile Gln Leu Gln Leu Ser Ala Glu
50 55 60
Ser Val Gly Glu Val Tyr Ile Lys Ser Thr Glu Thr Gly Gln Tyr Leu
65 70 75 80
Ala Met Asp Thr Asp Gly Leu Leu Tyr Gly Ser Gln Thr Pro Asn Glu
85 90 95
Glu Cys Leu Phe Leu Glu Arg Leu Glu Glu Asn His Tyr Asn Thr Tyr
100 105 110
Ile Ser Lys Lys His Ala Glu Lys Asn Trp Phe Val Gly Leu Lys Lys
115 120 125
Asn Gly Ser Cys Lys Arg Gly Pro Arg Thr His Tyr Gly Gln Lys Ala
130 135 140
Ile Leu Phe Leu Pro Leu Pro Val Ser Ser Asp
145 150 155
<210> 69
<211> 4833
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 69
cccggcttta tatctatata tacacaggta tatgtgtata ttttatataa ttgttctccg 60
ttcgttgata tcaaagacag ttgaaggaaa tgaattttga aacttcacgg tgtgccaccc 120
tacagtactg ccctgaccct tacatccagc gtttcgtaga aaccccagct catttctctt 180
ggaaagaaag ttattaccga tccaccatgt cccagagcac acagacaaat gaattcctca 240
gtccagaggt tttccagcat atctgggatt ttctggaaca gcctatatgt tcagttcagc 300
ccattgactt gaactttgtg gatgaaccat cagaagatgg tgcgacaaac aagattgaga 360
ttagcatgga ctgtatccgc atgcaggact cggacctgag tgaccccatg tggccacagt 420
acacgaacct ggggctcctg aacagcatgg accagcagat tcagaacggc tcctcgtcca 480
ccagtcccta taacacagac cacgcgcaga acagcgtcac ggcgccctcg ccctacgcac 540
agcccagctc caccttcgat gctctctctc catcacccgc catcccctcc aacaccgact 600
acccaggccc gcacagtttc gacgtgtcct tccagcagtc gagcaccgcc aagtcggcca 660
cctggacgta ttccactgaa ctgaagaaac tctactgcca aattgcaaag acatgcccca 720
tccagatcaa ggtgatgacc ccacctcctc agggagctgt tatccgcgcc atgcctgtct 780
acaaaaaagc tgagcacgtc acggaggtgg tgaagcggtg ccccaaccat gagctgagcc 840
gtgaattcaa cgagggacag attgcccctc ctagtcattt gattcgagta gaggggaaca 900
gccatgccca gtatgtagaa gatcccatca caggaagaca gagtgtgctg gtaccttatg 960
agccacccca ggttggcact gaattcacga cagtcttgta caatttcatg tgtaacagca 1020
gttgtgttgg agggatgaac cgccgtccaa ttttaatcat tgttactctg gaaaccagag 1080
atgggcaagt cctgggccga cgctgctttg aggcccggat ctgtgcttgc ccaggaagag 1140
acaggaaggc ggatgaagat agcatcagaa agcagcaagt ttcggacagt acaaagaacg 1200
gtgatggtac gaagcgcccg tttcgtcaga acacacatgg tatccagatg acatccatca 1260
agaaacgaag atccccagat gatgaactgt tatacttacc agtgaggggc cgtgagactt 1320
atgaaatgct gttgaagatc aaagagtccc tggaactcat gcagtacctt cctcagcaca 1380
caattgaaac gtacaggcaa cagcaacagc agcagcacca gcacttactt cagaaacaga 1440
cctcaataca gtctccatct tcatatggta acagctcccc acctctgaac aaaatgaaca 1500
gcatgaacaa gctgccttct gtgagccagc ttatcaaccc tcagcagcgc aacgccctca 1560
ctcctacaac cattcctgat ggcatgggag ccaacattcc catgatgggc acccacatgc 1620
caatggctgg agacatgaat ggactcagcc ccacccaggc actccctccc ccactctcca 1680
tgccatccac ctcccactgc acacccccac ctccgtatcc cacagattgc agcattgtca 1740
ggatctggca agtctgaaaa tccctgagca atttcgacat gcgatctgga agggcatcct 1800
ggaccaccgg cagctccacg aattctcctc cccttctcat ctcctgcgga ccccaagcag 1860
tgcctctaca gtcagtgtgg gctccagtga gacccggggt gagcgtgtta ttgatgctgt 1920
gcgattcacc ctccgccaga ccatctcttt cccaccccga gatgagtgga atgacttcaa 1980
ctttgacatg gatgctcgcc gcaataagca acagcgcatc aaagaggagg gggagtgagc 2040
ctcaccatgt gagctcttcc tatccctctc ctaactgcca gccccctaaa agcactcctg 2100
cttaatcttc aaagccttct ccctagctcc tccccttcct cttgtctgat ttcttagggg 2160
aaggagaagt aagaggctac ctcttaccta acatctgacc tggcatctaa ttctgattct 2220
ggctttaagc cttcaaaact atagcttgca gaactgtagc tgccatggct aggtagaagt 2280
gagcaaaaaa gagttgggtg tctccttaag ctgcagagat ttctcattga cttttataaa 2340
gcatgttcac ccttatagtc taagactata tatataaatg tataaatata cagtatagat 2400
ttttgggtgg ggggcattga gtattgttta aaatgtaatt taaatgaaag aaaattgagt 2460
tgcacttatt gaccattttt taatttactt gttttggatg gcttgtctat actccttccc 2520
ttaaggggta tcatgtatgg tgataggtat ctagagctta atgctacatg tgagtgacga 2580
tgatgtacag attctttcag ttctttggat tctaaataca tgccacatca aacctttgag 2640
tagatccatt tccattgctt attatgtagg taagactgta gatatgtatt cttttctcag 2700
tgttggtata ttttatatta ctgacatttc ttctagtgat gatggttcac gttggggtga 2760
tttaatccag ttataagaag aagttcatgt ccaaacgtcc tctttagttt ttggttggga 2820
atgaggaaaa ttcttaaaag gcccatagca gccagttcaa aaacacccga cgtcatgtat 2880
ttgagcatat cagtaacccc cttaaattta ataccagata ccttatctta caatattgat 2940
tgggaaaaca tttgctgcca ttacagaggt attaaaacta aatttcacta ctagattgac 3000
taactcaaat acacatttgc tactgttgta agaattctga ttgatttgat tgggatgaat 3060
gccatctatc tagttctaac agtgaagttt tactgtctat taatattcag ggtaaatagg 3120
aatcattcag aaatgttgag tctgtactaa acagtaagat atctcaatga accataaatt 3180
caactttgta aaaatctttt gaagcataga taatattgtt tggtaaatgt ttcttttgtt 3240
tggtaaatgt ttcttttaaa gaccctccta ttctataaaa ctctgcatgt agaggcttgt 3300
ttacctttct ctctctaagg tttacaatag gagtggtgat ttgaaaaata taaaattatg 3360
agattggttt tcctgtggca taaattgcat cactgtatca ttttcttttt taaccggtaa 3420
gagtttcagt ttgttggaaa gtaactgtga gaacccagtt tcccgtccat ctcccttagg 3480
gactacccat agacatgaaa ggtccccaca gagcaagaga taagtctttc atggctgctg 3540
ttgcttaaac cacttaaacg aagagttccc ttgaaacttt gggaaaacat gttaatgaca 3600
atattccaga tctttcagaa atataacaca tttttttgca tgcatgcaaa tgagctctga 3660
aatcttccca tgcattctgg tcaagggctg tcattgcaca taagcttcca ttttaatttt 3720
aaagtgcaaa agggccagcg tggctctaaa aggtaatgtg tggattgcct ctgaaaagtg 3780
tgtatatatt ttgtgtgaaa ttgcatactt tgtattttga ttattttttt tttcttcttg 3840
ggatagtggg atttccagaa ccacacttga aacctttttt tatcgttttt gtattttcat 3900
gaaaatacca tttagtaaga ataccacatc aaataagaaa taatgctaca attttaagag 3960
gggagggaag ggaaagtttt tttttattat ttttttaaaa ttttgtatgt taaagagaat 4020
gagtccttga tttcaaagtt ttgttgtact taaatggtaa taagcactgt aaacttctgc 4080
aacaagcatg cagctttgca aacccattaa ggggaagaat gaaagctgtt ccttggtcct 4140
agtaagaaga caaactgctt cccttacttt gctgagggtt tgaataaacc taggacttcc 4200
gagctatgtc agtactattc aggtaacact agggccttgg aaattcctgt actgtgtctc 4260
atggatttgg cactagccaa agcgaggcac ccttactggc ttacctcctc atggcagcct 4320
actctccttg agtgtatgag tagccagggt aaggggtaaa aggatagtaa gcatagaaac 4380
cactagaaag tgggcttaat ggagttcttg tggcctcagc tcaatgcagt tagctgaaga 4440
attgaaaagt ttttgtttgg agacgtttat aaacagaaat ggaaagcaga gttttcatta 4500
aatcctttta cctttttttt ttcttggtaa tcccctaaaa taacagtatg tgggatattg 4560
aatgttaaag ggatattttt ttctattatt tttataattg tacaaaatta agcaaatgtt 4620
aaaagtttta tatgctttat taatgttttc aaaaggtatt atacatgtga tacatttttt 4680
aagcttcagt tgcttgtctt ctggtacttt ctgttatggg cttttgggga gccagaagcc 4740
aatctacaat ctctttttgt ttgccaggac atgcaataaa atttaaaaaa taaataaaaa 4800
ctaattaaga aattgaaaaa aaaaaaaaaa aaa 4833
<210> 70
<211> 555
<212> PRT
<213> 人工序列
<220>
<223> 合成聚合物
<400> 70
Met Asn Phe Glu Thr Ser Arg Cys Ala Thr Leu Gln Tyr Cys Pro Asp
1 5 10 15
Pro Tyr Ile Gln Arg Phe Val Glu Thr Pro Ala His Phe Ser Trp Lys
20 25 30
Glu Ser Tyr Tyr Arg Ser Thr Met Ser Gln Ser Thr Gln Thr Asn Glu
35 40 45
Phe Leu Ser Pro Glu Val Phe Gln His Ile Trp Asp Phe Leu Glu Gln
50 55 60
Pro Ile Cys Ser Val Gln Pro Ile Asp Leu Asn Phe Val Asp Glu Pro
65 70 75 80
Ser Glu Asp Gly Ala Thr Asn Lys Ile Glu Ile Ser Met Asp Cys Ile
85 90 95
Arg Met Gln Asp Ser Asp Leu Ser Asp Pro Met Trp Pro Gln Tyr Thr
100 105 110
Asn Leu Gly Leu Leu Asn Ser Met Asp Gln Gln Ile Gln Asn Gly Ser
115 120 125
Ser Ser Thr Ser Pro Tyr Asn Thr Asp His Ala Gln Asn Ser Val Thr
130 135 140
Ala Pro Ser Pro Tyr Ala Gln Pro Ser Ser Thr Phe Asp Ala Leu Ser
145 150 155 160
Pro Ser Pro Ala Ile Pro Ser Asn Thr Asp Tyr Pro Gly Pro His Ser
165 170 175
Phe Asp Val Ser Phe Gln Gln Ser Ser Thr Ala Lys Ser Ala Thr Trp
180 185 190
Thr Tyr Ser Thr Glu Leu Lys Lys Leu Tyr Cys Gln Ile Ala Lys Thr
195 200 205
Cys Pro Ile Gln Ile Lys Val Met Thr Pro Pro Pro Gln Gly Ala Val
210 215 220
Ile Arg Ala Met Pro Val Tyr Lys Lys Ala Glu His Val Thr Glu Val
225 230 235 240
Val Lys Arg Cys Pro Asn His Glu Leu Ser Arg Glu Phe Asn Glu Gly
245 250 255
Gln Ile Ala Pro Pro Ser His Leu Ile Arg Val Glu Gly Asn Ser His
260 265 270
Ala Gln Tyr Val Glu Asp Pro Ile Thr Gly Arg Gln Ser Val Leu Val
275 280 285
Pro Tyr Glu Pro Pro Gln Val Gly Thr Glu Phe Thr Thr Val Leu Tyr
290 295 300
Asn Phe Met Cys Asn Ser Ser Cys Val Gly Gly Met Asn Arg Arg Pro
305 310 315 320
Ile Leu Ile Ile Val Thr Leu Glu Thr Arg Asp Gly Gln Val Leu Gly
325 330 335
Arg Arg Cys Phe Glu Ala Arg Ile Cys Ala Cys Pro Gly Arg Asp Arg
340 345 350
Lys Ala Asp Glu Asp Ser Ile Arg Lys Gln Gln Val Ser Asp Ser Thr
355 360 365
Lys Asn Gly Asp Gly Thr Lys Arg Pro Phe Arg Gln Asn Thr His Gly
370 375 380
Ile Gln Met Thr Ser Ile Lys Lys Arg Arg Ser Pro Asp Asp Glu Leu
385 390 395 400
Leu Tyr Leu Pro Val Arg Gly Arg Glu Thr Tyr Glu Met Leu Leu Lys
405 410 415
Ile Lys Glu Ser Leu Glu Leu Met Gln Tyr Leu Pro Gln His Thr Ile
420 425 430
Glu Thr Tyr Arg Gln Gln Gln Gln Gln Gln His Gln His Leu Leu Gln
435 440 445
Lys Gln Thr Ser Ile Gln Ser Pro Ser Ser Tyr Gly Asn Ser Ser Pro
450 455 460
Pro Leu Asn Lys Met Asn Ser Met Asn Lys Leu Pro Ser Val Ser Gln
465 470 475 480
Leu Ile Asn Pro Gln Gln Arg Asn Ala Leu Thr Pro Thr Thr Ile Pro
485 490 495
Asp Gly Met Gly Ala Asn Ile Pro Met Met Gly Thr His Met Pro Met
500 505 510
Ala Gly Asp Met Asn Gly Leu Ser Pro Thr Gln Ala Leu Pro Pro Pro
515 520 525
Leu Ser Met Pro Ser Thr Ser His Cys Thr Pro Pro Pro Pro Tyr Pro
530 535 540
Thr Asp Cys Ser Ile Val Arg Ile Trp Gln Val
545 550 555
<210> 71
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 71
tcttcaactg gcagct 16
<210> 72
<400> 72
000
<210> 73
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 73
cttcaactgg cagct 15
<210> 74
<211> 15
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 74
cttcaactgg cagct 15
<210> 75
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 75
tcttcaactg gcagct 16
<210> 76
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 76
tcttcaactg gcagct 16
<210> 77
<211> 17
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 77
ttcttcaact ggcagct 17
<210> 78
<211> 18
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 78
gttcttcaac tggcagct 18
<210> 79
<211> 22
<212> RNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 79
ugucaagaag uugaccgucg aa 22
<210> 80
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 80
gatacggaag gagggt 16
<210> 81
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 81
cacaatcgga caggct 16
<210> 82
<211> 16
<212> DNA
<213> 人工序列
<220>
<223> 合成聚合物
<400> 82
cgaatagtta gtagcg 16

Claims (34)

1.一种治疗或预防代谢失调的方法，所述方法包括施用有效量的miR-22的抑制剂给有此需要的受试者。
2.如权利要求1所述的方法，其中在施用所述抑制剂后，所述受试者中miR-22的表达和/或活性降低。
3.如权利要求1或2所述的方法，其中所述miR-22的抑制剂是基于寡核苷酸的抑制剂。
4.如权利要求3所述的方法，其中所述基于寡核苷酸的抑制剂包含与miR-22的成熟序列至少约75％、约80％、约85％、约90％、约95％、约96％、约97％、约98％、约99％或约100％互补的序列。
5.如权利要求3或4所述的方法，其中所述基于寡核苷酸的抑制剂包括脱氧核苷酸或核糖核苷酸。
6.如权利要求3至5任一项所述的方法，其中所述基于寡核苷酸的抑制剂是单链的。
7.如权利要求3至5任一项所述的方法，其中所述基于寡核苷酸的抑制剂是双链的。
8.如权利要求3至7任一项所述的方法，其中所述基于寡核苷酸的抑制剂包含一个或多个化学修饰的核苷酸。
9.如权利要求8所述的方法，其中所述化学修饰的核苷酸是锁核苷酸(LNA)。
10.如权利要求3至9任一项所述的方法，其中所述基于寡核苷酸的抑制剂包含约25个、约20个、约15个、约10个、约9个、约8个、约7个、约6个或约5个或更少的核苷酸。
11.如权利要求3至10任一项所述的方法，其中所述基于寡核苷酸的抑制剂与一个或多个N-乙酰半乳糖胺(GalNAc)部分结合。
12.如权利要求3至11任一项所述的方法，其中所述基于寡核苷酸的抑制剂是反义寡核苷酸抑制剂。
13.如权利要求3至11任一项所述的方法，其中所述基于寡核苷酸的抑制剂是小分子干扰RNA(siRNA)。
14.如权利要求3至11任一项所述的方法，其中所述基于寡核苷酸的抑制剂是适体。
15.如权利要求1或2所述的方法，其中所述miR-22的抑制剂是基于肽或基于蛋白的抑制剂。
16.如权利要求15所述的方法，其中所述基于蛋白的抑制剂是抗体或其抗原结合部分。
17.如权利要求1或2所述的方法，其中所述miR-22的抑制剂是基于小分子的抑制剂。
18.如上述权利要求任一项所述的方法，其中所述代谢失调是肥胖。
19.如权利要求18所述的方法，其中所述受试者患有普拉德-威利综合征。
20.如权利要求18所述的方法，其中所述受试者患有高胆固醇血症。
21.如权利要求18所述的方法，其中所述受试者具有脂肪量和肥胖相关蛋白(FTO)变体和/或显示FTO表达和/或活性的上调。
22.如权利要求18至21任一项所述的方法，其中所述受试者是肥胖的并且具有大于约30的体重指数。
23.如权利要求18至21任一项所述的方法，其中所述受试者是超重的并且具有约25-29.9的体重指数。
24.如权利要求18至23任一项所述的方法，其中所述方法引起体重减轻。
25.如权利要求24所述的方法，其中所述方法在所述受试者中引起约1％、约5％、约10％、约15％、约20％或约25％或更多的总体重减轻。
26.如权利要求18至23任一项所述的方法，其中所述方法防止体重增加。
27.如权利要求18至26任一项所述的方法，其中所述方法减少或预防脂肪组织生长。
28.如权利要求18至26任一项所述的方法，其中所述方法破坏脂肪细胞分化。
29.如上述权利要求任一项所述的方法，其中所述代谢失调是脂肪肝疾病。
30.如权利要求29所述的方法，其中所述脂肪肝疾病选自非酒精性脂肪酸肝病(NAFLD)或非酒精性脂肪性肝炎(NASH)。
31.如权利要求29或30所述的方法，其中所述方法减少或预防肝脂肪变性。
32.如权利要求29至31任一项所述的方法，其中所述方法减少或预防肝纤维化。
33.如权利要求1至32任一项所述的方法，其中所述方法降低下列的活性和/或表达：脂肪量和肥胖相关蛋白(FTO)、ALKB同源物5(ALKBH5)、CCAAT/增强子结合蛋白α(CEBPα)、过氧化物酶体增殖物激活受体γ(PPARγ)、过氧化物酶体增殖物激活受体α(PPARa)、ATP柠檬酸裂解酶(ACLY)、PPARγ共激活因子-α(PGC1-α)、特异性蛋白1(SP1)、成纤维细胞生长因子21(FGF-21)、解偶联蛋白1(UCP1)、DNA损伤诱导转录物4(DDIT-4，REDD1)、肿瘤蛋白p63(TP63)、成纤维细胞生长因子1(FGF1)和/或甲基转移酶样蛋白3(METTL3)。
34.如权利要求1至33任一项所述的方法，其中所述方法提高磷酸酶和张力蛋白同源蛋白(PTEN)和/或tet甲基胞嘧啶双加氧酶2(TET2)的活性和/或表达。
CN201980032204.4A 2018-03-14 2019-03-14 micro-RNA和肥胖 Pending CN112119159A (zh)

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Cited By (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115029347A (zh) * 2022-05-11 2022-09-09 珠海中科先进技术研究院有限公司 识别和调控肝肾细胞纤维化的分子监测序列、重组质粒、抑制病毒
CN117186178A (zh) * 2022-09-09 2023-12-08 湖南大学 一种多肽及其制备方法
CN117304258A (zh) * 2022-09-09 2023-12-29 湖南大学 一种多肽的用途

Families Citing this family (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
JP7318166B2 (ja) 2018-03-14 2023-08-01 ベス イスラエル デアコネス メディカル センター マイクロｒｎａ２２の阻害剤
CN110609142A (zh) * 2019-10-09 2019-12-24 广州医科大学附属第二医院 一种检测外周血fto蛋白与自身调控元件结合能力的方法与应用
EP4353823A1 (en) * 2022-10-12 2024-04-17 Resalis Therapeutics S.r.l. Inhibitors of micro-rna 22

Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104027818A (zh) * 2005-12-12 2014-09-10 北卡罗来纳大学查珀尔希尔分校 调节肌细胞增殖和分化的microrna
WO2017187426A1 (en) * 2016-04-29 2017-11-02 Aptamir Therapeutics, Inc. Inhibition of mir-22 mirna by apt-110

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5981505A (en) 1993-01-26 1999-11-09 The Trustees Of The University Of Pennsylvania Compositions and methods for delivery of genetic material
US5837533A (en) 1994-09-28 1998-11-17 American Home Products Corporation Complexes comprising a nucleic acid bound to a cationic polyamine having an endosome disruption agent
US5840710A (en) 1994-12-09 1998-11-24 Genzyme Corporation Cationic amphiphiles containing ester or ether-linked lipophilic groups for intracellular delivery of therapeutic molecules
US6217900B1 (en) 1997-04-30 2001-04-17 American Home Products Corporation Vesicular complexes and methods of making and using the same
DE69834038D1 (de) 1997-07-01 2006-05-18 Isis Pharmaceutical Inc Zusammensetzungen und verfahren zur verabreichung von oligonukleotiden über die speiseröhre
RU2211223C2 (ru) 1998-05-26 2003-08-27 Ай-Си-Эн Фармасьютикалз, Инк. Новые нуклеозиды, имеющие бициклическую сахарную группировку, и содержащие их олигонуклеотиды
US6838283B2 (en) 1998-09-29 2005-01-04 Isis Pharmaceuticals Inc. Antisense modulation of survivin expression
US6693187B1 (en) 2000-10-17 2004-02-17 Lievre Cornu Llc Phosphinoamidite carboxlates and analogs thereof in the synthesis of oligonucleotides having reduced internucleotide charge
US20060084617A1 (en) 2002-05-06 2006-04-20 Satishchandran C Methods for delivery of nucleic acids
EP2281889B1 (en) 2004-11-12 2014-07-30 Asuragen, Inc. Methods and compositions involving miRNA and miRNA inhibitor molecules
US20070213292A1 (en) * 2005-08-10 2007-09-13 The Rockefeller University Chemically modified oligonucleotides for use in modulating micro RNA and uses thereof
WO2007112754A2 (en) 2006-04-03 2007-10-11 Santaris Pharma A/S Pharmaceutical compositions comprising anti-mirna antisense oligonucleotides
AU2013254923A1 (en) * 2006-04-03 2013-11-28 Santaris Pharma A/S Pharmaceutical compositions comprising anti-miRNA antisense oligonucleotide
US8288356B2 (en) * 2007-10-04 2012-10-16 Santaris Pharma A/S MicroRNAs
WO2010120803A2 (en) * 2009-04-13 2010-10-21 Somagenics Inc. Methods and compositions for detection of small rnas
MA33488B1 (fr) 2009-06-08 2012-08-01 Miragen Therapeutics Motifs de modification chimique pour des inhibiteurs et mimétiques de miarn
TW201238973A (en) 2010-12-17 2012-10-01 Sanofi Sa MiRNAs in joint disease
AU2012242761A1 (en) 2011-04-12 2013-10-31 Beth Israel Deaconess Medical Center, Inc. Micro-RNA inhibitors and their uses in disease
EP2818549A4 (en) * 2012-02-23 2015-09-02 Sumitomo Bakelite Co METHOD FOR CLASSIFYING BODY FLUID SAMPLE OF TEST
US9034839B2 (en) 2012-04-20 2015-05-19 Aptamir Therapeutics, Inc. miRNA modulators of thermogenesis
WO2013181613A1 (en) 2012-05-31 2013-12-05 Research Development Foundation Mirna for the diagnosis and treatment of autoimmune and inflammatory disease
DK3354734T3 (da) * 2012-06-21 2020-06-29 Miragen Therapeutics Inc Oligonukleotid-baserede hæmmere omfattende låst nukleinsyremønster
US9822358B2 (en) 2013-10-18 2017-11-21 Beth Israel Deaconess Medical Center Treatment of cancers with micro-RNA inhibitors
EP3099797B1 (en) * 2014-01-30 2019-08-21 F. Hoffmann-La Roche AG Poly oligomer compound with biocleavable conjugates
US20180023081A1 (en) 2015-02-04 2018-01-25 Bristol-Myers Squibb Company Lna oligonucleotides with alternating flanks
EP3270984A4 (en) * 2015-03-16 2019-04-17 Duncan Ross TREATMENT METHOD WITH MEMBRANE-INCLUDED VESICLE
CN107432933A (zh) * 2017-07-13 2017-12-05 中南大学湘雅三医院 miR‑22作为靶位点在制备膀胱癌的化疗增敏治疗药物中的应用
WO2019053235A1 (en) * 2017-09-15 2019-03-21 Genfit NON-INVASIVE DIAGNOSIS OF NON ALCOHOLIC LIVER DISEASES, NON ALCOHOLIC STHEATHEPATITIS AND / OR HEPATIC FIBROSIS
JP7318166B2 (ja) 2018-03-14 2023-08-01 ベス イスラエル デアコネス メディカル センター マイクロｒｎａ２２の阻害剤
WO2019217907A1 (en) * 2018-05-11 2019-11-14 The Regents Of The University Of California Methods and compositions for the treatment of hepatic and metabolic diseases

Patent Citations (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN104027818A (zh) * 2005-12-12 2014-09-10 北卡罗来纳大学查珀尔希尔分校 调节肌细胞增殖和分化的microrna
WO2017187426A1 (en) * 2016-04-29 2017-11-02 Aptamir Therapeutics, Inc. Inhibition of mir-22 mirna by apt-110

Non-Patent Citations (3)

* Cited by examiner, † Cited by third party
Title
GABRIELA PLACONA DINIZ 等: "Loss of microRNA-22 prevents high-fat diet induced dyslipidemia and increases energy expenditure without affecting cardiac hypertrophy", 《CLINICAL SCIENCE》, vol. 131, pages 2885, XP055870272, DOI: 10.1042/CS20171368 *
王玉辛: "《肝脏病知识》", vol. 1, 31 May 1981, 上海科学技术出版社, pages: 97 *
郑晓筠等: "miR-22靶向SIRT1促进人脂肪肝细胞中脂肪沉积的机制研究", 《胃肠病学和肝病学杂志》, vol. 27, no. 2, pages 182 *

Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN115029347A (zh) * 2022-05-11 2022-09-09 珠海中科先进技术研究院有限公司 识别和调控肝肾细胞纤维化的分子监测序列、重组质粒、抑制病毒
CN115029347B (zh) * 2022-05-11 2024-02-20 珠海中科先进技术研究院有限公司 识别和调控肝肾细胞纤维化的分子监测序列、重组质粒、抑制病毒
CN117186178A (zh) * 2022-09-09 2023-12-08 湖南大学 一种多肽及其制备方法
CN117304258A (zh) * 2022-09-09 2023-12-29 湖南大学 一种多肽的用途

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