CN111108196A - 凝血因子变体及其用途 - Google Patents
凝血因子变体及其用途 Download PDFInfo
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Abstract
本文公开了凝血因子VII、VIII和IX的新型变体及其用途，例如在治疗患有凝血障碍例如血友病A或血友病B的受试者的方法中的用途。
Description
相关申请的交叉引用
本申请要求2017年5月9日提交的美国临时申请号62/503,766的优先权。将该临时专利申请通过引用以其整体并入。
技术领域
本发明涉及新型凝血因子蛋白质(例如凝血因子IX、凝血因子VIII和凝血因子VII蛋白质)，以及编码凝血因子蛋白质的重组核酸分子和载体，以及用于在受试者中治疗凝血障碍(例如血友病)的相关方法。
政府支持致谢
本发明是在美国国立卫生研究院授予的批准号为1R56 HL131059的政府支持下完成的。政府拥有本发明的某些权利。
背景技术
凝血因子VIII(fVIII)基因的突变导致减少的或缺陷的凝血因子(fVIII)蛋白质，从而导致特征为不受控出血的血友病A。类似地，血友病B与凝血因子IX(fIX)相关。类似地，前转变素缺乏症，为一种血友病样疾病，与凝血因子VII(fVII)相关。凝血障碍(例如血友病A、血友病B和前转变素缺乏症)的治疗通常需要终生，每周多次静脉输注人血浆来源的或重组的凝血因子，以替代患者体内缺失的凝血因子活性。由于费用昂贵昂，全球血友病群体中有不到30％接受这种治疗。此外，约有25％的用凝血因子替代产品治疗的患者产生中和抗体，从而使将来的治疗无效。因此，需要确定改进的疗法。
发明内容
本文公开了相对于相应的天然人凝血因子蛋白质具有增加的凝血因子活性的fVII、fVIII和fIX凝血因子的变体。
在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fIX蛋白质的核酸序列，所述fIX蛋白质包含与SEQ ID NO:1(An96 fIX Padua)的残基47-462或SEQ ID NO:2(An97 fIX Padua)的残基47-461至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fIX蛋白质的核酸序列，所述fIX蛋白质包含以SEQ ID NO:1(An96 fIX Padua)的残基47-462或SEQ ID NO:2(An97 fIXPadua)的残基47-461示出的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fIX蛋白质的核酸序列，所述fIX蛋白质包含与SEQ ID NO:1(An96fIX Padua)或SEQ ID NO:2(An97 fIX Padua)至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fIX蛋白质的核酸序列，所述fIX蛋白质包含以SEQ ID NO:1(An96 fIX Padua)或SEQ ID NO:2(An97 fIX Padua)示出的氨基酸序列。在一些实施方案中，所述核酸序列包含SEQ ID NO:9的核苷酸139-1389或SEQID NO:10的核苷酸139-1386。在一些实施方案中，所述核酸序列包含以SEQ ID NO:9或SEQID NO:10示出的序列。
在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVIII蛋白质的核酸序列，所述fVIII蛋白质包含与SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)的残基20-1458至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVIII蛋白质的核酸序列，所述fVIII蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQID NO:6(An97 fVIII BDD)的残基20-1458示出的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVIII蛋白质的核酸序列，所述fVIII蛋白质包含与SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVIII蛋白质的核酸序列，所述fVIII蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63fVIIIBDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97fVIII BDD)示出的氨基酸序列。在一些实施方案中，核苷酸序列包含SEQ ID NO:11-14中任一个的核苷酸58-4377。在一些实施方案中，核苷酸序列包含以SEQ ID NO:11-14中的任一个示出的序列。
在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVII蛋白质的核酸序列，所述fVII蛋白质包含与SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61fVII)的残基21-444至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVII蛋白质的核酸序列，所述fVII蛋白质包含以SEQ IDNO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)的残基21-444示出的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVII蛋白质的核酸序列，所述fVII蛋白质包含与SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)至少95％相同的氨基酸序列。在一些实施方案中，提供了分离的核酸分子，所述分离的核酸分子包含编码fVII蛋白质的核酸序列，所述fVII蛋白质包含以SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)示出的氨基酸序列。在一些实施方案中，核苷酸序列包含SEQ ID NO:15或SEQID NO:16的核苷酸61-1335。在一些实施方案中，核苷酸序列包含以SEQ ID NO:15或SEQ IDNO:16示出的序列。
还提供了载体(例如腺相关病毒(AAV)载体)，所述载体含有核酸分子，以及由核酸分子编码的分离的fVII、fVIII和fIX蛋白质。
在一些实施方案中，提供了一种在有需要的受试者中诱导血液凝结的方法。所述方法包括向所述受试者给予治疗有效量的编码本文所述的重组凝血因子的载体(例如AAV载体)。在一些实施方案中，所述受试者是患有凝血障碍(例如血友病A或血友病B)的受试者。在一些实施方案中，所述凝血障碍是血友病A，并且向所述受试者给予包含编码重组fVIII蛋白质的核酸分子的载体。在其他实施方案中，所述凝血障碍是血友病B，并且向所述受试者给予包含编码重组fIX蛋白质的核酸分子的载体。在一些实施方案中，所述凝血障碍是先天性前转变素缺乏症，并且向所述受试者给予包含编码重组fVII蛋白质的核酸分子的载体。
通过参考以下附图进行的若干实施方案的详细描述，本公开的前述及其他特征和优点将变得更加清楚。
附图说明
图1A和图1B展示了人fIX(SEQ ID NO:42)及其若干种变体的序列比对，所述变体包括An102 fIX(SEQ ID NO:25)、An97 fIX(SEQ ID NO:24)、An96 fIX(SEQ ID NO:23)、An95 fIX(SEQ ID NO:22)、An84 fIX(SEQ ID NO:20)、An63 fIX(SEQ ID NO:17)、An88 fIX(SEQ ID NO:21)、An65 fIX(SEQ ID NO:18)和An70 fIX(SEQ ID NO:19)蛋白质。
图2示出了使用编码所指示的fIX变体的AAV载体在HepG2细胞中表达的多种fIX变体的fIX活性水平。
图3示出了用编码所指示的fIX变体的AAV载体治疗的fIX缺陷小鼠的血清中fIX活性水平的体内数据。
图4示出了用含有肝脏定向启动子(HCB)并且编码所指示的fIX变体的AAV2/8载体治疗的fIX+/+小鼠的血清中fIX活性水平的体内数据。绘制了AAV给予前后fIX活性水平的变化。通过单因素方差分析和Holm-Sidak事后分析进行统计学比较。星号表示P<0.05。
图5示出了使用编码所指示的fVIII变体的质粒DNA表达载体在HEK293T17细胞中表达的多种fVIII变体的fVIII活性水平。
序列表
使用标准字母缩写表示核苷酸碱基和三个字母代码表示氨基酸(如在37C.F.R.1.822中所定义的)，示出了所附序列表中列出的核酸和氨基酸序列。仅显示每个核酸序列的一条链，但是应该理解对所示链的任何引用也包括互补链。序列表以命名为“Sequence.txt”(约348kb)的文件形式以ASCII文本文件提交，所示文件创建于2018年5月2日，将其通过引用并入本文。
具体实施方式
I.术语
除非另有说明，否则根据常规用法使用技术术语。分子生物学中常用术语的定义可以在Krebs等人(编),Lewin’s genes XII,Jones&Bartlett Learning出版,2017；Kendrew等人(编),The Encyclopedia of Molecular Biology,Blackwell Science Ltd.出版,2009(ISBN9780632021826)中找到。单数形式“一个/一种(a/an)”和“所述(the)”包括复数个指示物，除非上下文中另外明确指示。“包含A或B”意指包括A或B，或A和B。尽管在本公开的实践和测试中可以使用相似于或等效于本文中所述方法和材料的方法和材料，以下描述了合适的方法和材料。此外，材料、方法以及实施例仅仅是说明性的并不意在是限制性的。在发生冲突的情况下，以本说明书(包括术语解释)为准。为了便于审查本公开的多种实施方案，提供了以下特定术语的解释：
5'和/或3'：认为核酸分子(例如DNA和RNA)具有“5'末端”和“3'末端”，因为单核苷酸以一个单核苷酸戊糖环中的5'磷酸酯通过磷酸二酯键在一个方向上与其相邻者的3'氧附接的方式发生反应来产生多核苷酸。因此，当线性多核苷酸5'磷酸酯未与单核苷酸戊糖环的3'氧连接时，所述线性多核苷酸的一个末端是指“5'末端”。当多核苷酸的3'氧与另一个单核苷酸戊糖环的5'磷酸酯连接时，多核苷酸的另一末端是指“3'末端”。尽管一个单核苷酸戊糖环的5'磷酸酯附接到其相邻者的3'氧上，但内部核酸序列也可能被认为具有5'和3'末端。
在线性或环状核酸分子中，离散的内部元件是指“下游”或3'元件的“上游”或5'。关于DNA，此术语学反映了转录沿着DNA链以5'至3'的方向进行。引导所连接的基因转录的启动子和增强子元件通常位于编码区的5'或上游。然而，即使位于启动子元件和编码区的3′，增强子元件也可以发挥其作用。转录终止和聚腺苷酸化信号位于编码区的3'或下游。
腺相关病毒(AAV)：一种小的复制缺陷型非包膜病毒，其感染人类和一些其他灵长类动物物种。已知AAV不会引起疾病，并且引起非常轻微的免疫应答。利用AAV的基因治疗载体可以感染分裂细胞和静止细胞二者，并且可以以染色体外状态持续存在，而不会整合到宿主细胞的基因组中。这些特征使AAV成为用于基因疗法的有吸引力的病毒载体。目前有11种公认的AAV血清型(AAV1-11)。
给予(Administration/Administer)：通过任何有效途径向受试者提供或给出药剂，例如治疗剂(例如重组AAV)。示例性给予途径包括但不限于注射(例如皮下、肌肉内、皮内、腹膜内和静脉内)、口服、管内、舌下、直肠、透皮、鼻内、阴道和吸入途径。
出血时间测定：用于测量受试者血液凝结所花费时间的测定。将血压袖带放在上臂并且充气。在下臂上制造两个切口。它们约10mm(不到1/2英寸)长，并且1mm深(深度刚好足以使出血最小)。将血压袖带立即放气。每30秒用吸水纸接触切口，直到出血停止为止。记录切口停止出血所花费的时间长度。在正常的非血友病患者中，出血会在约一分钟至十分钟内停止，并且可能因实验室的不同而异，这取决于测定的测量方式。相比之下，适当凝血因子水平低于正常水平的1％的重度血友病患者具有大于60分钟的全血凝血时间。在小鼠中，通过横切尾巴的尖端并且定期接触吸水纸直到在尾巴的尖端形成凝块为止来测定出血时间。正常的出血时间在2分钟至4分钟之间。相比之下，适当凝血因子水平低于正常水平的1％的血友病小鼠具有大于15分钟的出血时间。
cDNA(互补DNA)：缺少内部非编码区段(内含子)和决定转录的调控序列的一段DNA。通过从细胞提取的信使RNA逆转录，在实验室中合成cDNA。cDNA也可以含有负责在相应RNA分子中进行翻译控制的非翻译区(UTR)。
凝血障碍：导致不良血液凝结和持续出血的广泛医学问题的通用术语。医生还通过术语，例如凝血病、异常出血和出血障碍来指代凝血障碍。凝血障碍包括导致异常(或病理性)出血的任何先天性、获得性或诱发性缺陷。例子包括但不限于凝血或止血不足的障碍，例如血友病A(fVIII缺乏)、血友病B(fIX缺乏)、血友病C(因子XI缺乏)、前转变素缺乏症(fVII缺乏)、凝血因子抑制剂水平异常、血小板障碍、血小板减少症、维生素K缺乏症和冯·维勒布兰德病(von Willebrand's disease)。
一些凝血障碍在出生时就存在，并且在一些情况下是遗传性障碍。具体的例子包括但不限于：血友病A、血友病B、蛋白质C缺乏症和冯·维勒布兰德病。在某些疾患(例如维生素K缺乏症、严重的肝脏疾病)或治疗(例如使用抗凝药或长期使用抗生素)期间会产生一些凝血障碍。
凝血因子VII(fVII)：fVII是有效血液凝结所需的维生素K依赖性酶原蛋白质。当与组织因子组合时，fVII以蛋白质水解方式被活化(fVIIa)，并且在凝血中作为因子IX和因子X的活化剂起作用。在超生理水平上，fVIIa也可以显示非组织因子依赖的促凝血活性。认为血液中约0.5μg/ml的fVII浓度是正常的。fVII的缺乏与先天性前转变素缺乏症(表现为血友病样出血障碍)相关。fVII被生物合成为单链酶原，其含有具有N末端信号肽的结构域结构(约残基-20至-1)、富含γ-羧基谷氨酸(Gla)的结构域(约残基1至63)、两个表皮生长因子(EGF)样结构域(约残基64-100[EGF1]和101-170[EGF2])和潜在的C末端丝氨酸蛋白酶结构域(约残基171-444)。为了活化，fVII需要在Arg190-Iso191处进行单肽键裂解。这导致由轻链组成的fVIIa的形成，所述轻链由Gla、EGF1和EGF2结构域组成，所述轻链通过单个二硫键与含有蛋白酶结构域的重链连接。关于fVII蛋白质的结构和功能有大量信息可用；参见，例如，Vadivel等人“Structure and function of Vitamin K-dependent coagulantand anticoagulant proteins.”Hemostasis and Thrombosis-Basic Principles andClinical Practice.第6版.Marder等人(编).Philadelphia:Lippincott Williams andWilkens,2013.第208-232页，通过引用以其整体并入本文。fVII核酸和蛋白质序列是可公开获得的(例如，参见UniProtKB/Swiss-Prot参考号P08709.1)。本文提供了具有增加的用于血液凝结的fVII活性的fVII变体。
凝血因子VIII(fVIII)：fVIII是血液有效凝结所需的蛋白质，并且在凝血中作为辅因子在fIX活化X因子中起作用。FVIII含有多个结构域(A1-A2-B-ap-A3-C1-C2)，并且在血液中以与冯·维勒布兰德因子(VWF)结合的失活形式循环。凝血酶裂解fVIII，导致fVIII与VWF解离，最终导致通过fIX形成纤维蛋白。先天性血友病A与fVIII基因的基因突变相关，并且由于低于循环fVIII的正常水平，导致凝血功能受损。认为在血液中fVIII约100ng/ml的浓度是在正常范围内。当患者的fVIII低于正常量的1％(即每毫升血液中fVIII低于约1ng)时，可以导致血友病A的严重形式。fVIII被合成为约2351个氨基酸的单链前体蛋白质，其通过蛋白质水解方式被加工。人VIII因子基因(186,000个碱基对)由26个外显子组成，大小范围为69bp到3,106bp，并且内含子高达32.4千碱基(kb)。fVIII核酸和蛋白质序列的例子是可公开获得的(例如，参见Genbank登录号：K01740、M14113和E00527)。本文提供了fVIII变体，其具有用于血液凝结的增加的fVIII活性但是尺寸减小(例如缺乏fVIII B结构域的fVIII变体)，并且还具有提供增加的fVIII活性的一种或多种氨基酸变化。
凝血因子IX(fIX)：fIX是血液有效凝结所需的维生素K依赖性蛋白质，并在凝血中作为因子X的活化剂起作用。认为fIX在血液中约1-5μg/ml的浓度在正常范围内。fIX的缺乏与血友病B相关，并且当fIX的浓度小于fIX正常浓度的约1％(即每毫升血液中fIX低于约0.01-0.05μg)时，导致严重的病例。fIX被生物合成为单链酶原，其含有具有N末端信号肽的结构域结构(约残基-28至-1)、富含γ-羧基谷氨酸(Gla)的结构域(约残基1至40)、短的疏水性区段(约残基41-46)、两个表皮生长因子(EGF)样结构域(约残基47-84[EGF1]和85-127[EGF2])、活化肽(约残基146-180)和潜在的C末端丝氨酸蛋白酶结构域(约残基181-415)。为了活化，fIX需要进行两次肽键裂解，一次在Arg145-Ala146处，一次在Arg180-Val181处，释放35个残基的活化肽。这导致由轻链组成的活化fIX(fIXa)的形成，所述轻链由Gla、EGF1和EGF2结构域构成，所述轻链通过单个二硫键与含有蛋白酶结构域(185-415)的重链连接。关于fIX蛋白质的结构和功能有大量信息可用；参见，例如，Vadivel等人“Structure andfunction of Vitamin K-dependent coagulant and anticoagulant proteins.”Hemostasis and Thrombosis-Basic Principles and Clinical Practice.第6版.Marder等人(编).Philadelphia:Lippincott Williams and Wilkens,2013.第208-232页，通过引用以其整体并入本文。fIX核酸和蛋白质序列是可公开获得的(参见，例如，UniProtKB/Swiss-Prot参考号P00740.2)。本文提供了fIX变体，其具有用于血液凝结的增加的fIX活性。
密码子优化：“密码子优化”的核酸是指核酸序列经改变以使密码子在特定系统(例如特定物种或物种组)中对于表达是最优的。例如，可以优化核酸序列以在哺乳动物细胞或特定哺乳动物物种(例如人细胞)中表达。密码子优化不会改变所编码的蛋白质的氨基酸序列。
术语“肝脏特异性氨基酸密码子”是指与人基因组的整个编码区的密码子使用相比，在人肝脏内高度表达的基因中具有差异使用代表性的密码子。肝脏密码子优化策略使用最大量的肝脏特异性氨基酸密码子，力图避免代表性不足的密码子，代表性不足例如是由于肝脏细胞中密码子匹配tRNA的量少导致蛋白质翻译较慢。
对照：参考标准。在一些实施方案中，对照是从健康患者获得的阴性对照样品。在其他实施方案中，对照是从诊断为血友病的患者获得的阳性对照样品。在再其他实施方案中，对照是历史对照或标准参考值或值范围(例如先前测试过的对照样品、例如一组已知预后或结果的血友病A患者、或代表基线或正常值的一组样品)。
测试样品与对照之间的差异可以是增加，或反之可以是减少。所述差异可以是定性差异或定量差异，例如统计学显著差异。在一些例子中，差异是相对于对照，增加或减少至少约5％，例如至少约10％、至少约20％、至少约30％、至少约40％、至少约50％、至少约60％、至少约70％、至少约80％、至少约90％、至少约100％、至少约150％、至少约200％、至少约250％、至少约300％、至少约350％、至少约400％、至少约500％或大于500％。
DNA(脱氧核糖核酸)：DNA是长链聚合物，其包含大多数活生物体的基因材料(一些病毒具有包含核糖核酸(RNA)的基因)。DNA聚合物中的重复单元是四个不同的核苷酸，每个核苷酸都包含以下四个碱基中的一个：腺嘌呤(A)、鸟嘌呤(G)、胞嘧啶(C)和胸腺嘧啶(T)，这些碱基结合到磷酸基团附接的脱氧核糖上。核苷酸的三联体(称为密码子)编码多肽中的每个氨基酸或终止信号。术语密码子也用于DNA序列所转录出的mRNA中三个核苷酸的对应(和互补)序列。
除非另有说明，否则对DNA分子的任何提及旨在包括此DNA分子的反向互补体。除了本文的文本要求单链的地方以外，DNA分子，尽管书写为仅描绘单链，仍涵盖双链DNA分子的两条链。因此，对编码特定蛋白质或其片段的核酸分子的提及涵盖有义链及其反向互补体。例如，从所公开的核酸分子的反向互补体序列产生探针或引物是合适的。
表达：核酸序列的转录或翻译。例如，当编码的核酸序列(例如基因)的DNA转录为RNA或RNA片段(在一些实施例中被加工变成mRNA)时，所述编码的核酸序列(例如基因)可得以表达。当编码的核酸序列(例如基因)的mRNA翻译成氨基酸序列(例如蛋白质或蛋白质片段)时，所述编码的核酸序列(例如基因)也可得以表达。在特定的例子中，当异源基因转录为RNA时，则所述异源基因得以表达。在另一个例子中，当异源基因的RNA翻译成氨基酸序列时，则所述异源基因得以表达。表达的调控可以包括对以下的控制：转录，翻译，RNA转运和加工，中间分子(例如mRNA)的降解，或在特定蛋白质分子产生后通过所述特定蛋白质分子的活化、失活、区室化或降解。
表达控制序列：调控与之可操作地连接的异源核酸序列表达的核酸序列。当表达控制序列控制和调控核酸序列的转录和翻译(适当时)时，表达控制序列可操作地连接至核酸序列。因此，表达控制序列可以包括适当的启动子、增强子、转录终止子、蛋白质编码基因前的起始密码子(ATG)、内含子的剪接信号、所述基因的正确阅读框的维持(以允许mRNA的正确翻译)、和终止密码子。术语“控制序列”旨在包括至少其存在可影响表达的组分，并且还可以包括其存在有利的另外的组分，例如前导序列和融合伴侣序列。表达控制序列可以包括启动子。
基因：一种核酸序列，通常为DNA序列，其包含转录为RNA(无论是mRNA还是其他形式)所必需的控制和编码序列。例如，基因可以包含启动子、一个或多个增强子或沉默子、编码RNA和/或多肽的核酸序列、下游调控序列和可能的涉及mRNA表达调控的其他核酸序列。
如本领域所熟知的，大多数真核基因都含有外显子和内含子。术语“外显子”是指在基因组DNA中发现的核酸序列，其在生物信息学上被预测和/或在实验上被确认为对成熟的mRNA转录物贡献了连续序列。术语“内含子”是指在基因组DNA中发现的核酸序列，其被预测和/或被确认为不贡献于成熟的mRNA转录物，而是在转录物加工期间被“剪接掉”。
基因疗法：将异源核酸分子引入一个或多个受体细胞，其中异源核酸在受体细胞中的表达影响细胞的功能并在受试者中产生治疗效果。例如，异源核酸分子可以编码影响受体细胞功能的蛋白质。
血友病：一种由凝血因子活性不足(降低了止血)引起的凝血障碍。当凝血因子的浓度小于正常受试者中凝血因子的正常浓度的约1％时，则导致严重形式。在一些受试者中，血友病是由于导致凝血因子表达受损的基因突变所致。在其他受试者中，血友病是自身免疫性障碍，称为获得性血友病，其中在受试者中针对凝血因子产生的抗体导致止血降低。
血友病A是由功能性凝血fVIII的缺乏引起的，而血友病B是由功能性凝血fIX的缺乏引起的。这些由于基因突变所致的病症是由遗传性连锁隐性性状引起的，所述遗传性连锁隐性性状的缺陷基因位于X染色体上，因此这种疾病通常只在男性中发现。症状的严重性可能因此疾病而异，并且严重形式在早期就变得明显。出血是所述疾病的标志，并且通常在男婴环割包皮时发生。当婴儿活动时，会出现另外的出血表现。轻度病例可能被忽视，直到晚年，才响应于手术或创伤出现。内部出血可能发生在任何地方，并且关节出血很常见。
止血：通过血块形成阻止出血。凝血时间是使外周血凝结所需的时间长度，使用活化部分凝血活酶时间测定(APTT)或通过测量出血时间得出。在特定的实施方案中，当与给予如本文所述的编码适当凝血因子的治疗载体之前受试者的凝血时间相比时，凝血时间减少至少50％，例如至少60％、至少70％、至少75％、至少80％、至少90％、至少95％、至少98％、至少99％或甚至约100％(即，凝血时间与在正常受试者中观察到的凝血时间相似)。在又另一个实施方案中，在口服给予治疗有效量的适当凝血因子后，将受累及受试者中的凝血时间校正为正常受试者的约50％、为正常受试者的约75％、为正常受试者的约90％(例如为约95％、例如为约100％)。如本文所用，“约”是指相对于参考值正负5％。因此，约50％是指47.5％至52.5％。
分离的：“分离的”生物组分(例如核酸分子、蛋白质、病毒或细胞)已经从生物体的细胞或组织或生物体本身中的其他生物组分(其中所述组分是天然存在的，例如其他染色体和染色体外的DNA和RNA、蛋白质和细胞)基本上分离或纯化。已经“分离的”核酸分子和蛋白质包括通过标准纯化方法纯化的那些。所述术语还涵盖通过在宿主细胞中重组表达制备的核酸分子和蛋白质，以及化学合成的核酸分子和蛋白质。
核酸分子：核苷酸的聚合形式，其可以包括RNA、cDNA、基因组DNA的有义链和反义链，以及上述物质的合成形式和混合聚合物。核苷酸是指核糖核苷酸、脱氧核苷酸或两种类型之一的核苷酸的修饰形式。如本文所用，术语“核酸分子”与“核酸”和“多核苷酸”同义。除非另有说明，否则核酸分子的长度通常是至少10个碱基。所述术语包括单链和双链形式的DNA。多核苷酸可以包括通过天然存在和/或非天然存在的核苷酸连接而连接在一起的天然存在的核苷酸和修饰的核苷酸之一或二者。“cDNA”是指呈单链或双链形式的与mRNA互补或相同的DNA。“编码”是指多核苷酸(例如基因、cDNA或mRNA)中特定核苷酸序列的固有特性，以在生物加工中用作合成其他聚合物和大分子的模板，所述其他聚合物和大分子具有限定的核苷酸序列(即rRNA、tRNA和mRNA)或限定的氨基酸序列以及由此产生的生物学特性。
可操作地连接：当第一核酸序列与第二核酸序列处于功能关系时，第一核酸序列与第二核酸序列可操作地连接。例如，如果启动子影响编码序列的转录或表达，则所述启动子与编码序列可操作地连接。通常，可操作地连接的DNA序列是连续的，并且在需要连接两个蛋白质编码区域的情况下，是在同一阅读框中。
药学上可接受的载体：使用的药学上可接受的载体是常规的。Remington:TheScience and Practice of Pharmacy,第22版,London,UK:Pharmaceutical Press,2013，描述了适用于所公开的载体的药物递送的组合物和配制品。
通常，载体的性质将取决于所采用的特定给予模式。例如，肠胃外配制品通常包括注射液，注射液包含药学上和生理学上可接受的流体，例如水、生理盐水、平衡盐溶液、右旋糖水溶液、甘油等作为媒介物。对于固体组合物(例如，粉末、丸剂、片剂或胶囊剂形式)，常规的无毒固体载体可以包括例如药物级的甘露糖醇、乳糖、淀粉或硬脂酸镁。除生物中性载体外，待给予的药物组合物(例如载体组合物)可以含有少量无毒辅助物质，例如润湿剂或乳化剂、防腐剂和pH缓冲剂等，例如乙酸钠或失水山梨糖醇单月桂酸酯。在具体的实施方案中，适于向受试者给予的载体可以是无菌的、和/或悬浮的或以其他方式包含在单位剂型中，所述单位剂型含有一个或多个测量剂量的组合物(适合于诱导所需的免疫应答)。也可能伴随药物一块用于治疗目的。单位剂型可以例如在含有无菌内容物的密封小瓶中、或用于注射到受试者体内的注射器中，或冻干用于后续溶解和给予，或在固体或控释剂量中。
纯化的：术语纯化的不需要绝对的纯度；而是，它旨在作为一个相对术语。因此，例如，纯化的蛋白质制剂是其中蛋白质(例如fVII、fVIII或fIX蛋白质)比其在细胞内自然环境中的肽或蛋白质更富集的蛋白质制剂。在一个实施方案中，纯化制剂，使得蛋白质代表所述制剂的总蛋白质含量的至少50％。
多肽：不考虑长度或翻译后修饰(例如糖基化或磷酸化)的任何氨基酸链。“多肽”适用于氨基酸聚合物，包括天然存在的氨基酸聚合物和非天然存在的氨基酸聚合物，以及其中一个或多个氨基酸残基是非天然氨基酸(例如相应的天然存在的氨基酸的人工化学模拟物)的氨基酸聚合物。“残基”是指通过酰胺键或酰胺键模拟物掺入多肽中的氨基酸或氨基酸模拟物。多肽具有氨基末端(N末端)和羧基末端(C末端)。“多肽”与肽或蛋白质可互换使用，并且在本文中用于指氨基酸残基的聚合物。
预防、治疗或改善疾病：“预防”疾病(例如血友病)是指抑制疾病的全面发展。“治疗”是指在疾病或病理状态开始发展后改善所述疾病或病理状态的体征或症状的治疗干预。“改善”是指降低疾病的体征或症状的数量或严重性。
启动子：引导/启动核酸(例如基因)转录的DNA区域。启动子包括转录起始位点附近必需的核酸序列。通常，启动子位于它们转录的基因附近。启动子还任选地包括远端增强子或阻遏物元件，其可以位于从转录起始位点多达数千个碱基对的位置处。组织特异性启动子是在单一类型的组织或细胞中主要引导/启动转录的启动子。例如，肝脏特异性启动子是与其他组织类型相比实质上更大程度地引导/启动肝脏组织中转录的启动子。
蛋白质：由基因或其他编码核酸(例如cDNA)表达并且由氨基酸构成的生物分子。
纯化的：术语“纯化的”不需要绝对的纯度；而是，它旨在作为一个相对术语。因此，例如，纯化的肽、蛋白质、病毒或其他活性化合物是从天然相关的蛋白质和其他污染物中全部或部分分离的一种。在某些实施方案中，术语“基本上纯化的”是指已经从细胞、细胞培养基或其他粗制剂中分离，并且经受分级以去除初始制剂的多种组分(例如蛋白质、细胞碎片和其他组分)的肽、蛋白质、病毒或其他活性化合物。
重组：重组核酸分子是具有非天然存在序列的核酸分子，例如，包括一个或多个核酸取代、缺失或插入，和/或具有通过将序列的两个原本分离的区段人工组合产生的序列。此人工组合可以通过化学合成或更普遍地通过对分离的核酸区段进行人工操作(例如通过基因工程技术)来完成。
重组病毒是包含含有重组核酸分子的基因组的病毒。如本文所用，“重组AAV”是指其中已经包装了重组核酸分子(例如，编码凝血因子的重组核酸分子)的AAV粒子。
重组蛋白质是具有非天然存在的序列或具有通过将序列的两个原本分离的区段人工组合产生的序列的蛋白质。在若干实施方案中，重组蛋白质由已经引入宿主细胞(例如细菌或真核细胞)或引入重组病毒基因组中的异源(例如重组)核酸编码。
序列同一性：根据序列之间的同一性或相似度表示两个或更多个核酸序列或者两个或更多个氨基酸序列之间的同一性或相似度。序列同一性可以根据百分比同一性来测量；百分比越高，序列越相同。序列相似度可以根据百分比相似度(考虑到保守的氨基酸取代)测量；百分比越高，序列越相似。当使用标准方法比对时，核酸或氨基酸序列的同系物或直系同源物具有相对高程度的序列同一性/相似度。与较远相关的物种(例如人和秀丽隐杆线虫序列)相比，当直系同源蛋白质或cDNA来源于更紧密相关的物种(例如人和小鼠序列)时，这种同源性更为显著。
用于比较的序列比对方法是本领域熟知的。多种程序和比对算法描述于：Smith&Waterman,Adv.Appl.Math.2:482,1981；Needleman&Wunsch,J.Mol.Biol.48:443,1970；Pearson&Lipman,Proc.Natl.Acad.Sci.USA 85:2444,1988；Higgins&Sharp,Gene,73:237-44,1988；Higgins&Sharp,CABIOS 5:151-3,1989；Corpet等人,Nuc.Acids Res.16:10881-90,1988；Huang等人Computer Appls.in the Biosciences 8,155-65,1992；以及Pearson等人,Meth.Mol.Bio.24:307-31,1994。Altschul等人,J.Mol.Biol.215:403-10,1990，提供了对序列比对方法和同源性计算的详细考量。
NCBI基本局部比对搜索工具(BLAST)(Altschul等人,J.Mol.Biol.215:403-10,1990)可从一些资源中获得，所述资源包括美国国家生物技术信息中心(NCBI)和互联网上，以用于与序列分析程序blastp、blastn、blastx、tblastn和tblastx结合使用。可以在NCBI网站上找到另外的信息。
如本文所用，对“至少90％同一性”的提及是指与指定参考序列具有“至少90％、至少91％、至少92％、至少93％、至少94％、至少95％、至少96％、至少97％、至少98％、至少99％或甚至100％同一性”。
受试者：活的多细胞脊椎动物生物体，为包括人类和非人类哺乳动物的类别。
治疗有效量：即足以预防、治疗(包括预防法)、减轻和/或改善障碍或疾病的症状和/或潜在致因从而例如预防、抑制和/或治疗血友病的药剂(例如公开的编码凝血因子的重组AAV载体)的量。例如，这可以是编码如本文所述的新型凝血因子的重组AAV载体的量，所述重组AAV载体生产足够量的凝血因子以减少受试者的血液凝结所需的时间。
在一个例子中，例如，如使用出血时间测定测量的，期望的反应是减少受试者(例如患有血友病的受试者)的凝血时间。关于所述方法有效而言，凝血时间并不需要完全恢复到未患血友病的正常健康受试者的凝血时间。例如，与合适的对照相比，本文所公开的治疗有效量的载体(例如fIX编码载体)的给予可以将凝血时间(或血友病的其他症状)减少所需量，例如减少至少20％、至少30％、至少40％、至少50％、至少60％、至少70％、至少80％、至少90％、至少95％、至少98％、至少100％或更高。
可以理解，为了获得对疾病或病症的治疗反应，可能需要多次给予治疗剂。因此，治疗有效量涵盖分剂量，所述分剂量与先前或随后给予相组合有助于在患者中获得治疗结果。例如，治疗有效量的药剂可以在治疗历程期间以单个剂量或几个剂量(例如每天)给予。然而，治疗有效量可以取决于所治疗的受试者、所治疗病症的严重性和类型、以及给予的方式。药剂的单位剂型可以是以一个治疗量或多个治疗量包装，例如包装于具有无菌组分的小瓶(例如带有可刺穿的盖子)或注射器中。
载体：载体是允许外来核酸插入而不破坏载体在宿主细胞中复制和/或整合的能力的核酸分子。载体可以包括允许其在宿主细胞中复制的核酸序列，例如复制起点。载体还可以包括一个或多个选择性标记基因和其他基因元件。表达载体是包含必要的调控序列以允许插入的一个或多个基因转录和翻译的载体。在本文的一些实施方案中，所述载体是腺相关病毒(AAV)载体。在一些实施方案中，所述载体是γ-逆转录病毒载体、慢病毒载体或腺病毒载体。
II.新型凝血因子
凝血系统是蛋白质水解级联。凝血因子在血浆中以酶原存在，换言之，以非活性形式存在，在活化时会经历蛋白质水解裂解，以从前体分子中释放活性因子。最终目标是产生凝血酶。凝血酶将纤维蛋白原转换为纤维蛋白，形成凝块。
因子X是共同途径的第一分子，并且由含有活化fIX、fVIII、钙和在血小板表面上的磷脂的分子复合物活化。FVIII被凝血酶活化，并且它促进fIXa活化因子X。先天性血友病A与fVIII基因的基因突变相关，并且由于低于循环fVIII的正常水平，导致凝血功能受损。相似地，血友病B与fIX基因的基因突变相关。相似地，前转变素缺乏症与fVII基因的突变相关。
如实施例1-实施例3中所讨论的，从相应的祖先变体中鉴定出新型fVII、fVIII和fIX序列，并且评估凝血因子活性。相对于相应的人凝血因子，若干序列提供了增加的凝血因子活性。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fIX活性的蛋白质，所述蛋白质包含以SEQ ID NO:1的残基47-462(不具有信号肽和前肽的An96 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:1的残基1-46是fIX信号肽和前肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fIX活性的蛋白质，所述蛋白质包含以SEQ ID NO:1(具有信号肽和前肽的An96 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ ID NO:1的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例1中所讨论的，对编码An96 fIX Padua的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:9提供了示例性的肝脏密码子优化的An96 fIX Padua序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:9的核苷酸139-1389示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:9示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An96 fIX Padua序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An96 fIX Padua序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fIX活性的蛋白质，所述蛋白质包含以SEQ ID NO:2的残基47-461(不具有信号肽和前肽的An97 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:2的残基1-46是fIX信号肽和前肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fIX活性的蛋白质，所述蛋白质包含以SEQ ID NO:2(具有信号肽和前肽的An97 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ ID NO:2的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例1中所讨论的，对编码An97 fIX Padua的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:10提供了示例性的肝脏密码子优化的An97 fIX Padua序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:10的核苷酸139-1386示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:10示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An96 fIX Padua序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An96 fIX Padua序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:3的残基20-1458(不具有信号肽的An84 fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:3的残基1-19是fVIII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:3(具有信号肽的An84fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ IDNO:3的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例2中所讨论的，对编码An84 fVIII BDD的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:11提供了示例性的肝脏密码子优化的An84 fVIII BDD序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:11的核苷酸58-4377示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:11示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An84 fVIII BDD序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An84 fVIII序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:4的残基20-1458(不具有信号肽的An63 fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:4的残基1-19是fVIII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:4(具有信号肽的An63fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ IDNO:4的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例2中所讨论的，对编码An63 fVIII BDD的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:12提供了示例性的肝脏密码子优化的An63 fVIII BDD序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:12的核苷酸58-4377示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:12示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An63 fVIII BDD序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An63 fVIII序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:5的残基20-1458(不具有信号肽的An96 fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:5的残基1-19是fVIII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:5(具有信号肽的An96fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ IDNO:5的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例2中所讨论的，对编码An96 fVIII BDD的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:13提供了示例性的肝脏密码子优化的An96 fVIII BDD序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:13的核苷酸58-4377示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:13示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An96 fVIII BDD序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An96 fVIII序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:6的残基20-1458(不具有信号肽的An97 fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQ ID NO:6的残基1-19是fVIII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVIII活性的蛋白质，所述蛋白质包含以SEQ ID NO:6(具有信号肽的An97fVIII BDD)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽和/或前肽代替SEQ IDNO:6的信号肽和/或前肽，例如IL2信号肽和/或因子X前肽。
如实施例2中所讨论的，对编码An97 fVIII BDD的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:14提供了示例性的肝脏密码子优化的An97 fVIII BDD序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:14的核苷酸58-4377示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:14示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An97 fVIII BDD序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An97 fVIII序列。
An84 fVIII BDD、An63 fVIII BDD、An96 fVIII BDD和An97 fVIII BDD蛋白质是B-结构域缺失的fVIII蛋白质，其中A2结构域和活化肽通过接头(以SFSQNPPVLKRHQR(SEQID NO:3的残基761-774)示出)融合。在一些实施方案中，可选的接头序列可以被取代，只要可选的接头序列包括针对B-结构域的PACE/弗林蛋白酶加工序列的RHQR(SEQ ID NO:3的残基770-774)识别序列，并且不能破坏fVIII蛋白质的折叠和功能。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVII活性的蛋白质，所述蛋白质包含以SEQ ID NO:7的残基21-444(不具有信号肽的An81 fVII)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQID NO:7的残基1-20是fVII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVII活性的蛋白质，所述蛋白质包含以SEQ ID NO:7(具有信号肽的An81 fVII)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽(例如IL2信号肽)代替SEQ ID NO:7的信号肽。
如实施例3中所讨论的，对编码An81 fVII的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:15提供了示例性的肝脏密码子优化的An81 fVII序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:15的核苷酸61-1335示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:15示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An81 fVII序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An81 fVII序列。
在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVII活性的蛋白质，所述蛋白质包含以SEQ ID NO:8的残基21-444(不具有信号肽的An61 fVII)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。SEQID NO:8的残基1-20是fVII信号肽。在一些实施方案中，提供了核酸分子，所述核酸分子编码具有fVII活性的蛋白质，所述蛋白质包含以SEQ ID NO:8(具有信号肽的An61 fVII)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同的氨基酸序列。在可选的实施方案中，可以使用不同的信号肽(例如IL2信号肽)代替SEQ ID NO:8的信号肽。
如实施例3中所讨论的，对编码An61 fVII的核苷酸序列进行密码子优化以在人肝脏中表达。以SEQ ID NO:16提供了示例性的肝脏密码子优化的An61 fVII序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:16的核苷酸61-1335示出的核苷酸序列。在一些实施方案中，提供了重组核酸分子，其包含以SEQ ID NO:16示出的核苷酸序列。在一些实施方案中，可以去除在密码子优化的An61 fVII序列中的CpG基序，以提供CpG缺失的、肝脏密码子优化的An61 fVII序列。
在另外的实施方案中，提供了由本文提供的fVII、fVIII或fIX序列中的任一个编码的分离的成熟fVII、fVIII或fIX蛋白质。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:1(An96 fIX Padua)的残基47-462示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同并且具有fIX活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:1(An96 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同并且具有fIX活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:2(An97 fIX Padua)的残基47-461示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同并且具有fIX活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:2(An97 fIX Padua)示出的氨基酸序列或与其至少95％、至少96％、至少97％、至少98％或至少99％相同并且具有fIX活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)的残基20-1458示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:4(An63 fVIII BDD)的残基20-1458示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:4(An63 fVIII BDD)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:5(An96 fVIII BDD)的残基20-1458示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:5(An96 fVIII BDD)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:6(An97 fVIII BDD)的残基20-1458示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:6(An97 fVIII BDD)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVIII活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:7(An81 fVII)的残基21-444示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:7(An81 fVII)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVII活性的氨基酸序列。
在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:8(An61 fVII)的残基21-444示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVII活性的氨基酸序列。在一些实施方案中，提供了分离的蛋白质，所述分离的蛋白质包含以SEQ ID NO:8(An61 fVII)示出的氨基酸序列或与其至少98％或至少99％相同并且具有fVII活性的氨基酸序列。
上述分离的蛋白质是凝血因子蛋白质。在若干实施方案中，所述凝血因子蛋白质是具有凝血因子活性的成熟凝血因子蛋白质。
因此，提供了对所公开的新型凝血因子以及所述凝血因子的纯化形式进行编码的核酸分子(例如cDNA或RNA分子)。使用本文提供的氨基酸序列和遗传密码可以容易地产生编码这些分子的核酸。在若干实施方案中，所述核酸分子可以在宿主细胞(例如哺乳动物细胞)中表达以产生所公开的凝血因子。
遗传密码可以用于构建各种功能上等效的核酸序列，例如序列不同但编码相同多肽序列的核酸。
编码本文所公开的新型凝血因子的核酸分子可以通过任何合适的方法制备，所述方法包括例如克隆适当的序列或通过标准方法直接化学合成。化学合成产生单链寡核苷酸。单链寡核苷酸通过与互补序列杂交或通过使用此单链作为模板用DNA聚合酶聚合来转化为双链DNA。
可以通过克隆技术制备示例性核酸。可以在例如以下中发现适当的克隆和测序技术的例子：Green和Sambrook(Molecular Cloning:A Laboratory Manual,第4版,NewYork:Cold Spring Harbor Laboratory Press,2012)和Ausubel等人(编)(CurrentProtocols in Molecular Biology,New York:John Wiley and Sons,包括增补,2017)。
核酸也可以通过扩增方法制备。扩增方法包括聚合酶链式反应(PCR)、连接酶链反应(LCR)、基于转录的扩增系统(TAS)和自维持的序列复制系统(self-sustained sequencereplication system，3SR)。
核酸分子可以在重组工程化细胞例如细菌、植物、酵母、昆虫和哺乳动物细胞中表达。通过将编码凝血因子的DNA序列转移到合适的宿主细胞中，可以在体外表达所述DNA序列。所述细胞可以是原核的或真核的。可以用于蛋白质表达的多种表达系统包括大肠杆菌(E.coli)、其他细菌宿主、酵母和多种高等真核细胞(例如COS、CHO、HeLa和骨髓瘤细胞系)，可以用于表达所公开的新型凝血因子。稳定转移(意指外来DNA在宿主中连续保持)的方法是本领域已知的。
通过将DNA或cDNA可操作地连接到启动子(其为组成型或诱导型)，然后掺入表达盒中，可以实现编码本文所述的所公开的新型凝血因子的核酸的表达。所述启动子可以是任何目的启动子，包括肝脏特异性启动子，例如HCB启动子。任选地，构建体中包括增强子，例如巨细胞病毒增强子。所述盒可以适用于在原核生物或真核生物中复制和整合。典型的表达盒含有可用于调控编码所述蛋白质的DNA表达的特定序列。例如，所述表达盒可以包括适当的启动子、增强子、转录和翻译终止子、起始序列、蛋白质编码基因前的起始密码子(即ATG)、内含子的剪接信号、维持所述基因的正确阅读框的序列(以允许mRNA的正确翻译)、和终止密码子。所述载体可以编码选择性标记，例如编码药物抗性(例如，氨苄青霉素或四环素抗性)的标记。
为了获得克隆基因的高水平表达，理想的是构建表达盒，所述表达盒含有例如引导转录的强启动子、用于翻译起始的核糖体结合位点(例如内部核糖体结合序列)、和转录/翻译终止子。对于大肠杆菌(E.coli)，所述表达盒可以包含启动子(例如T7、trp、lac或λ启动子)、核糖体结合位点、和优选的转录终止信号。对于真核细胞，控制序列可以包括衍生自例如免疫球蛋白基因、HTLV、SV40或巨细胞病毒的启动子和/或增强子，以及聚腺苷酸化序列，并且可以进一步包括剪接供体和/或受体序列(例如CMV和/或HTLV剪接受体和供体序列)。可以将所述盒通过熟知的方法(例如针对大肠杆菌的转化或电穿孔以及针对哺乳动物细胞的磷酸钙处理、电穿孔或脂质转染)转移到选择的宿主细胞中。可以通过由盒中含有的基因(例如amp、GPt、neo和hyg基因)赋予的抗生素抗性来选择由所述盒转化的细胞。
可以对编码本文所述多肽的核酸在不降低其生物学活性的情况下进行修饰。可以进行一些修饰以促进靶分子的克隆、表达或掺入到融合蛋白质中。此类修饰包括，例如，终止密码子、产生方便定位的限制性位点的序列、和在氨基末端添加甲硫氨酸的序列(以提供起始位点)、或另外的氨基酸(例如聚His)(以帮助纯化步骤)。
一旦表达，可以根据本领域的标准程序纯化所公开的新型凝血因子，所述标准程序包括硫酸铵沉淀、亲和柱、柱色谱等(通常参见，Simpson等人(编),Basic methods inProtein Purification and Analysis:A Laboratory Manual,New York:Cold SpringHarbor Laboratory Press,2009)。所公开的新型凝血因子不需要是100％纯的。一旦根据需要纯化、部分纯化或达到同质，如果要用于治疗，则多肽应该基本上不含内毒素。
III.重组载体和基因疗法应用
以上讨论的编码fIX蛋白质、fVIII蛋白质、fVII蛋白质或其变体的重组核酸分子中的任一个都可以包括在载体(例如AAV载体)中，以在细胞或受试者中表达。
本文所公开的核酸序列可用于产生载体(例如rAAV载体)，并且还可用于反义递送载体、基因治疗载体或疫苗载体中。在某些实施方案中，本公开提供用于含有本文所公开的核酸序列的基因递送载体和宿主细胞。在一些实施方案中，可以通过任何合适的方法将选择的载体递送至受试者，以将转基因引入所述受试者，所述方法包括静脉注射、离体转导、转染、电穿孔、脂质体递送、膜融合技术、高速DNA包被丸粒、病毒感染或原生质体融合。
在某些实施方案中，本公开涉及病毒粒子(例如衣壳)，其含有编码本文所公开的fVII、fVIII或fIX蛋白质的核酸序列。病毒粒子、衣壳和重组载体可用于将编码fVII、fVIII或fIX蛋白质的核酸序列递送至靶细胞。核酸可以容易地用于多种载体系统、衣壳和宿主细胞中。在某些实施方案中，核酸在被容纳于包含cap蛋白质的衣壳内的载体中，所述cap蛋白质包括AAV衣壳蛋白vp1、vp2、vp3和高变区。
在某些实施方案中，编码fVII、fVIII或fIX蛋白质的核酸序列可以是可被递送至宿主细胞的任何基因元件(载体)的一部分，所述基因元件例如为裸DNA、质粒、噬菌体、转座子、粘粒、附加体、非病毒递送媒介物中的蛋白质(例如基于脂质的载体)、病毒等，其转移携带在其上的序列。
在某些实施方案中，载体可以是基于慢病毒的(含有慢病毒基因或序列)载体，例如具有衍生自VSVG或GP64假型或二者的核酸序列。在某些实施方案中，衍生自VSVG或GP64假型的核酸序列可以是具有超过1000、500、400、300、200、100、50或25个连续核苷酸的至少一种或者两种或更多种基因或基因片段，或者是与所述基因或片段具有大于50％、60％、70％、80％、90％、95％或99％同一性的核苷酸序列。
在一些实施方案中，本文所公开的核酸和启动子序列可用于产生AAV载体。AAV属于细小病毒科(Parvoviridae)和依赖病毒属(Dependovirus)。AAV是小的非包膜病毒，其包装线性单链DNA基因组。AAV DNA的有义链和反义链以等比例被包装在AAV衣壳中。AAV基因组的特征是位于两个开放阅读框(ORF)的侧翼的两个反向末端重复序列(ITR)。在AAV2基因组中，例如，ITR的前125个核苷酸是回文序列，所述回文序列自身折叠以使碱基配对最大化并且形成T形发夹结构。ITR的其他20个碱基(称为D序列)保持未配对。ITR是对AAV DNA复制重要的顺式作用序列；ITR是复制的起点，并且作为由DNA聚合酶进行第二链合成的引物。在此合成期间形成的双链DNA，称为复制形式单体，用于第二轮自引发复制并且形成复制形式的二聚体。这些双链中间体通过链置换机制被加工，从而产生用于包装的单链DNA和用于转录的双链DNA。位于ITR内的是Rep结合元件和一个末端解离位点(TRS)。在AAV复制期间，病毒调控蛋白质Rep使用这些特征加工双链中间体。除了在AAV复制中的作用外，ITR对于AAV基因组包装、转录、非许可条件下的负调控、和位点特异性整合也是必需的(Daya和Berns,Clin Microbiol Rev 21(4):583-593,2008)。
AAV的左ORF含有Rep基因，所述基因编码四种蛋白质-Rep78、Rep68、Rep52和Rep40。右ORF含有Cap基因，所述基因产生三种病毒衣壳蛋白(VP1、VP2和VP3)。AAV衣壳含有60种病毒衣壳蛋白，它们排列成二十面体对称结构。VP1、VP2和VP3以1:1:10的摩尔比存在(Daya和Berns,Clin Microbiol Rev 21(4):583-593,2008)。
AAV载体通常在ITR之间含有取代rep和cap基因的转基因表达盒。通过将细胞用含有载体基因组的质粒和包装/辅助构建体(反式表达rep和cap蛋白质)共转染来产生载体粒子。在感染期间，AAV载体基因组进入细胞核，并且可以按多种分子状态持续存在。一种常见的结果是通过第二链合成或互补链配对将AAV基因组转化为双链环状附加体。
在AAV载体的上下文中，所公开的载体通常具有包含以下结构的重组基因组：
(5'AAV ITR)-(启动子)-(转基因)-(3'AAV ITR)
如以上所讨论的，这些重组AAV载体在ITR之间含有取代rep和cap基因的转基因表达盒。例如，通过将细胞用含有重组载体基因组的质粒和包装/辅助构建体(反式表达rep和cap蛋白质)共转染来产生载体粒子。
转基因的侧翼可以是调控序列，例如5'Kozak序列和/或3'聚腺苷酸化信号。
AAV ITR、和本文所述的其他选择的AAV组分可以容易地选自任何AAV血清型，包括但不限于AAV1、AAV2、AAV3、AAV4、AAV5、AAV6、AAV7、AAV8、AAV9及其功能变体。可以使用本领域技术人员可用的技术容易地从AAV血清型分离这些ITR或其他AAV组分。可以从学术、商业或公共来源(例如美国菌种保藏中心(American Type Culture Collection)，Manassas，Va.)分离或获得这种AAV。可选地，可以通过参考在参考文献或在数据库(例如GenBank、PubMed等)中可获得的公开序列，通过合成或其他合适的手段获得AAV序列。
在一些实施方案中，重组AAV载体基因组可以具有肝脏特异性启动子，例如在WO2016/168728中提出的HCB、HSh-HCB、5'HSh-HCB、3'HSh-HCB、ABP-HP1-God-TSS、HSh-SynO-TSS或sHS-SynO-TSS启动子中的任何一种，将此申请通过引用以其整体并入本文。
目前AAV是用于基因疗法的最常用病毒之一。尽管AAV感染人类和一些其他灵长类动物物种，但是尚不知道会引起疾病并且引起非常轻微的免疫应答。利用AAV的基因治疗载体可以感染分裂细胞和静止细胞二者，并且以染色体外状态持续存在，而不会整合到宿主细胞的基因组中。由于AAV的有利特征，本公开考虑了将AAV用于本文所公开的重组核酸分子和方法。
AAV具有基因治疗载体的几个理想特征，包括结合并且进入靶细胞的能力、进入细胞核、在细胞核中长时间表达的能力、以及低毒性。然而，AAV基因组的小尺寸限制了可以整合的异源DNA的大小。为了最小化此问题，已构建了不编码Rep和整合效率元件(IEE)的AAV载体。保留了ITR，因为它们是包装所需的顺式信号(Daya和Berns,Clin Microbiol Rev 21(4):583-593,2008)。
产生适用于基因疗法的rAAV的方法是已知的(参见，例如，美国专利申请号2012/0100606；2012/0135515；2011/0229971；和2013/0072548；以及Ghosh等人,Gene Ther 13(4):321-329,2006)，并且可以用于本文所公开的重组核酸分子和方法。
在一些实施方案中，本文所公开的核酸是表达盒或转基因的一部分。参见例如，美国专利申请公开案20150139953。表达盒由转基因和调控序列(例如启动子和5'和3'AAV反向末端重复序列(ITR))构成。在一种理想的实施方案中，使用AAV血清型2或8的ITR。然而，可以选择来自其他合适血清型的ITR。通常将表达盒包装到衣壳蛋白中并且递送至选定的宿主细胞中。
在一些实施方案中，本公开提供了产生具有AAV血清型衣壳或其一部分的重组腺相关病毒(AAV)的方法。这种方法涉及培养宿主细胞，所述宿主细胞包含：编码腺相关病毒(AAV)血清型衣壳蛋白的核酸序列；功能性rep基因；由AAV反向末端重复序列(ITR)和转基因构成的表达盒；以及足够的辅助功能以允许将表达盒包装到AAV衣壳蛋白中。参见例如，美国专利申请公开案20150139953。
用于在宿主细胞中培养以将AAV表达盒包装到AAV衣壳中的组分可以以反式提供给宿主细胞。可选地，可以通过稳定的宿主细胞提供任何一种或多种组分(例如，表达盒、rep序列、cap序列和/或辅助功能)，已经使用本领域技术人员已知的方法将所述稳定的宿主细胞工程化以含有一种或多种所需组分。最合适地，这种稳定的宿主细胞将在诱导型启动子的控制下含有一种或多种组分。然而，一种或多种所需组分可以在组成型启动子的控制下。在再另一个可选方案中，选择的稳定宿主细胞可以含有在组成型启动子控制下的一种或多种所选组分和在一个或多个诱导型启动子控制下的一种或多种其他所选组分。例如，可以产生稳定的宿主细胞，其衍生自293细胞(其包含在组成型启动子的控制下的E1辅助功能)，但是包含在诱导型启动子的控制下的rep和/或cap蛋白质。本领域技术人员还可以产生其他稳定的宿主细胞。
在一些实施方案中，本公开涉及重组载体，其包含与转基因可操作地组合的肝特异性启动子核酸序列。转基因是如下核酸序列，其与转基因侧翼的载体序列是异源的，所述核酸序列编码本文所公开的新型fVII、fVIII或fIX蛋白质，以及任选地一种或多种其他目的蛋白质。核酸编码序列以允许转基因在宿主细胞中转录、翻译和/或表达的方式与调控组分可操作地连接。
表达盒可以被携带在任何合适的载体例如质粒上，将所述合适的载体递送至宿主细胞。可以将在本公开中有用的质粒工程化，使得它们适合于复制以及任选地整合入原核细胞、哺乳动物细胞或二者中。这些质粒(或携带5'AAV ITR-异源分子-3'ITR的其他载体)含有允许在真核生物和/或原核生物中的表达盒复制的序列以及这些系统的选择标记。优选地，将携带表达盒的分子转染到细胞中，在所述细胞中表达盒可以瞬时存在。可选地，无论是在染色体处还是作为附加体，可以将表达盒(携带5'AAV ITR-异源分子-3'ITR)稳定地整合到宿主细胞的基因组中。在某些实施方案中，表达盒可以以多个拷贝存在，任选地以头对头、头对尾或尾对尾多联体形式存在。合适的转染技术是已知的，并且可以容易地用于将表达盒递送至宿主细胞。
通常，当通过转染来递送包含表达盒的载体时，考虑例如选择的载体、递送方法和选择的宿主细胞等因素，可以调节载体和载体DNA相对于宿主细胞的相对量。除表达盒外，宿主细胞还含有驱动AAV衣壳蛋白在宿主细胞中表达的序列、以及具有与表达盒中发现的AAV ITR血清型相同的血清型或交叉互补血清型的rep序列。尽管提供rep和cap的一个或多个分子可以瞬时存在于宿主细胞中(即通过转染)，但是优选rep和cap蛋白质中的一个或二者以及控制其表达的一个或多个启动子在宿主细胞中稳定表达，例如作为附加体或整合到宿主细胞的染色体中。
包装宿主细胞通常还含有用于包装本公开的rAAV的辅助功能。任选地，这些功能可以由疱疹病毒提供。最期望的是，必需的辅助功能各自从人类或非人类灵长类动物腺病毒来源(例如以上描述的那些)提供和/或从多种来源(包括美国菌种保藏中心(ATCC)，Manassas，Va.(美国))获得。所需的辅助功能可以使用允许它们在细胞中表达的任何手段来提供。
可以通过本领域已知的或如上所公开的任何手段将载体引入宿主细胞，所述手段包括转染、感染、电穿孔、脂质体递送、膜融合技术、高速DNA包被丸粒、病毒感染或原生质体融合等。一种或多种腺病毒基因可以稳定整合到宿主细胞的基因组中，稳定表达为附加体，或瞬时表达。基因产物都可以瞬时表达、在附加体上或稳定整合，或一些基因产物可以稳定表达，而其他基因产物瞬时表达。此外，每个腺病毒基因的启动子可以独立地选自组成型启动子、诱导型启动子或天然腺病毒启动子。例如，启动子可以通过生物体或细胞的特定生理状态(即，通过分化状态或在复制或静止的细胞中)或通过外源性添加的因子来调控。
AAV技术可以改编以用于这些和其他病毒载体系统中以进行体外、离体或体内基因递送。在某些实施方案中，本公开考虑了本文所公开的核酸和载体在多种rAAV和非rAAV载体系统中的用途。此类载体系统可以包括例如慢病毒、逆转录病毒、痘病毒、牛痘病毒(vaccinia virus)和腺病毒系统等。
在一些实施方案中，预期本文所公开的病毒粒子、核酸和载体可用于多种目的，包括用于递送治疗性分子以用于治疗性蛋白质的基因表达。
由本文报道的核酸(例如可操作地与启动子组合)编码的治疗性蛋白质包括用于治疗凝血障碍的那些，所述凝血障碍包括血友病B(例如使用如本文提供的fIX蛋白质)、血友病A(例如使用如本文提供的fVIII蛋白质)和先天性前转变素缺乏症(例如使用如本文提供的fVII蛋白质)。
在一些实施方案中，提供了一种在有需要的受试者中诱导血液凝结的方法。所述方法包括向受试者给予治疗有效量的载体(例如AAV载体、慢病毒载体或逆转录病毒载体)，所述载体编码如本文所述的对fVII、fVIII或fIX蛋白质进行编码的核酸序列。在一些实施方案中，所述受试者是患有凝血障碍(例如血友病A或血友病B)的受试者。在一些实施方案中，所述凝血障碍是血友病A，并且向所述受试者给予载体，所述载体包含编码具有fVIII活性的蛋白质的核酸分子。在其他实施方案中，所述凝血障碍是血友病B，并且向所述受试者给予载体，所述载体包含编码具有fIX活性的蛋白质的核酸分子。在其他实施方案中，所述凝血障碍是先天性前转变素缺乏症，并且向所述受试者给予载体，所述载体包含编码具有fVII活性的蛋白质的核酸分子。
对诊断为血友病A的患者的治疗选择是重组fVIII的外源性给予，有时也称为fVIII替代疗法。相似的替代疗法用于治疗血友病B(使用外源性fIX的给予)和先天性前转变素缺乏症(使用外源性fVII的给予)。在一些实施方案中，可以通过给予如本文所述的重组fVIII或fIX蛋白质治疗患有血友病A或B的患者。在一些患者中，这些疗法可导致与所给予的凝血因子结合的抗体的产生。随后，凝血因子-抗体结合的缀合物，通常称为抑制剂，干扰或延迟外源凝血因子引起血液凝结的能力。抑制性自身抗体有时也自发出现在没有凝血障碍(例如血友病)遗传风险(称为获得性血友病)的受试者中。通常在进行外源性凝血因子治疗之前进行抑制性抗体测定，以确定抗凝治疗是否有效。
历史上已经使用“贝塞斯达测定(Bethesda assay)”来定量fVIII结合抗体的浓度的抑制强度。在所述测定中，例如在进行手术之前，制备了来自患者的血浆的系列稀释物，并且将每种稀释物与等体积的作为fVIII来源的正常血浆混合。孵育几个小时后，测量每种稀释混合物中fVIII的活性。在多次重复稀释后，具有防止fVIII凝血活性的抗体抑制剂浓度表明了不受控出血的风险增加。稀释约十次后，感觉到具有抑制剂滴度的患者不太可能对外源性fVIII输注产生反应以停止出血。贝塞斯达滴度定义为稀释度的倒数，所述稀释度导致存在于正常人血浆中FVIII活性的50％抑制。认为贝塞斯达滴度大于10是对FVIII替代疗法反应的阈值。
在某些实施方案中，本公开涉及诱导血液凝结的方法，所述方法包括向有需要的受试者给予有效量的病毒粒子或衣壳，所述病毒粒子或衣壳包含含有编码本文所公开的凝血因子的核酸的载体。
在某些实施方案中，所述受试者被诊断为患有血友病A或B或获得性血友病或者不太可能对外源性凝血因子输注有反应(例如基于贝塞斯达测定结果)。
在一些实施方案中，本公开涉及用于治疗血友病B的基因转移方法，所述方法使用编码人fIX的腺相关病毒(AAV)载体作为基因递送媒介物。尽管用于血友病B的若干种此类基于AAV的基因疗法已经进入人类临床试验，但是由于病毒给予后仅导致疾病部分修正，治疗性蛋白质(凝血因子fIX)低表达，这些基因疗法受到阻碍。AAV载体毒性限制了可以安全给予的病毒剂量。通常，载体以低于毒性阈值的病毒剂量提供fIX的有效表达。
在一些实施方案中，本公开涉及用于治疗血友病A的基因转移方法，所述方法使用编码人fVIII的腺相关病毒(AAV)载体作为基因递送媒介物。尽管用于血友病A的若干种此类基于AAV的基因疗法已经进入人类临床试验，但是由于病毒给予后仅导致疾病部分修正，治疗性蛋白质(凝血因子fVIII)低表达，这些基因疗法受到阻碍。AAV载体毒性限制了可以安全给予的病毒剂量。通常，载体以低于毒性阈值的病毒剂量提供fVIII的有效表达。
在一些实施方案中，本公开涉及用于治疗先天性前转变素缺乏症的基因转移方法，所述方法使用编码人fVII的腺相关病毒(AAV)载体作为基因递送媒介物。尽管用于血友病A的基于AAV的基因疗法已经进入人类临床试验，但是由于病毒给予后仅导致疾病部分修正，治疗性蛋白质(凝血因子fVII)低表达，这些基因疗法受到阻碍。AAV载体毒性限制了可以安全给予的病毒剂量。通常，载体以低于毒性阈值的病毒剂量提供fVII的有效表达。
在一些实施方案中，本公开涉及用于治疗血友病B的基因转移方法，所述方法使用编码人fIX的慢病毒载体作为基因递送媒介物。编码转基因的慢病毒载体的递送可以例如通过直接给予受试者或通过离体转导以及将造血干细胞和祖细胞与载体一起移植。通常，载体以低于毒性阈值的病毒剂量提供fVII的有效表达。
在一些实施方案中，本公开涉及用于治疗血友病A的基因转移方法，所述方法使用编码人fVIII的慢病毒载体作为基因递送媒介物。编码转基因的慢病毒载体的递送可以例如通过直接给予受试者或通过离体转导以及将造血干细胞和祖细胞与载体一起移植。通常，载体以低于毒性阈值的病毒剂量提供fVII的有效表达。
在一些实施方案中，本公开涉及用于治疗先天性前转变素缺乏症的基因转移方法，所述方法使用编码人fVII的慢病毒载体作为基因递送媒介物。编码转基因的慢病毒载体的递送可以例如通过直接给予受试者或通过离体转导以及将造血干细胞和祖细胞与载体一起移植。通常，载体以低于毒性阈值的病毒剂量提供fVII的有效表达。
在一些实施方案中，包含本文所公开的核酸的重组病毒粒子、衣壳或载体可以经由肝动脉、门静脉或静脉内递送至肝脏，以在血液中产生治疗水平的治疗性蛋白质或凝血因子。体优地将衣壳或载体(vector)悬浮于生理相容的载体中，可以给予人类或非人类哺乳动物患者。鉴于转移病毒所针对的适应症，本领域技术人员可以容易地选择合适的载体(carrier)。例如，一种合适的载体包括盐水，其可以用多种缓冲溶液(例如磷酸盐缓冲盐水)配制。其他示例性载体包括无菌盐水、乳糖、蔗糖、磷酸钙、明胶、葡聚糖、琼脂、果胶、芝麻油和水。
任选地，本公开的组合物可以含有其他药学上可接受的赋形剂，例如防腐剂或化学稳定剂。合适的示例性防腐剂包括三氯叔丁醇、山梨酸钾、山梨酸、二氧化硫、没食子酸丙酯、对羟基苯甲酸酯、乙基香兰素、甘油、苯酚和对氯酚。合适的化学稳定剂包括明胶和白蛋白。
以足够的量将重组病毒粒子、衣壳或载体给予以转染细胞，并且以提供足够水平的基因转移和表达，以提供没有不当副作用或具有医学上可接受的生理作用的治疗益处，所述治疗益处可以由医学领域的技术人员确定。给药的常规的且药学上可接受的途径包括但不限于直接递送至所需器官(例如，肝脏(可选地经由肝动脉)或肺)、口服、吸入、鼻内、气管内、动脉内、眼内、静脉内、肌内、皮下、皮内和其他肠胃外给药途径。如果需要，可以组合给药途径。
重组病毒粒子、衣壳或载体的剂量将主要取决于例如所治疗的病症、患者的年龄、体重和健康状况等因素，并且因此可能因患者而异。例如，病毒载体的治疗有效的人剂量通常在约0.1ml至约100ml溶液的范围内，所述溶液含有从约1x109至1x1016个基因组病毒载体的浓度。
本公开的重组病毒载体提供了一种有效的基因转移媒介物，即使在生物体具有针对所述蛋白质的中和抗体的情况下，所述基因转移媒介物也可以在体内或离体将所选蛋白质递送至所选宿主细胞。在一个实施方案中，本文所公开的载体和细胞离体混合；使用常规方法培养感染的细胞；并且将转导细胞重新输注到患者中。
实施例
提供以下实施例以说明某些特定特征和/或实施方案。这些实施例不应该解释为将本公开限制于所描述的特定特征或实施方案。
实施例1
通过祖先蛋白质重构对凝血因子IX进行生物工程化
此实施例说明了fIX序列的优化，以改善凝血因子活性、用于蛋白质表达的实用性、和治疗应用(例如基因疗法)。
用于治疗血友病B的转化性血友病治疗学的发展受到凝血因子(例如fIX)的大小、不稳定性、免疫原性和生物合成无效性的阻碍。因此，期望找到具有增加的活性(例如，由于增加的血清半衰期或增加的酶活性所致)的其他fIX序列，因为这有可能在实现完全预防的同时减少输注的频率。
为了搜索可有助于改善血友病B凝血因子替代疗法的其他fIX序列，在PAML 4.1版中使用基于DNA和氨基酸的模型通过贝叶斯推理构建了具有相应祖先节点(An)序列的哺乳动物fIX系统发生树。最初，选择了九个An-fIX序列进行重构，如下所示：
An63 fIX(SEQ ID NO:17)
An65 fIX(SEQ ID NO:18)
An70 fIX(SEQ ID NO:19)
An84 fIX(SEQ ID NO:20)
An88 fIX(SEQ ID NO:21)
An95 fIX(SEQ ID NO:22)
An96 fIX(SEQ ID NO:23)
An97 fIX(SEQ ID NO:24)
An102 fIX(SEQ ID NO:25)
图1示出了以上fIX蛋白质与hfIX序列的序列比对，所述hfIX序列提供为SEQ IDNO:42：
另外，将“Padua”突变引入An96和An97 fIX蛋白质中，以确定此突变的添加是否可能增加因子IX的活性。Padua突变是在成熟fIX氨基酸的R338L取代，其增加fIX活性(“fIXPadua,”参见Paolo等人,“X-Linked Thrombophilia with a Mutant Factor IX”N Engl JMed；361:1671-1675,2009)。具有Padua突变(以粗体下划线示出)的An96和An97 fIX蛋白质的序列如下所示：
An96 fIX Padua(SEQ ID NO:1)
An97 fIX Padua(SEQ ID NO:2)
在SEQ ID NO:1中，残基1-28是信号肽(粗体，称为fIX残基-46至-18)，残基29-46是前肽(斜体，称为fIX残基-18至-1)，以及残基47-462是成熟fIX序列(称为成熟fIX残基+1至415)。在SEQ ID NO:2中，残基1-28是信号肽(粗斜体，称为成熟fIX残基-46至-18)，残基29-46是前肽(粗体，称为fIX残基-18至-1)，以及残基47-461是成熟fIX残基(称为成熟fIX残基+1至415)。关于SEQ ID NO:1，残基47-92是GLA结构域，残基93-129是第一EGF样结构域，残基130-192是第二EGF样结构域，残基193-227是活化肽，以及残基228-462是催化结构域。相应的结构域也存在于SEQ ID NO:2中。
相对于对相应的人类非密码子优化序列进行编码的天然存在的核苷酸序列，例如使用WO 2016/168728中所述的肝脏密码子优化方案，将编码这些fIX蛋白质的cDNA核苷酸序列通过实施对人肝脏细胞特异的密码子使用偏倚性来优化。产生了密码子优化的、用于在肝组织中表达的、对SEQ ID NO:1和SEQ ID NO:2进行编码的核酸序列，并且提供如下：
An96 fIX Padua(SEQ ID NO:9)
An97 fIX Padua(SEQ ID NO:10)
在SEQ ID NO:9和10中，信号肽以粗体示出，前肽以粗斜体示出，以及Padua突变的突变核苷酸以粗体下划线示出。可以将经肝脏密码子优化的fIX Padua序列包括在载体(例如AAV载体)中，并且可操作地与启动子(例如肝脏特异性启动子，例如HCB启动子)连接，以用于给予受试者，例如以治疗受试者的血友病B。
在用相应的fIX表达载体瞬时转染的HepG2细胞中评估了优化的fIX序列的体外表达(参见图2)。将HepG2细胞以300,000个细胞/孔接种于24孔板中，所述板含有补充有10％FBS和1％Pen/Strep的DMEM。在转染当天，细胞大约70％-80％汇合。将转染复合物混合物按以下最终浓度制备：0.5μg质粒DNA、1.5μl TransIT-X2转染试剂，以及OptiMEM补充至50μL的最终体积。将所有的An-fIX转基因克隆到自身失活慢病毒载体表达盒中，所述表达盒含有驱动An-fIX表达的内部EF1α启动子。人fIX-Padua(R338L)构建体是从scAAV3 ITR盒中表达的，所述盒含有在人类fIX转基因之前的HHS4增强子-转甲状腺素蛋白启动子和小鼠内含子的微小病毒。将转染复合物用移液器上下吹打以混合，并且允许在室温下孵育15分钟至30分钟，之后逐滴添加到铺板的细胞中并且轻轻摇动以均匀分布。24小时后，将培养基更换为补充有10％FBS和1％Pen/Strep的DMEM，并且使用单阶段凝血测定来测定条件培养基的fX活性。每个An-fIX蛋白质在利用人血友病B血浆作为底物的凝血测定中显示出活性，从而证明了进化的哺乳动物的相容性。如图2所示，将Padua突变掺入An96和An97序列中，相对于相应的未修饰的An96和An97蛋白质，大大增加了fIX活性。另外，An96 Padua和An97 Padua蛋白质提供了比人fIX蛋白质(hfIX)显著更高的fIX活性，所述人fIX蛋白质也由肝脏密码子优化的序列编码(增加约3.7倍)。
另外，在血友病B小鼠中评估了优化的fIX序列的体内表达(图3)。将肝密码子优化的人fIX Padua(R338L)、An96 fIX和An96fIX Padua(R338L，SEQ ID NO:9)转基因克隆到含有scAAV3-ITR-HHS4-TTR-MVM-FIX-sPa重组AAV表达盒的质粒中。将质粒用保留侧接转基因的ITRS的酶线性化，并且在65℃下热灭活20分钟。筛选每种消化物以进行DNA质量比较，并且在注射前显示是可接受的。将小鼠随机化，并且使用加温至37℃的
-EEDelivery Solution，以5μg/mL制备质粒DNA稀释物。每只实验动物在≤8s内接受以流体动力学方式递送的0.5μg/g线性化质粒DNA。对3个治疗组盲式进行注射：1)scAAV3-HHS4-TTR-MVM-fIX_An96-LCO-sPa，2)scAAV3-HHS4-TTR-MVM-fIX_An96-Padua-LCO-sPa，3)s cAAV3-HHS4-TTR-MVM-fIX-148T-Padua-LCO-NCO-sPA，以及第四个仅盐水对照注射组。总共使用了9周龄至11周龄的15只实验小鼠。每个治疗组接受5只小鼠。选择三只12周龄的血友病A E16小鼠作为对照。前一天将小鼠的耳朵打孔并且称重。在质粒给予后1、3、7和14天使小鼠出血。处理血浆，并且使用单阶段凝血测定来分析fI X活性。用An96 fIX Padua载体治疗的动物，但是不是用An96 fI X或hfIX治疗的动物，经两周达到了持续的超生理血浆fIX活性水平(分别为约15-20IU/ml fIX活性与0-10IU/ml fIX活性)。
另外，在fIX+/+小鼠中评估了优化的fIX序列的体内表达(图4)。生产含有以下项的AAV2/8载体：肝脏定向启动子(HCB)、小鼠内含子的微小病毒、以及三个fIX转基因(人fIX-Padua、An96-fIX-Padua(SEQ ID NO:9)或hfIX Q11R-E240K-H243P-R338L)之一。盲式对随机wt fIX+/+小鼠进行测定。经由尾静脉向雄性9周龄至11周龄的wt fIX+/+小鼠注射5x1011个载体基因组/kg重组AAV(n＝3/组)。在基线处，在AAV给予之前，和AAV给予后4周，使小鼠出血，并且通过单阶段凝血测定评估血浆fIX活性水平。在图4中绘制了AAV给予前后fIX活性水平的变化。通过单因素方差分析和Holm-Sidak事后分析进行统计学比较。星号表示P<0.05。与对照、hfIX-Padua或hfIX Q11R-E240K-H243P-R338L小鼠相比，用AAV-2/8-AN96-fIX-PAgua治疗的小鼠显示fIX活性显著更大的增加。没有其他组彼此之间存在显著不同。
实施例2
通过祖先蛋白质重构对凝血因子VIII进行生物工程化
此实施例说明了fVIII序列的优化，以改善凝血因子活性、蛋白质表达、和治疗应用(例如基因疗法)。
用于治疗血友病A的转化性血友病治疗学的发展受到凝血因子(例如fVIII)的大小、不稳定性、免疫原性和生物合成无效性的阻碍。通过对现有脊椎动物物种的fVIII直系同源物的研究，发现了可以克服人fVIII的某些限制的独特分子特性、细胞特性和生化特性。尽管此方法促进了用于获得性血友病A的重组猪FVIII的开发，但仍需要改进。例如，期望发现具有增加的活性(例如由于增加的血清半衰期或增加的酶活性所致)的其他fVIII序列，因为这有可能在获得完全预防的同时减少输注的频率。
为了搜索可有助于改善血友病A凝血因子替代疗法的其他fVIII序列，在PAML 4.1版中使用基于DNA和氨基酸的模型通过贝叶斯推理构建了具有相应祖先节点(An)序列的哺乳动物fVIII系统发生树。最初，选择了九个An-fVIII序列进行重构，如下所示：
An63 fVIII(SEQ ID NO:26)
An65 fVIII(SEQ ID NO:27)
An70 fVIII(SEQ ID NO:28)
An84 fVIII(SEQ ID NO:29)
An88 fVIII(SEQ ID NO:30)
An95 fVIII(SEQ ID NO:31)
An96 fVIII(SEQ ID NO:32)
An97 fVIII(SEQ ID NO:33)
An102 fVIII(SEQ ID NO:34)
修饰An84、An63、An96和An97 fVIII蛋白质的序列，以去除B-结构域，并且通过肽接头(B结构域缺失的或“BDD”fVIII蛋白质)将A2结构域与活化肽连接。修饰的氨基酸序列如下：
An84 fVIII BDD(SEQ ID NO:3)
An63 fVIII BDD(SEQ ID NO:4)
An96 fVIII BDD(SEQ ID NO:5)
An97 fVIII BDD(SEQ ID NO:6)
以SEQ ID NO:3提供的An84 fVIII序列包括信号肽(SEQ ID NO:3的残基1-19，以粗体示出)，A1结构域(SEQ ID NO:3的残基20-393)，A2结构域(SEQ ID NO:3的残基394-760)，B-结构域缺失同时A2结构域与活化肽通过接头(SEQ ID NO:3的残基761-774，以粗体下划线示出)连接，活化肽(SEQ ID NO:3的残基775-815)，A3结构域(SEQ ID NO:3的残基816-1145)，C1结构域(SEQ ID NO:3的残基1146-1298)，和C2结构域(SEQ ID NO:3的残基1298-1458)。相应的结构域也存在于SEQ ID NO:4-6中。
相对于对相应的人类非密码子优化序列进行编码的天然存在的核苷酸序列，例如使用WO 2016/168728中所述的肝脏密码子优化方案，将编码这些fIX蛋白质的cDNA核苷酸序列通过实施对人肝脏细胞特异的密码子使用偏倚性来优化。产生了密码子优化的、用于在肝组织中表达的、对SEQ ID NO:3-6进行编码的核酸序列，并且提供如下：
An84 fVIII BDD(SEQ ID NO:11)
An63 fVIII BDD(SEQ ID NO:12)
An96 fVIII BDD(SEQ ID NO:13)
An97 fVIII BDD(SEQ ID NO:14)
在SEQ ID NO:12-14中，信号肽以粗体示出。可以将经肝脏密码子优化的fVIIIBDD序列包括在载体(例如AAV载体)中，并且可操作地与启动子(例如肝脏特异性启动子，例如HCB启动子)连接，以用于给予受试者，例如以治疗受试者的血友病A。
评估了优化的fVIII序列的体外凝血活性(参见图5)。使用瞬时转染的表达载体在HEK293T17细胞中表达AN63、An84、AN96、An97、An102、HSQ、Et3和53K fVIII蛋白质。在24孔板中将HEK293T17细胞用编码所指示fVIII蛋白质的500ng质粒DNA使用PEI以2:1(w:w)的比率瞬时转染。在收集上清液之前24小时，将培养基更换为无血清SFM4CHO培养基。每个构建体以一式三份转染，并且经由单阶段凝血测定测量fVIII活性。所有的构建体均是经肝脏密码子优化的，并且转基因由EF1α启动子驱动。
实施例3
通过祖先蛋白质重构对凝血因子VIII进行生物工程化
此实施例说明了fVII序列的优化，以改善凝血因子活性、蛋白质表达、和治疗应用(例如基因疗法)。
用于治疗先天性前转变素缺乏症的转化性血友病治疗学的发展受到凝血因子(例如fVII)的大小、不稳定性、免疫原性和生物合成无效性阻碍。因此，期望发现具有增加的活性(例如由于增加的血清半衰期或增加的酶活性所致)的其他fVII序列，因为这有可能在获得完全预防的同时减少输注的频率。
为了搜索可有助于改善疗法(例如凝血因子替代疗法)的fVII序列，在PAML 4.1版中使用基于DNA和氨基酸的模型通过贝叶斯推理构建了具有相应祖先节点(An)序列的哺乳动物fVII系统发生树。最初，选择了九个An-fVII序列进行重构，如下所示：
An61 fVII(SEQ ID NO:8)
An63 fVII(SEQ ID NO:35)
An68 fVII(SEQ ID NO:36)
An81 fVII(SEQ ID NO:7)
An85 fVII(SEQ ID NO:37)
An91 fVII(SEQ ID NO:38)
An92 fVII(SEQ ID NO:39)
An93 fVII(SEQ ID NO:40)
An98 fVII(SEQ ID NO:41)
关于SEQ ID NO:7的fVII序列，残基1-20是信号肽，残基21-83是GLA结构域，残基84-120是第一EGF样结构域，残基121-190是第二EGF样结构域，残基191-444是催化结构域。相应的结构域也存在于SEQ ID NO:8和35-41中。
如上所讨论的，相对于对相应的人类非密码子优化序列进行编码的天然存在的核苷酸序列，将编码这些fVII蛋白质的cDNA核苷酸序列通过实施对人肝脏细胞特异的密码子使用偏倚性来优化。产生了密码子优化的、用于在肝组织中表达的、对SEQ ID NO:3-6进行编码的核酸序列，并且提供如下：
An81 fVII(SEQ ID NO:15)
An61 fVII(SEQ ID NO:16)
在SEQ ID NO:15和16中，信号肽以粗体示出。可以将经肝脏密码子优化的fVII序列包括在载体(例如AAV载体)中，并且可操作地与启动子(例如肝脏特异性启动子，例如HCB启动子)连接，以用于给予受试者，例如以治疗受试者的血友病B。
实施例4
使用基于AAV的基因疗法治疗人血友病A
此实施例描述了临床上使用编码fVIII的AAV载体治疗血友病A的示例性方法。
选择诊断为患有血友病A的患者进行治疗。向患者给予治疗有效量的在HCB启动子控制下的编码An84 BDD fVIII变体(例如SEQ ID NO:11)的重组AAV。可以静脉内给予重组AAV。可以由医学从业者选择适当的治疗剂量。在一些情况下，治疗有效剂量在1x 1011至1x1014个病毒粒子(vp)/kg的范围内，例如约1x 1012个vp/kg。在大多数情况下，向患者给予单个剂量。可以随时间监测受试者的健康，以确定治疗的有效性。
实施例5
使用基于AAV的基因疗法治疗人血友病B
此实施例描述了临床上使用编码fIX的AAV载体治疗血友病B的示例性方法。
选择诊断为血友病B的患者进行治疗。向患者给予治疗有效量的在HCB启动子控制下的编码An96 fIX Padua变体(例如SEQ ID NO:9)的重组AAV。可以静脉内给予重组AAV。可以由医学从业者选择适当的治疗剂量。在一些情况下，治疗有效剂量在1x 1011至1x 1014个病毒粒子(vp)/kg的范围内，例如约1x 1012个vp/kg。在大多数情况下，向患者给予单个剂量。可以随时间监测受试者的健康，以确定治疗的有效性。
清楚的是，在不脱离所描述的实施方案的精神的情况下，可以改变或修改所描述的方法或组合物的精确细节。我们要求落入以下权利要求的范围和精神内的所有此类修改和改变。
序列表
<110> 爱莫里大学(Emory University)
亚特兰大儿童医疗保健公司(Children's Healthcare of Atlanta, Inc.)
佐治亚技术研究公司(Georgia Tech Research Corporation)
<120> 凝血因子变体及其用途
<130> 6975-100557-02
<150> US 62/503,766
<151> 2017-05-09
<160> 42
<170> PatentIn version 3.5
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305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val
755 760 765
Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Ser Glu
770 775 780
Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Ile Glu Met Lys Arg
785 790 795 800
Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Gly Pro Arg Ser
805 810 815
Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu
820 825 830
Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala
835 840 845
Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe
850 855 860
Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
865 870 875 880
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn
885 890 895
Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr
900 905 910
Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro
915 920 925
Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
930 935 940
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala
945 950 955 960
Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly
965 970 975
Leu Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
980 985 990
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile
995 1000 1005
Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg
1010 1015 1020
Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe
1025 1030 1035
Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1040 1045 1050
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp
1055 1060 1065
Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His
1070 1075 1080
Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys
1085 1090 1095
Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu
1100 1105 1110
Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile
1115 1120 1125
Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr
1130 1135 1140
Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile
1145 1150 1155
Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala
1160 1165 1170
Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp
1175 1180 1185
Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala
1190 1195 1200
Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys
1205 1210 1215
Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu
1220 1225 1230
Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr
1235 1240 1245
Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His
1250 1255 1260
Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His
1265 1270 1275
Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1280 1285 1290
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser
1295 1300 1305
Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr
1310 1315 1320
Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu
1325 1330 1335
Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys
1340 1345 1350
Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly
1355 1360 1365
Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val
1370 1375 1380
Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr
1385 1390 1395
Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln
1400 1405 1410
Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu
1415 1420 1425
Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile
1430 1435 1440
Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu Tyr
1445 1450 1455
<210> 4
<211> 1458
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 4
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Pro Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Ser Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Arg Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Ile Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Ala Asn Glu Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Arg Pro Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Pro Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Tyr Asp Ser Asp Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Ile His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Thr Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asn Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Met Pro Ile Met Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Leu Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Phe Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Asp
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Asn
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val
755 760 765
Leu Lys His His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Pro Glu
770 775 780
Gln Glu Lys Ile Asp Tyr Asp Asp Thr Leu Ser Ile Glu Met Lys Arg
785 790 795 800
Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Gly Pro Arg Ser
805 810 815
Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu
820 825 830
Trp Asp Tyr Gly Met Ser Arg Ser Pro His Ala Leu Arg Asn Arg Ala
835 840 845
Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe
850 855 860
Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
865 870 875 880
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn
885 890 895
Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr
900 905 910
Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro
915 920 925
Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
930 935 940
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala
945 950 955 960
Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Leu His Ser Gly
965 970 975
Leu Ile Gly Pro Leu Leu Ile Cys Arg Thr Asn Thr Leu Asn Pro Ala
980 985 990
His Gly Arg Gln Leu Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile
995 1000 1005
Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg
1010 1015 1020
Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe
1025 1030 1035
Lys Lys Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1040 1045 1050
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp
1055 1060 1065
Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His
1070 1075 1080
Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys
1085 1090 1095
Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu
1100 1105 1110
Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile
1115 1120 1125
Gly Glu His Leu Gln Ala Gly Met Ser Thr Leu Phe Leu Val Tyr
1130 1135 1140
Ser Lys Glu Cys Gln Thr Pro Leu Gly Met Ala Ser Gly Arg Ile
1145 1150 1155
Arg Asp Ser Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala
1160 1165 1170
Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp
1175 1180 1185
Ser Thr Lys Asp Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala
1190 1195 1200
Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys
1205 1210 1215
Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu
1220 1225 1230
Asp Gly Lys Lys Trp Gln Ser Tyr Arg Gly Asn Ser Thr Gly Thr
1235 1240 1245
Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His
1250 1255 1260
Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His
1265 1270 1275
Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1280 1285 1290
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser
1295 1300 1305
Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr
1310 1315 1320
Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu
1325 1330 1335
Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys
1340 1345 1350
Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly
1355 1360 1365
Ile Thr Thr Gln Gly Ala Lys Ser Leu Leu Thr Ser Met Tyr Val
1370 1375 1380
Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr
1385 1390 1395
Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln
1400 1405 1410
Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu
1415 1420 1425
Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His His Ile
1430 1435 1440
Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu Tyr
1445 1450 1455
<210> 5
<211> 1458
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 5
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val
755 760 765
Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Ser Glu
770 775 780
Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Ile Glu Met Lys Arg
785 790 795 800
Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Gly Pro Arg Ser
805 810 815
Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu
820 825 830
Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala
835 840 845
Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe
850 855 860
Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
865 870 875 880
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn
885 890 895
Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr
900 905 910
Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro
915 920 925
Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
930 935 940
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala
945 950 955 960
Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly
965 970 975
Leu Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
980 985 990
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile
995 1000 1005
Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg
1010 1015 1020
Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe
1025 1030 1035
Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1040 1045 1050
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp
1055 1060 1065
Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His
1070 1075 1080
Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys
1085 1090 1095
Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu
1100 1105 1110
Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile
1115 1120 1125
Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr
1130 1135 1140
Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile
1145 1150 1155
Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala
1160 1165 1170
Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp
1175 1180 1185
Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala
1190 1195 1200
Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys
1205 1210 1215
Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu
1220 1225 1230
Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr
1235 1240 1245
Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His
1250 1255 1260
Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His
1265 1270 1275
Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1280 1285 1290
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser
1295 1300 1305
Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr
1310 1315 1320
Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu
1325 1330 1335
Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys
1340 1345 1350
Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly
1355 1360 1365
Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val
1370 1375 1380
Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr
1385 1390 1395
Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln
1400 1405 1410
Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu
1415 1420 1425
Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile
1430 1435 1440
Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu Tyr
1445 1450 1455
<210> 6
<211> 1458
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 6
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Met Gln Asp Thr
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asn
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Ser Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Pro Pro Val
755 760 765
Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Ser Asp
770 775 780
Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Thr Glu Met Lys Arg
785 790 795 800
Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Gly Pro Arg Ser
805 810 815
Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg Leu
820 825 830
Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn Arg Ala
835 840 845
Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe Gln Glu Phe
850 855 860
Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly Glu Leu Asn Glu
865 870 875 880
His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala Glu Val Glu Asp Asn
885 890 895
Ile Met Val Thr Phe Lys Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr
900 905 910
Ser Ser Leu Ile Ser Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro
915 920 925
Arg Lys Asn Phe Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys
930 935 940
Val Gln His His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala
945 950 955 960
Trp Ala Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly
965 970 975
Leu Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
980 985 990
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile
995 1000 1005
Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg
1010 1015 1020
Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe
1025 1030 1035
Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp
1040 1045 1050
Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp
1055 1060 1065
Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His
1070 1075 1080
Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys
1085 1090 1095
Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu
1100 1105 1110
Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile
1115 1120 1125
Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr
1130 1135 1140
Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile
1145 1150 1155
Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala
1160 1165 1170
Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp
1175 1180 1185
Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala
1190 1195 1200
Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys
1205 1210 1215
Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu
1220 1225 1230
Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr
1235 1240 1245
Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His
1250 1255 1260
Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His
1265 1270 1275
Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met
1280 1285 1290
Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser
1295 1300 1305
Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr
1310 1315 1320
Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu
1325 1330 1335
Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys
1340 1345 1350
Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly
1355 1360 1365
Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val
1370 1375 1380
Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr
1385 1390 1395
Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln
1400 1405 1410
Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu
1415 1420 1425
Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile
1430 1435 1440
Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu Tyr
1445 1450 1455
<210> 7
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 7
Met Ala Pro Arg Ala Leu Ala Leu Leu Cys Phe Leu Leu Gly Leu Gln
1 5 10 15
Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His Ser Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Arg Ser Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Asp Gln Leu Ile
115 120 125
Cys Met Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Glu Ala Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Thr Leu Gln Ala
145 150 155 160
Asp Gly Val Ser Cys Thr Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Val Leu Glu Lys Arg Asn Ala Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Val Leu
195 200 205
Lys Leu Asn Gly Ala Leu Leu Cys Gly Gly Thr Leu Leu Asp Thr Ser
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Arg Ser Trp Arg
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu Asp Gly
245 250 255
Asp Glu Gln Glu Arg Gln Val Ala Gln Val Ile Ile Pro Asp Lys Tyr
260 265 270
Val Pro Gly Lys Thr Asp His Asp Ile Ala Leu Leu Arg Leu Arg Arg
275 280 285
Pro Val Ala Leu Thr Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Arg Thr Leu Ala Tyr Ile Arg Phe Ser Arg Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu Gln Ser
340 345 350
Lys Arg Arg Ala Asp Ser Pro Ala Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Thr Glu Trp Leu Ser Arg Leu Met Asp Ser Glu
420 425 430
Pro His Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 8
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 8
Met His Ser Arg Arg Leu Ala Phe Leu Cys Phe Leu Leu Gly Leu Gln
1 5 10 15
Gln Ser Leu Thr Ala Val Phe Ile Asn Gln Glu Glu Ala Asn Ser Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Ser
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Lys Ser Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Thr Tyr Asn Asp Gly Asn Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Val Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Glu
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Ser Gln Leu Ile
115 120 125
Cys Met Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp Asn Pro
130 135 140
Glu Thr Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Thr Leu Met Ala
145 150 155 160
Asp Gly Val Ser Cys Thr Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Val Leu Glu Lys Arg Asn Asp Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Val Ile
195 200 205
Lys Leu Asn Gly Glu Leu Leu Cys Gly Gly Thr Leu Leu Asp Ala Thr
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Leu Arg Asn Trp Lys
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu Asp Gly
245 250 255
Asp Glu Gln Glu Arg Gln Val Ala Gln Ile Ile Ile Pro Asp Lys Tyr
260 265 270
Ile Pro Gly Lys Thr Asp His Asp Ile Ala Leu Leu Arg Leu Arg Thr
275 280 285
Pro Val Asn Phe Thr Asp Tyr Val Val Pro Leu Cys Leu Pro Glu Lys
290 295 300
Ala Phe Ser Glu Gln Thr Leu Ala Tyr Ile Arg Phe Ser Ser Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Thr Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu Gln Thr
340 345 350
Lys Arg Thr Ala Asn Ser Pro Ala Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Thr Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Lys Tyr Gln Gly Thr Trp Tyr Leu Thr Gly Ile Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Ile Glu Trp Leu Asn Arg Leu Met Asp Ser Lys
420 425 430
Pro Ser Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 9
<211> 1389
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 9
atgcagtgcc tgaacatgat catggccgag tcccccggcc tgatcaccat ctgcctgctg 60
gggtacctgc tgagcgccga gtgcaccgtg ttcctggacc acgagaacgc caccaagatc 120
ctgaacaggc ccaagagata caactccggc aagctggagg agttcgtgag ggggaacctg 180
gagagagagt gcatcgagga gaagtgcagc ttcgaggagg ccagggaggt gttcgagaac 240
accgagaaga ccaccgagtt ctggaagcag tacgtggacg gcgaccagtg cgagtccaac 300
ccctgcctga acggcgggtc ctgcaaggac gacatcaaca gctacgagtg ctggtgcagg 360
ttcggcttcg aggggaagaa ctgcgagctg gacgccacct gcagcatcaa gaacggcaga 420
tgcaagcagt tctgcaagaa gtccgccgac aacaaggtgg tgtgcagctg caccgaggga 480
tacagactgg ctgaggacca gaagtcctgc gagccagctg tgccattccc atgcgggagg 540
gtgtccgtga gccacaccag caagaagctg accagagccg aaaccatctt ctccaacatg 600
gactacgaga acagcaccga ggccgaaacc atcctggaca acgtgaccca gtccacccag 660
agcttcaacg acttcacccg ggtggtggga ggagagaacg ctaagccagg acagttccca 720
tggcaggtgc tgctgaacgg gaagatcgac gccttctgcg gcgggtccat catcaacgag 780
aagtgggtgg tgaccgctgc tcactgcatc gagccaggag tgaagatcac cgtggtggct 840
ggggagcaca acatcgagaa gaccgagccc accgagcaga agcgcaacgt gatccgcgtg 900
atcccccacc acaactacaa cgccaccatc aacaagtact cccacgacat cgccctgctg 960
gagctggaca agcccctgac cctgaacagc tacgtgaccc ccatctgcat cgccaacagg 1020
gagtacacca acatcttcct gaagttcgga tccggatacg tgagcggatg gggacgcgtg 1080
ttcaaccgcg gccggtccgc cagcatcctg cagtacctga gagtgccact ggtggacaga 1140
gctacctgcc tgctgtccac caagttcacc atctacaaca acatgttctg cgctggatac 1200
cacgagggag ggaaggactc ctgccagggg gacagcggag gaccacacgt gaccgaggtg 1260
gagggcacct ccttcctgac cggcatcatc agctgggggg aggagtgcgc catgaagggc 1320
aagtacggga tctacaccaa ggtgagcaga tacgtgaact ggatcaagga gaagaccaag 1380
ctgacctga 1389
<210> 10
<211> 1386
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 10
atgcagtgcc tgaacatgat catggccgag tcccccggcc tgatcaccat ctgcctgctg 60
gggtacctgc tgagcgccga gtgcaccgtg ttcctggacc acgagaacgc caacaagatc 120
ctgaacaggc ccaagagata caactccggc aagctggagg agttcgtgag ggggaacctg 180
gagagagagt gcatcgagga gaagtgcagc ttcgaggagg ccagggaggt gttcgagaac 240
accgagaaga ccaccgagtt ctggaagcag tacgtggacg gcgaccagtg cgagtccaac 300
ccctgcctga acggcgggtc ctgcaaggac gacatcaaca gctacgagtg ctggtgcagg 360
ttcggcttcg aggggaagaa ctgcgagctg gacgccacct gcagcatcaa gaacggcaga 420
tgcaagcagt tctgcaagaa gtccgccgac aacaaggtgg tgtgcagctg caccgaggga 480
tacagactgg ctgaggacca gaagtcctgc gagccagctg tgccattccc atgcgggagg 540
gtgtccgtga gccacaccag caagctgacc agagccgaaa ccatcttctc caacatggac 600
tacgagaaca gcaccgaggc cgaaaccatc ctggacaacg tgacccagtc cacccagagc 660
ttcaacgact tcacccgggt ggtgggagga gagaacgcta agccaggaca gttcccatgg 720
caggtgctgc tgaacgggaa gatcgacgcc ttctgcggcg ggtccatcat caacgagaag 780
tgggtggtga ccgctgctca ctgcatcgag ccaggagtga agatcaccgt ggtggctggg 840
gagcacaaca tcgagaagac cgagcccacc gagcagaagc gcaacgtgat ccgcgtgatc 900
ccccaccaca actacaacgc caccatcaac aagtactccc acgacatcgc cctgctggag 960
ctggacaagc ccctgaccct gaacagctac gtgaccccca tctgcatcgc cgacagggag 1020
tacaccaaca tcttcctgaa gttcggatcc ggatacgtga gcggatgggg acgcgtgttc 1080
aaccgcggcc ggtccgccag catcctgcag tacctgagag tgccactggt ggacagagct 1140
acctgcctgc tgtccaccaa gttcaccatc tacaacaaca tgttctgcgc tggataccac 1200
gagggaggga aggactcctg ccagggggac agcggaggac cacacgtgac cgaggtggag 1260
ggcacctcct tcctgaccgg catcatcagc tggggggagg agtgcgccat gaagggcaag 1320
tacgggatct acaccaaggt gagcagatac gtgaactgga tcaaggagaa gaccaagctg 1380
acctga 1386
<210> 11
<211> 4377
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 11
atgcagatcg agctgtccac ctgcttcttc ctgtgcctgc tgcgcttctc cttcagcgcc 60
acccgccggt actacctggg agctgtggag ctgagctggg actacatgca gtccgacctg 120
ctgagcgagc tgcacgtgga caccagattc ccacccaggg tgccaagatc cttccccttc 180
aacaccagcg tgatgtacaa gaagaccgtg ttcgtggagt tcaccgacca cctgttcaac 240
atcgccaagc ccaggccccc ctggatgggc ctgctgggac caaccatctg ggctgaggtg 300
tacgacaccg tcgtcatcac cctgaagaac atggcctccc accccgtgag cctgcacgct 360
gtgggcgtgt cctactggaa ggctagcgag ggagctgagt acgacgacca gacctcccag 420
agagagaagg aggacgacaa ggtgttcccc ggcgagagcc acacctacgt gtggcaggtg 480
ctgaaggaga acggaccaat ggcttccgac ccaccatgcc tgacctactc ctacctgagc 540
cacgtggacc tggtgaagga cctgaactcc ggcctgatcg gggccctgct ggtgtgcaga 600
gagggcagcc tggctaagga gagaacccag accctgcacg agttcgtgct gctgttcgcc 660
gtgttcgacg aggggaagtc ctggcacagc gaaaccaagg actccctgac ccaggctatg 720
gactccgcca gcgcccaggc ttggccaaag atgcacaccg tgaacggata cgtgaaccgc 780
tccctgccag gcctgatcgg atgccacaga aagagcgtgt actggcacgt gatcggaatg 840
ggaaccaccc cagaggtgca cagcatcttc ctggaggggc acaccttcct ggtgcgcaac 900
cacagacagg cttccctgga gatcagcccc atcaccttcc tgaccgctca gaccctgctg 960
atggacctgg gacagttcct gctgttctgc cacatctcca gccaccagca cgacgggatg 1020
gaggcctacg tgaaggtgga ctcctgccca gaggagccac agctgcggat gaagaacaac 1080
gaggaggagg aggactacga cgacgacctg gacgactccg agatggacgt gctgcgcttc 1140
gacgacgaca actcccccag cttcatccag atccggagcg tggccaagaa gcaccccaag 1200
acctgggtgc actacatcgc tgctgaggag gaggactggg actacgctcc aagcgtgctg 1260
accccagacg acaggtccta caagagccag tacctgaaca acggccccca gaggatcggg 1320
agaaagtaca agaaggtgag gttcatggcc tacaccgacg aaaccttcaa gaccagagag 1380
gccatccagt acgagtccgg aatcctggga ccactgctgt acggagaagt gggggacacc 1440
ctgctgatca tcttcaagaa ccaggccagc aggccctaca acatctaccc acacggaatc 1500
accgacgtgt ccccactgca cagcggcaga ctgccaaagg gggtgaagca cctgaaggac 1560
ctgcccatcc tgcccggcga gatcttcaag tacaagtgga ccgtgaccgt ggaggacgga 1620
ccaaccaagt ccgacccacg ctgcctgacc cggtactact ccagcttcat caacctggag 1680
cgcgacctgg ctagcggcct gatcggaccc ctgctgatct gctacaagga gtccgtggac 1740
cagaggggca accagatgat gagcgacaag agaaacgtga tcctgttctc cgtgttcgac 1800
gagaaccaga gctggtacct gaccgaaaac atgcagcggt tcctgcccaa cgctgctgga 1860
gtgcagccac aggacccaga gttccaggct tccaacatca tgcacagcat caacggctac 1920
gtgttcgact ccctgcagct gagcgtgtgc ctgcacgagg tggcctactg gtacatcctg 1980
tccgtgggag ctcaaaccga cttcctgtcc gtgttcttca gcgggtacac cttcaagcac 2040
aagatggtgt acgaggacac cctgaccctg ttccccttct ccggcgaaac cgtgttcatg 2100
agcatggaga acccaggcct gtgggtgctg ggatgccaca actccgactt caggaacaga 2160
ggcatgaccg ccctgctgaa ggtgtccagc tgcgaccgca acaccgggga ctactacgag 2220
gacacctacg aggacatccc cacctacctg ctgagcgaga acaacgtgat cgagccacgg 2280
tccttcagcc agaacccacc cgtgctgaag agacaccaga gagagatcac cctgaccacc 2340
ctgcagtccg agcaggagga gatcgactac gacgacacca tcagcatcga gatgaagagg 2400
gaggacttcg acatctacgg cgaggacgag aaccaggggc ccagatcctt ccagaagcgc 2460
acccggcact acttcatcgc tgctgtggag cgcctgtggg actacggcat gtccagctcc 2520
ccccacgtgc tgaggaacag agctcagtcc ggaagcgtgc cacagttcaa gaaggtggtg 2580
ttccaggagt tcaccgacgg atccttcacc cagccactgt acagaggaga gctgaacgag 2640
cacctgggcc tgctgggacc atacatcaga gccgaggtgg aggacaacat catggtgacc 2700
ttcaagaacc aggcctcccg gccctacagc ttctacagct ccctgatcag ctacgaggag 2760
gaccagaggc agggagctga gcccagaaag aacttcgtga agcccaacga aaccaagacc 2820
tacttctgga aggtgcagca ccacatggcc cccaccaagg acgagttcga ctgcaaggcc 2880
tgggcctact tctccgacgt ggacctggag aaggacatgc acagcggcct gatcggacca 2940
ctgctgatct gccacaccaa caccctgaac ccagctcacg gcaggcaggt gaccgtgcag 3000
gagttcgccc tgttcttcac catcttcgac gaaaccaagt cctggtactt caccgagaac 3060
atggagagga actgcagagc cccctgcaac atccagatgg aggaccccac cttcaaggag 3120
aactacagat tccacgccat caacggctac gtgatggaca ccctgccagg cctggtcatg 3180
gctcaggacc agcgcatccg gtggtacctg ctgtccatgg gcagcaacga gaacatccac 3240
tccatccact tcagcgggca cgtgttcacc gtgaggaaga aggaggagta caagatggcc 3300
gtgtacaacc tgtaccccgg cgtgttcgaa accgtggaga tgctgcccag caaggccggg 3360
atctggagag tggagtgcct gatcggagag cacctgcacg ctggaatgtc caccctgttc 3420
ctggtgtaca gcaagcagtg ccagacccca ctgggaatgg cttccggaca catccgcgac 3480
ttccagatca ccgctagcgg acagtacgga cagtgggctc ccaagctggc ccggctgcac 3540
tactccggca gcatcaacgc ctggtccacc aaggagccct tcagctggat caaggtggac 3600
ctgctggccc ccatgatcat ccacggcatc aagacccagg gggccaggca gaagttcagc 3660
tccctgtaca tctcccagtt catcatcatg tacagcctgg acggcaagaa gtggcagacc 3720
tacagaggca actccaccgg gaccctgatg gtgttcttcg gcaacgtgga cagctccggg 3780
atcaagcaca acatcttcaa cccccccatc atcgctagat acatcagact gcacccaacc 3840
cactactcca tcaggagcac cctgagaatg gagctgatgg gctgcgacct gaactcctgc 3900
agcatgcccc tggggatgga gtccaaggcc atcagcgacg cccagatcac cgccagctcc 3960
tacttcacca acatgttcgc tacctggtcc cccagccagg ctagactgca cctgcagggc 4020
cgcaccaacg cctggcggcc ccaggtgaac aaccccaagg agtggctgca ggtggacttc 4080
cagaagacca tgaaggtgac cggcatcacc acccagggcg tgaagtccct gctgaccagc 4140
atgtacgtga aggagttcct gatcagctcc agccaggacg gacaccactg gaccctgttc 4200
ctgcagaacg gcaaggtgaa ggtgttccag gggaaccagg actccttcac cccagtggtg 4260
aacagcctgg atccaccact gctgaccagg tacctgagaa tccaccccca gtcctgggtg 4320
caccagatcg ccctgagact ggaggtgctg ggatgcgagg cccagcagct gtactga 4377
<210> 12
<211> 4388
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 12
atgcagatcg agctgagcac ctgcttcttc ctgtgcctgc tgcccttcag cttctccgcc 60
acccgccggt actacctggg agctgtggag ctgtcctggg actacatgca gagcgacctg 120
ctgtccgagc tgcacgtgga caccagattc ccaccccgcg tgccacggag cttccccttc 180
aacacctccg tgatgtacaa gaagaccgtg ttcgtggagt tcaccgacca cctgttcaac 240
atcgccaagc ctcgcccgcc ctggatgggc ctgctgggac caaccatccg ggccgaggtg 300
tacgacaccg tcgtcatcac cctgaagaac atggccagcc accccgtgtc cctgcacgct 360
gtgggcgtga gctactggaa ggcttccgag ggagctgagt acgacgacca gaccagccag 420
cgggagaagg aggacgacaa ggtcatcccc ggcgagtccc acacctacgt gtggcaggtg 480
ctgaaggaga acggaccaat ggcttccgac ccaccatgcc tgacctacag ctacctgtcc 540
cacgtggacc tggtgaagga cctgaacagc ggcctgatcg gggccctgct ggtgtgcaga 600
gagggctccc tggctaagga gagaacccag accctgcacg agttcgtgct gctgttcgcc 660
gtgttcgacg aggggaagag ctggcactcc gaggccaacg agagcctgac ccaggctatg 720
gacagcgcct ccgcccgccc ctggcccaag atgcacaccg tgaacggcta cgtgaacagg 780
agcctgccag gcctgatcgg atgccacaga aagtccgtgt actggcacgt gatcggaatg 840
ggaaccaccc cagaggtgca ctccatcttc ctggaggggc acaccttcct ggtgaggaac 900
cacagacagg ccagcctgga gatctccccc atcaccttcc tgaccgctca gaccctgctg 960
atggacctgg gacagttcct gctgttctgc cacatcccaa gccaccagca cgacggaatg 1020
gaggcctacg tgaaggtgga ctcctgccca gaggagccac agctgaggat gaagaacaac 1080
gaggaggagg aggactacga cgacgacctg tacgacagcg acatggacgt gctgcgcttc 1140
gacgacgaca acagcccccc cttcatccag atccggtccg tggccaagaa gcaccccaag 1200
acctggatcc actacatcgc tgctgaggag gaggactggg actacgctcc atccgtgctg 1260
accccaaccg acagaagcta caagtcccag tacctgaaca acggaccaca gagaatcgga 1320
cggaagtaca agaaggtgag gttcatggcc tacaccgacg aaaccttcaa gaccagagag 1380
gccatccagt acgagagcgg aatcctggga ccactgctgt acggagaagt gggggacacc 1440
ctgctgatca tcttcaagaa ccaggcctcc cgcccctaca acatctaccc ccacggcatc 1500
accaacgtga gcccactgca ctccggccgg ctgcccaagg gggtgaagca cctgaaggac 1560
atgcccatca tgcccggcga gatcttcaag tacaagtgga ccgtgaccct ggaggacgga 1620
ccaaccaaga gcgacccacg ctgcctgacc cggtactact ccagcttcat caacctggag 1680
cgcgacctgg cttccggcct gatcggaccc ctgctgatct gctacaagga gagcgtggac 1740
cagcgcggca accagatgat gtccgacaag cggaacgtga tcctgttcag cgtgttcgac 1800
gagaaccgct cctggtacct gaccgagaac atgcagcggt tcctgcccaa cgctgctgga 1860
gtgcagccac aggacccaga gttccaggct agcaacatca tgcactccat caacggctac 1920
gtgttcgaca gcctgcagct gtccgtgtgc ctgcacgagg tggcctactg gtacatcctg 1980
tccgtgggag ctcagaccga cttcctgagc gtgttcttct ccgggtacac cttcaagcac 2040
aagatggtgt tcgaggacac cctgaccctg ttccccttca gcggcgaaac cgtgttcatg 2100
tccatggaga acccaggcct gtgggtgctg ggatgccaca actccgactt caggaacaga 2160
gggatgaccg ccctgctgaa ggtgtccagc tgcgaccgga acaccgacga ctactacgag 2220
gacacctacg aggacatccc cacctacctg ctgaacgaga acaacgtgat cgagcccagg 2280
agcttctccc agaacccccc cgtgctgaag caccaccaga gagagatcac cctgaccacc 2340
ctgcagcccg agcaggagaa gatcgactac gacgacaccc tgagcatcga gatgaagcgc 2400
gaggacttcg acatctacgg agaggacgag aaccagggac cacggtcctt ccagaagaga 2460
acccggcact acttcatcgc tgctgtggag aggctgtggg actacggcat gagcagatcc 2520
ccccacgccc tgaggaacag agctcagagc ggatccgtgc cacagttcaa gaaggtggtg 2580
ttccaggagt tcaccgacgg cagcttcacc cagcccctgt acaggggaga gctgaacgag 2640
cacctgggcc tgctgggacc ctacatcaga gccgaggtgg aggacaacat catggtgacc 2700
ttcaagaacc aggccagccg cccctactcc ttctactcca gcctgatctc ctacgaggag 2760
gaccagaggc agggagctga gcccagaaag aacttcgtga agcccaacga aaccaagacc 2820
tacttctgga aggtgcagca ccacatggcc cccaccaagg acgagttcga ctgcaaggcc 2880
tgggcctact tcagcgacgt ggacctggag aaggacctgc actccggcct gatcggacca 2940
ctgctgatct gcaggaccaa caccctgaac ccagctcacg gcagacagct gaccgtgcag 3000
gagttcgccc tgttcttcac catcttcgac gaaaccaagt cctggtactt caccgagaac 3060
atggagagga actgcagagc cccctgcaac atccagatgg aggaccccac cttcaagaag 3120
aactacaggt tccacgccat caacggctac gtgatggaca ccctgccagg cctggtcatg 3180
gctcaggacc agcgcatccg gtggtacctg ctgagcatgg gctccaacga gaacatccac 3240
agcatccact tctccgggca cgtgttcacc gtgcgcaaga aggaggagta caagatggcc 3300
gtgtacaacc tgtaccccgg cgtgttcgaa accgtggaga tgctgccaag caaggctgga 3360
atctggagag tggagtgcct gatcggagag cacctgcagg ctggaatgag caccctgttc 3420
ctggtgtact ccaaggagtg ccagacccca ctgggaatgg cttccgggag gatcagagac 3480
agccagatca ccgcttccgg acagtacgga cagtgggctc ccaagctggc ccggctgcac 3540
tacagcggct ccatcaacgc ctggagcacc aaggacccct tctcctggat caaggtggac 3600
ctgctggccc ccatgatcat ccacggcatc aagacccagg gggccaggca gaagttctcc 3660
agcctgtaca tcagccagtt catcatcatg tactccctgg acggcaagaa gtggcagagc 3720
tacagaggca actccaccgg gaccctgatg gtgttcttcg gcaacgtgga ctccagcggg 3780
atcaagcaca acatcttcaa cccccccatc atcgctagat acatcagact gcacccaacc 3840
cactacagca tcaggtccac cctgagaatg gagctgatgg gctgcgacct gaacagctgc 3900
tccatgcccc tggggatgga gagcaaggcc atctccgacg cccagatcac cgcctccagc 3960
tacttcacca acatgttcgc cacctggagc ccctcccagg ccaggctgca cctgcaggga 4020
agaaccaacg cttggcggcc ccaggtgaac aaccccaagg agtggctgca ggtggacttc 4080
cagaagacca tgaaggtgac cggaatcacc acccagggag ctaagagcct gctgacctcc 4140
atgtacgtga aggagttcct gatctccagc tcccaggacg gacaccactg gaccctgttc 4200
ctgcagaacg gcaaggtgaa ggtgttccag gggaaccagg acagcttcac cccagtggtg 4260
aactccctgg atccaccact gctgaccagg tacctgagaa tccaccccca gtcctgggtg 4320
caccacatcg ccctgagact ggaggtgctg ggatgcgagg ctcagcagct gtactgagcg 4380
gccgctga 4388
<210> 13
<211> 4377
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 13
atgcagatcg agctgtccac ctgcttcttc ctgtgcctgc tgcgcttctc cttcagcgcc 60
acccgccggt actacctggg agctgtggag ctgtcctggg actacatgca gagcgacctg 120
ctgggagagc tgcacgtgga caccagattc ccacccaggg tgccaagatc cttccccttc 180
aacaccagcg tgatgtacaa gaagaccgtg ttcgtggagt tcaccgacca cctgttcaac 240
atcgccaagc ccaggccccc ctggatgggc ctgctgggac caaccatctg ggctgaggtg 300
tacgacaccg tcgtcatcac cctgaagaac atggcctccc accccgtgag cctgcacgct 360
gtgggcgtgt cctactggaa ggctagcgag ggagctgagt acgacgacca gacctcccag 420
agagagaagg aggacgacaa ggtgttcccc ggcgagagcc acacctacgt gtggcaggtg 480
ctgaaggaga acggaccaat ggcttccgac ccaccatgcc tgacctactc ctacctgagc 540
cacgtggacc tggtgaagga cctgaactcc ggcctgatcg gggccctgct ggtgtgcaga 600
gagggcagcc tggctaagga gagaacccag accctgcacg agttcgtgct gctgttcgcc 660
gtgttcgacg aggggaagtc ctggcacagc gaaaccaagg actccctgac ccaggctatg 720
gactccgcca gcgcccaggc ttggccaaag atgcacaccg tgaacggata cgtgaaccgc 780
tccctgccag gcctgatcgg atgccacaga aagagcgtgt actggcacgt gatcggaatg 840
ggaaccaccc cagaggtgca cagcatcttc ctggaggggc acaccttcct ggtgcgcaac 900
cacagacagg cttccctgga gatcagcccc atcaccttcc tgaccgctca gaccctgctg 960
atggacctgg gacagttcct gctgttctgc cacatctcca gccaccagca cgacgggatg 1020
gaggcctacg tgaaggtgga ctcctgccca gaggagccac agctgcggat gaagaacaac 1080
gaggaggagg aggactacga cgacgacctg gacgactccg agatggacgt gctgcgcttc 1140
gacgacgaca actcccccag cttcatccag atccggagcg tggccaagaa gcaccccaag 1200
acctgggtgc actacatcgc tgctgaggag gaggactggg actacgctcc aagcgtgctg 1260
accccagacg acaggtccta caagagccag tacctgaaca acggccccca gaggatcggg 1320
agaaagtaca agaaggtgag gttcatggcc tacaccgacg aaaccttcaa gaccagagag 1380
gccatccagt acgagtccgg aatcctggga ccactgctgt acggagaagt gggggacacc 1440
ctgctgatca tcttcaagaa ccaggccagc aggccctaca acatctaccc acacggaatc 1500
accgacgtgt ccccactgca cagcggcaga ctgccaaagg gggtgaagca cctgaaggac 1560
ctgcccatcc tgcccggcga gatcttcaag tacaagtgga ccgtgaccgt ggaggacgga 1620
ccaaccaagt ccgacccacg ctgcctgacc cggtactact ccagcttcat caacctggag 1680
cgcgacctgg ctagcggcct gatcggaccc ctgctgatct gctacaagga gtccgtggac 1740
cagaggggca accagatgat gagcgacaag agaaacgtga tcctgttctc cgtgttcgac 1800
gagaaccaga gctggtacct gaccgaaaac atgcagcggt tcctgcccaa cgctgctgga 1860
gtgcagccac aggacccaga gttccaggct tccaacatca tgcacagcat caacggctac 1920
gtgttcgact ccctgcagct gagcgtgtgc ctgcacgagg tggcctactg gtacatcctg 1980
tccgtgggag ctcaaaccga cttcctgtcc gtgttcttca gcgggtacac cttcaagcac 2040
aagatggtgt acgaggacac cctgaccctg ttccccttct ccggcgaaac cgtgttcatg 2100
agcatggaga acccaggcct gtgggtgctg ggatgccaca actccgactt caggaacaga 2160
ggcatgaccg ccctgctgaa ggtgtccagc tgcgaccgca acaccgggga ctactacgag 2220
gacacctacg aggacatccc cacctacctg ctgagcgaga acaacgtgat cgagccacgg 2280
tccttcagcc agaacccacc cgtgctgaag agacaccaga gagagatcac cctgaccacc 2340
ctgcagtccg agcaggagga gatcgactac gacgacacca tcagcatcga gatgaagagg 2400
gaggacttcg acatctacgg cgaggacgag aaccaggggc ccagatcctt ccagaagcgc 2460
acccggcact acttcatcgc tgctgtggag cgcctgtggg actacggcat gtccagctcc 2520
ccccacgtgc tgaggaacag agctcagtcc ggaagcgtgc cacagttcaa gaaggtggtg 2580
ttccaggagt tcaccgacgg atccttcacc cagccactgt acagaggaga gctgaacgag 2640
cacctgggcc tgctgggacc atacatcaga gccgaggtgg aggacaacat catggtgacc 2700
ttcaagaacc aggcctcccg gccctacagc ttctacagct ccctgatcag ctacgaggag 2760
gaccagaggc agggagctga gcccagaaag aacttcgtga agcccaacga aaccaagacc 2820
tacttctgga aggtgcagca ccacatggcc cccaccaagg acgagttcga ctgcaaggcc 2880
tgggcctact tctccgacgt ggacctggag aaggacatgc acagcggcct gatcggacca 2940
ctgctgatct gccacaccaa caccctgaac ccagctcacg gcaggcaggt gaccgtgcag 3000
gagttcgccc tgttcttcac catcttcgac gaaaccaagt cctggtactt caccgagaac 3060
atggagagga actgcagagc cccctgcaac atccagatgg aggaccccac cttcaaggag 3120
aactacagat tccacgccat caacggctac gtgatggaca ccctgccagg cctggtcatg 3180
gctcaggacc agcgcatccg gtggtacctg ctgtccatgg gcagcaacga gaacatccac 3240
tccatccact tcagcgggca cgtgttcacc gtgaggaaga aggaggagta caagatggcc 3300
gtgtacaacc tgtaccccgg cgtgttcgaa accgtggaga tgctgcccag caaggccggg 3360
atctggagag tggagtgcct gatcggagag cacctgcacg ctggaatgtc caccctgttc 3420
ctggtgtaca gcaagcagtg ccagacccca ctgggaatgg cttccggaca catccgcgac 3480
ttccagatca ccgctagcgg acagtacgga cagtgggctc ccaagctggc ccggctgcac 3540
tactccggca gcatcaacgc ctggtccacc aaggagccct tcagctggat caaggtggac 3600
ctgctggccc ccatgatcat ccacggcatc aagacccagg gggccaggca gaagttcagc 3660
tccctgtaca tctcccagtt catcatcatg tacagcctgg acggcaagaa gtggcagacc 3720
tacagaggca actccaccgg gaccctgatg gtgttcttcg gcaacgtgga cagctccggg 3780
atcaagcaca acatcttcaa cccccccatc atcgctagat acatcagact gcacccaacc 3840
cactactcca tcaggagcac cctgagaatg gagctgatgg gctgcgacct gaactcctgc 3900
agcatgcccc tggggatgga gtccaaggcc atcagcgacg cccagatcac cgccagctcc 3960
tacttcacca acatgttcgc tacctggtcc cccagccagg ctagactgca cctgcagggc 4020
cgcaccaacg cctggcggcc ccaggtgaac aaccccaagg agtggctgca ggtggacttc 4080
cagaagacca tgaaggtgac cggcatcacc acccagggcg tgaagtccct gctgaccagc 4140
atgtacgtga aggagttcct gatcagctcc agccaggacg gacaccactg gaccctgttc 4200
ttccagaacg gcaaggtgaa ggtgttccag gggaaccagg actccttcac cccagtggtg 4260
aacagcctgg atccaccact gctgaccagg tacctgagaa tccaccccca gtcctgggtg 4320
caccagatcg ccctgagact ggaggtgctg ggatgcgagg cccagcagct gtactga 4377
<210> 14
<211> 4388
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 14
atgcagatcg agctgtccac ctgcttcttc ctgtgcctgc tgcgcttctc cttcagcgcc 60
acccgccggt actacctggg agctgtggag ctgtcctggg actacatgca gagcgacctg 120
ctgggagagc tgcacgtgga caccagattc ccaccccgcg tgccacggtc cttccccttc 180
aacaccagcg tgatgtacaa gaagaccgtg ttcgtggagt tcaccgacca cctgttcaac 240
atcgccaagc ccaggccccc ctggatgggc ctgctgggac caaccatcca ggctgaggtg 300
tacgacaccg tcgtcatcac cctgaagaac atggcctccc accccgtgag cctgcacgct 360
gtgggcgtgt cctactggaa ggctagcgag ggagctgagt acgacgacca gacctcccag 420
cgcgagaagg aggacgacaa ggtgttcccc ggcgagagcc acacctacgt gtggcaggtg 480
ctgaaggaga acggaccaat ggcttccgac ccaccatgcc tgacctactc ctacctgagc 540
cacgtggacc tggtgaagga cctgaactcc ggcctgatcg gggccctgct ggtgtgcaga 600
gagggcagcc tggctaagga gagaacccag accctgcacg agttcgtgct gctgttcgcc 660
gtgttcgacg aggggaagtc ctggcacagc gaaaccaagg actccctgat gcaggatacc 720
gactccgcca gcgcccaggc ttggccaaag atgcacaccg tgaacggata cgtgaaccgc 780
tccctgccag gcctgatcgg atgccacaga aagagcgtgt actggcacgt gatcggaatg 840
ggaaccaccc cagaggtgca cagcatcttc ctggaggggc acaccttcct ggtgaggaac 900
cacagacagg cctccctgga gatcagcccc atcaccttcc tgaccgctca gaccctgctg 960
atggacctgg gacagttcct gctgttctgc cacatctcca gccaccagca cgacgggatg 1020
gaggcctacg tgaaggtgga ctcctgccca gaggagccac agctgcggat gaagaacaac 1080
gaggaggagg aggactacga caacgacctg gacgactccg agatggacgt gctgcgcttc 1140
gacgacgaca actcccccag cttcatccag atccggagcg tggccaagaa gcaccccaag 1200
acctgggtgc actacatcgc tgctgaggag gaggactggg actacgctcc aagcgtgctg 1260
accccagacg acaggtccta caagagccag tacctgaaca acggaccaca gagaatcgga 1320
cggaagtaca agaaggtgag gttcatggcc tacaccgacg aaaccttcaa gaccagagag 1380
gccatccagt acgagtccgg aatcctggga ccactgctgt acggagaagt gggggacacc 1440
ctgctgatca tcttcaagaa ccaggccagc cgcccctaca acatctaccc acacggaatc 1500
accgacgtgt ccccactgca cagcggccgg ctgcccaagg gggtgaagca cctgaaggac 1560
ctgcccatcc tgcccggcga gatcttcaag tacaagtgga ccgtgaccgt ggaggacgga 1620
ccaaccaagt ccgacccaag gtgcctgacc agatactact ccagcttcat caacctggag 1680
cgcgacctgg ctagcggcct gatcggaccc ctgctgatct gctacaagga gtccgtggac 1740
cagaggggca accagatgat gagcgacaag agaaacgtga tcctgttctc cgtgttcgac 1800
gagaaccaga gctggtacct gaccgaaaac atgcagcggt tcctgcccaa cgctgctgga 1860
gtgcagccac aggacccaga gttccaggct tccaacatca tgcacagcat caacggctac 1920
gtgttcgact ccctgcagct gagcgtgtgc ctgcacgagg tggcctactg gtacatcctg 1980
tccatcggcg cccagaccga cttcctgtcc gtgttcttca gcgggtacac cttcaagcac 2040
aagatggtgt acgaggacac cctgaccctg ttccccttct ccggcgaaac cgtgttcatg 2100
agcatggaga acccaggcct gtgggtgctg ggatgccaca acagcgactt caggaacaga 2160
ggcatgaccg ccctgctgaa ggtgtccagc tgcgacagga acaccgggga ctactacgag 2220
gacacctacg aggacatctc cacctacctg ctgagcgaga acaacgtgat cgagcccaga 2280
tccttcagcc agaatccccc cgtgctgaag aggcaccaga gagagatcac cctgaccacc 2340
ctgcagtccg atcaggagga gatcgactac gacgacacca tcagcaccga gatgaagcgc 2400
gaggacttcg acatctacgg agaggacgag aaccagggac caaggtcctt ccagaagaag 2460
accagacact acttcatcgc tgctgtggag cggctgtggg actacggaat gtccagctcc 2520
ccacacgtgc tgagaaacag agctcagtcc gggagcgtgc cccagttcaa gaaggtggtg 2580
ttccaggagt tcaccgacgg ctccttcacc cagcccctgt acaggggaga gctgaacgag 2640
cacctgggcc tgctgggacc ctacatcaga gccgaggtgg aggacaacat catggtgacc 2700
ttcaagaacc aggcctcccg cccctacagc ttctacagct ccctgatcag ctacgaggag 2760
gaccagagac agggagctga gccacggaag aacttcgtga agcccaacga aaccaagacc 2820
tacttctgga aggtgcagca ccacatggcc cccaccaagg acgagttcga ctgcaaggcc 2880
tgggcctact tctccgacgt ggacctggag aaggacatgc acagcggcct gatcggacca 2940
ctgctgatct gccacaccaa caccctgaac ccagctcacg gcaggcaggt gaccgtgcag 3000
gagttcgccc tgttcttcac catcttcgac gaaaccaagt cctggtactt caccgagaac 3060
atggagcgca actgccgggc cccctgcaac atccagatgg aggaccccac cttcaaggag 3120
aactacagat tccacgccat caacggctac gtgatggaca ccctgccagg cctggtcatg 3180
gctcaggacc agaggatcag atggtacctg ctgtccatgg gcagcaacga gaacatccac 3240
tccatccact tcagcgggca cgtgttcacc gtgaggaaga aggaggagta caagatggcc 3300
gtgtacaacc tgtaccccgg cgtgttcgaa accgtggaga tgctgcccag caaggccggg 3360
atctggagag tggagtgcct gatcggagag cacctgcacg ctggaatgtc caccctgttc 3420
ctggtgtaca gcaagcagtg ccagacccca ctgggaatgg cttccggaca catcagggac 3480
ttccagatca ccgctagcgg acagtacgga cagtgggctc caaagctggc tagactgcac 3540
tactccggca gcatcaacgc ctggtccacc aaggagccct tcagctggat caaggtggac 3600
ctgctggccc ccatgatcat ccacggcatc aagacccagg gagctagaca gaagttcagc 3660
tccctgtaca tctcccagtt catcatcatg tacagcctgg acggcaagaa gtggcagacc 3720
taccggggca actccaccgg gaccctgatg gtgttcttcg gcaacgtgga cagctccggg 3780
atcaagcaca acatcttcaa cccccccatc atcgccaggt acatcagact gcaccccacc 3840
cactactcca tccgcagcac cctgcggatg gagctgatgg gctgcgacct gaactcctgc 3900
agcatgcccc tggggatgga gtccaaggcc atcagcgacg cccagatcac cgccagctcc 3960
tacttcacca acatgttcgc tacctggtcc cccagccagg ctagactgca cctgcaggga 4020
aggaccaacg cttggcgccc ccaggtgaac aaccccaagg agtggctgca ggtggacttc 4080
cagaagacca tgaaggtgac cggcatcacc acccagggcg tgaagtccct gctgaccagc 4140
atgtacgtga aggagttcct gatcagctcc agccaggacg gacaccactg gaccctgttc 4200
ttccagaacg gcaaggtgaa ggtgttccag gggaaccagg actccttcac cccagtggtg 4260
aacagcctgg atccaccact gctgaccaga tacctgcgga tccaccccca gtcctgggtg 4320
caccagatcg ccctgagact ggaggtgctg ggatgcgagg cccagcagct gtactgagcg 4380
gccgctga 4388
<210> 15
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 15
atggctcccc gggccctggc cctgctgtgc ttcctgctgg gcctgcaggg gtccctggct 60
gccgtgttca tcacccagga ggaggctcac agcgtgctgc acaggcagag aagagctaac 120
tccttcctgg aggagctgcg ccccggcagc ctggagcgcg agtgcaagga ggagcagtgc 180
tccttcgagg aggccaggga gatcttcaga agcaccgagc gcaccaagca gttctggatc 240
tcctacaacg acggcgacca gtgcgctagc aacccatgcc agaacggagg atcctgcgag 300
gaccagctgc agagctacat ctgcttctgc ctgccagact tcgagggaag aaactgcgaa 360
accaacaaga acgaccagct gatctgcatg aacgagaacg gcgggtgcga gcagtactgc 420
tccgaccacg ctgaggctaa gcgcagctgc agatgccacg agggatacac cctgcaggct 480
gacggggtgt cctgcacccc aaccgtggag tacccatgcg gcaagatccc cgtgctggag 540
aagcggaacg ctagcaaccc acagggaagg atcgtgggag ggaaggtgtg cccaaaggga 600
gagtgcccat ggcaggccgt gctgaagctg aacggggccc tgctgtgcgg agggaccctg 660
ctggacacct cctgggtggt gagcgccgct cactgcttcg acaagatcag gtcctggaga 720
aacctgaccg tggtgctggg agagcacgac ctgagcgagg aggacgggga cgagcaggag 780
agacaggtgg cccaggtcat catccccgac aagtacgtgc ccggcaagac cgaccacgac 840
atcgccctgc tgagactgcg caggcccgtg gccctgaccg accacgtggt gccactgtgc 900
ctgccagaga gagccttctc cgagaggacc ctggcctaca tccgcttctc ccgggtgagc 960
ggatggggac agctgctgga cagaggagcc accgccctgg agctgatggc catcgacgtg 1020
cccaggctga tgacccagga ctgcctggag cagtccaaga gaagagctga cagcccagcc 1080
atcaccgaga acatgttctg cgctggatac ctggacggat ccaaggacgc ctgcaagggc 1140
gacagcggag gaccacacgc taccaggtac agaggcacct ggtacctgac cggagtggtg 1200
tcctggggag agggatgcgc tgctgtggga cacttcgggg tgtacaccag agtgagccag 1260
tacaccgagt ggctgtcccg cctgatggac agcgagccac accccggcgt gctgctgcgc 1320
gcccccttcc cctga 1335
<210> 16
<211> 1335
<212> DNA
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 16
atgcactccc gccggctggc cttcctgtgc ttcctgctgg gcctgcagca gagcctgacc 60
gccgtgttca tcaaccagga ggaggccaac tccgtgctgc acaggcagag gagagccaac 120
agcttcctgg aggagctgcg ctccgggagc ctggagagag agtgcaagga ggagcagtgc 180
tccttcgagg aggccaggga gatcttcaag agcaccgaga gaaccaagca gttctggatc 240
acctacaacg acggcaacca gtgcgcttcc aacccatgcc agaacggagg atcctgcgtg 300
gaccagctgc agagctacat ctgcttctgc ctggaggact tcgaggggag aaactgcgaa 360
accaacaaga acagccagct gatctgcatg aacgagaacg gcgggtgcga gcagtactgc 420
tccgacaacc ccgaaaccaa gaggagctgc agatgccacg agggctacac cctgatggct 480
gacggggtgt cctgcacccc aaccgtggag tacccatgcg gcaagatccc cgtgctggag 540
aagcgcaacg acagcaaccc acagggaaga atcgtgggag ggaaggtgtg cccaaaggga 600
gagtgcccat ggcaggccgt gatcaagctg aacggggagc tgctgtgcgg agggaccctg 660
ctggacgcta cctgggtggt gtccgccgct cactgcttcg acaagctgcg caactggaag 720
aacctgaccg tggtgctggg agagcacgac ctgagcgagg aggacgggga cgagcaggag 780
agacaggtgg cccagatcat catccccgac aagtacatcc ccggcaagac cgaccacgac 840
atcgccctgc tgagactgag aacccccgtg aacttcaccg actacgtggt gccactgtgc 900
ctgccagaga aggccttctc cgagcagacc ctggcctaca tcaggttctc cagcgtgagc 960
ggatggggac agctgctgga cagaggagcc accgccctgg agctgatgac catcgacgtg 1020
ccccgcctga tgacccagga ctgcctggag cagaccaaga gaaccgctaa ctccccagct 1080
atcaccgaga acatgttctg cgctggatac ctggacggaa ccaaggacgc ttgcaagggc 1140
gacagcggag gaccccacgc caccaagtac cagggcacct ggtacctgac cggaatcgtg 1200
tcctggggag agggatgcgc tgctgtggga cacttcgggg tgtacaccag ggtgagccag 1260
tacatcgagt ggctgaacag actgatggac tccaagccca gccccggcgt gctgctgcgc 1320
gcccccttcc cctga 1335
<210> 17
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 17
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Met Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Gly Ala Asp Asn Lys Val Val Cys Ser Cys Thr Thr Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Lys Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Thr Glu Glu Thr
275 280 285
Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His
290 295 300
Ser Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asn Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Lys Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Lys Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 18
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 18
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Leu Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Gly Ala Asp Asn Lys Val Val Cys Ser Cys Thr Thr Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Thr Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Thr Glu Glu Thr
275 280 285
Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His
290 295 300
Ser Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asp Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Lys Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Lys Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 19
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 19
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Val Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp Arg Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Arg Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Leu Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Gly Ala Asp Asn Lys Val Val Cys Ser Cys Thr Thr Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Thr Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Ile Ile Leu Asp Asn Val Thr Gln Ser Asn Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Ile Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Thr Glu Glu Thr
275 280 285
Glu Pro Thr Glu Gln Lys Arg Asn Val Ile Arg Ala Ile Pro His His
290 295 300
Ser Tyr Asn Ala Thr Val Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Glu Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asp Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Lys Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Lys Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Val Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 20
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 20
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Gly Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Lys Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr
275 280 285
Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His
290 295 300
Asn Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asn Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Arg Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 21
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 21
Met Gln His Leu Asn Thr Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Phe Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Ala Val Phe Leu
20 25 30
Asp Arg Glu Asn Ala Thr Lys Ile Leu Thr Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Arg Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Lys Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Arg Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Asn Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Asn Gly Ala Asp Asn Lys Val Ile Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Gln Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser Tyr Ser Ser Lys Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Glu Asn Ser Glu Ser Leu Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Ile Pro
225 230 235 240
Trp Gln Val Ile Leu Asn Gly Glu Ile Glu Ala Phe Cys Gly Gly Ala
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Leu Lys Pro
260 265 270
Gly Asp Lys Ile Glu Val Val Ala Gly Glu Tyr Asn Ile Asp Glu Lys
275 280 285
Glu Asp Thr Glu Gln Arg Arg Asn Val Ile Arg Thr Ile Pro His His
290 295 300
His Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Ile Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Val Ala Asn Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Lys Val Phe Asn Lys Gly Arg Gln Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Thr Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr
385 390 395 400
Arg Glu Gly Gly Lys Asp Ser Cys Glu Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 22
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 22
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Gln Val Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Gly Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Lys Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr
275 280 285
Glu His Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His
290 295 300
Asn Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asn Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Arg Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 23
<211> 462
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 23
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Thr Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Arg Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Arg Phe Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Lys Lys Leu Thr Arg
180 185 190
Ala Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala
195 200 205
Glu Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp
210 215 220
Phe Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro
225 230 235 240
Trp Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser
245 250 255
Ile Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro
260 265 270
Gly Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Lys Thr
275 280 285
Glu Pro Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His
290 295 300
Asn Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu
305 310 315 320
Glu Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys
325 330 335
Ile Ala Asn Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly
340 345 350
Tyr Val Ser Gly Trp Gly Arg Val Phe Asn Arg Gly Arg Ser Ala Ser
355 360 365
Ile Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu
370 375 380
Arg Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr
385 390 395 400
His Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His
405 410 415
Val Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp
420 425 430
Gly Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val
435 440 445
Ser Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 24
<211> 461
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 24
Met Gln Cys Leu Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Arg Gly Asn Leu Glu Arg Glu Cys
50 55 60
Ile Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Arg Phe Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Ala Thr Cys Ser Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Lys Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asp Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser His Thr Ser Lys Leu Thr Arg Ala
180 185 190
Glu Thr Ile Phe Ser Asn Met Asp Tyr Glu Asn Ser Thr Glu Ala Glu
195 200 205
Thr Ile Leu Asp Asn Val Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe
210 215 220
Thr Arg Val Val Gly Gly Glu Asn Ala Lys Pro Gly Gln Phe Pro Trp
225 230 235 240
Gln Val Leu Leu Asn Gly Lys Ile Asp Ala Phe Cys Gly Gly Ser Ile
245 250 255
Ile Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Pro Gly
260 265 270
Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Lys Thr Glu
275 280 285
Pro Thr Glu Gln Lys Arg Asn Val Ile Arg Val Ile Pro His His Asn
290 295 300
Tyr Asn Ala Thr Ile Asn Lys Tyr Ser His Asp Ile Ala Leu Leu Glu
305 310 315 320
Leu Asp Lys Pro Leu Thr Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile
325 330 335
Ala Asp Arg Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr
340 345 350
Val Ser Gly Trp Gly Arg Val Phe Asn Arg Gly Arg Ser Ala Ser Ile
355 360 365
Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Arg
370 375 380
Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Tyr His
385 390 395 400
Glu Gly Gly Lys Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val
405 410 415
Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly
420 425 430
Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser
435 440 445
Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 25
<211> 461
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 25
Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Lys Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Lys Gln Phe
130 135 140
Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala
180 185 190
Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu
195 200 205
Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe
210 215 220
Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp
225 230 235 240
Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile
245 250 255
Val Asn Glu Lys Trp Val Val Thr Ala Ala His Cys Ile Glu Thr Gly
260 265 270
Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu
275 280 285
His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn
290 295 300
Tyr Asn Ala Thr Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu
305 310 315 320
Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile
325 330 335
Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr
340 345 350
Val Ser Gly Trp Gly Arg Val Phe Asn Lys Gly Arg Ser Ala Ser Val
355 360 365
Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Arg
370 375 380
Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His
385 390 395 400
Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val
405 410 415
Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly
420 425 430
Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser
435 440 445
Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
<210> 26
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 26
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Pro Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Ser Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Arg Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Ile Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Ala Asn Glu Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Arg Pro Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Pro Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Tyr Asp Ser Asp Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Ile His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Thr Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asn Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Met Pro Ile Met Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Leu Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Phe Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Asp
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Asn
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Pro Arg Gln Lys Gln Phe Lys Ala Thr Thr Thr Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Phe Gly Glu Arg Thr Gln Leu Leu
785 790 795 800
Lys Ala Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Gly Ala Ile Glu Ser Asn
835 840 845
Glu Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Thr Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Glu Thr Thr Ile Thr Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Val Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Leu Asn Met Pro Val His Phe Ser Ser Gln Leu Gly Thr Ile Leu Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Gly Ser Gly Val Pro Leu His Leu
945 950 955 960
Ser Glu Arg Asp Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Glu Asn Val Ser Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Lys Arg Val His Gly Pro Ala Ser Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Pro Asn Asn Ser Thr Thr Asn Gly Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Asn Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Ile Ile Leu Glu Asn Asp Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asn Glu Met Phe Met Asp Lys Asn Thr Thr Ala Leu Gly
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Asp Pro Val Pro Leu Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Asp Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Ser Ser
1130 1135 1140
Glu Gln Gly Pro Ser Pro Lys Gln Leu Ile Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Ser Lys Val
1160 1165 1170
Ala Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Asn Ser Lys Ser Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Phe Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Thr Tyr Ala Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Ala Gly Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Arg Arg Glu Glu Ala Asn Leu Glu Gly Leu Arg Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Phe Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Gly Leu Pro Leu Glu Glu Ile Glu Leu Glu Arg Gly
1340 1345 1350
Leu Ile Val Asn Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys
1370 1375 1380
Glu Lys Arg Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Ser Met
1385 1390 1395
Arg Asn His Gly Ile Thr Gln Thr Asn Asp Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Lys Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Asn Tyr Thr Phe Arg Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Ser Ala
1460 1465 1470
Ile Leu Thr Leu Glu Met Ile Arg Gly Gln Glu Lys Val Gly Ser
1475 1480 1485
Leu Gly Thr Ser Ala Thr Asn Ser Leu Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Pro Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Lys Val His Val His Gln Glu Asp Ser Phe
1520 1525 1530
Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Glu Glu Ile Leu Leu Gln Lys Thr Gln Gly Ala Ile Lys Leu Asn
1550 1555 1560
Lys Val Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Gly Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Leu Pro Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Gln Ile Pro Arg Glu Glu Trp Lys
1595 1600 1605
Ser Gln Glu Lys Ser Pro Lys Asn Thr Ala Phe Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Pro Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Arg Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Ala Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys His His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln
1670 1675 1680
Pro Glu Gln Glu Lys Ile Asp Tyr Asp Asp Thr Leu Ser Ile Glu
1685 1690 1695
Met Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Gly Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Arg Ser Pro His
1730 1735 1740
Ala Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Leu His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys Arg Thr Asn Thr Leu Asn Pro Ala
1880 1885 1890
His Gly Arg Gln Leu Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Lys Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Glu Cys Gln Thr Pro Leu Gly Met Ala Ser Gly Arg
2045 2050 2055
Ile Arg Asp Ser Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Asp Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Ser Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
2210 2215 2220
Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Ala Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp
2285 2290 2295
Thr Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
2315 2320 2325
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His His
2330 2335 2340
Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 27
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 27
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Pro Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Glu Leu Leu Ser Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Arg Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Glu Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Ile Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Asn Glu Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Pro Ala Ser Ala Gln Ala Gln Pro Glu Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Tyr Asp Ser Asp Met Asp Val Val Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asn Asp Arg Ser Tyr Lys Ser Leu Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Arg Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Asp Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Val Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asn Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Ser Leu Leu Asn
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Thr Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Ser Gly Glu Arg Thr Gln Leu Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Asn Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Leu Pro Gly Ala Ile Glu Arg Asn
835 840 845
Lys Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Arg Val Phe Thr Pro Glu Pro Glu Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Thr Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Ile Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Lys Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Phe Ser Ser Gln Leu Gly Thr Ile Val Phe
930 935 940
Gly Lys Asn Ser Ser His Leu Ile Gly Ser Gly Val Pro Leu Gly Leu
945 950 955 960
Ser Glu Gly Asp Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Glu Asn Val Leu Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Glu Arg Val His Gly Pro Ala Ser Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Pro Ile Asn Ser Thr Thr Asn Arg Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Ile Ile Leu Glu Ser Asn Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Glu Thr Phe Met Asp Lys Asn Thr Thr Ala Leu Gly
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Leu Gly Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Asp Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Ser Ser
1130 1135 1140
Gly Gln Arg Pro Ser Pro Lys Gln Leu Thr Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Asn Ser Lys Ser Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Ser Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Lys Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Lys Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Thr Tyr Thr Pro Ile Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Ala Gly Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Ile Arg Glu Glu Ala Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Lys Leu Glu Arg Gly
1340 1345 1350
Val Ile Leu Asn Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Glu Tyr Asn Glu Lys
1370 1375 1380
Glu Lys Arg Ala Ile Thr Gln Ser Leu Leu Ser Asp Cys Ser Met
1385 1390 1395
Arg Asn His Gly Ile Ile Gln Thr Asn Asp Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Lys Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Asn Tyr Thr Phe Arg Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala
1460 1465 1470
Phe Leu Thr Leu Glu Met Ile Arg Gly Gln Gly Lys Ile Ser Ser
1475 1480 1485
Leu Gly Lys Ser Ala Thr Asn Ser Leu Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Ser Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Lys Val His Val His Gln Glu Asp Ser Phe
1520 1525 1530
Pro Thr Lys Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Glu Glu Ile Phe Leu Gln Lys Thr Gln Gly Pro Val Lys Leu Asn
1550 1555 1560
Lys Val Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Trp Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Gln Ile Pro Arg Glu Glu Trp Lys
1595 1600 1605
Ser Gln Glu Lys Ser Gln Lys Asn Thr Ala Phe Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Pro Leu Asp Pro Cys Glu Asn Asn His Ser Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Lys Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Ala Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln
1670 1675 1680
Pro Glu Glu Asp Lys Ile Asp Tyr Asp Asp Thr Phe Ser Ile Glu
1685 1690 1695
Met Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Gly Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Arg Ser Pro His
1730 1735 1740
Ala Leu Arg Asn Arg Ala Gln Ser Gly Asp Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Lys Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Ile Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys Arg Ala Asn Thr Leu Asn Pro Ala
1880 1885 1890
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Val Gly Ile Trp Arg Ile Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly Arg
2045 2050 2055
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Asp Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Ser Ile Met Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Ser Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Leu
2210 2215 2220
Asn Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Asn Trp
2285 2290 2295
Thr Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
2315 2320 2325
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Ala His His
2330 2335 2340
Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 28
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 28
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Pro Phe
1 5 10 15
Ser Phe Ser Ala Ile Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Glu Leu Leu Ser Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp Gln Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ser
115 120 125
Ser Glu Gly Ala Glu Tyr Glu Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Ile Pro Gly Lys Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Thr Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Thr Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Gly Lys Asn Glu Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Pro Ala Ser Ala Arg Ala Gln Pro Ala Met His Thr Ile Asn Gly
245 250 255
Tyr Ile Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Lys Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Tyr Asp Ser Asp Met Asp Val Val Arg Phe Asp Gly Asp Asn
370 375 380
Ala Pro Pro Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Ser Asn Asp Arg Ser Tyr Lys Ser Leu Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Ile Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Phe Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Met Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Val Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Ile Gln Arg Phe Leu Pro Asn Ala Asp Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Val Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Tyr Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Phe Leu Leu Asn
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Thr Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Ser Gly Glu Arg Thr Gln Leu Leu
785 790 795 800
Lys Glu Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Asn Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Arg
820 825 830
Asn Glu Ala Ile Pro Asp Asp His Leu Pro Gly Ala Ile Glu Arg Asn
835 840 845
Lys Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Glu Arg Val Phe Thr Pro Glu Pro Glu Leu Pro Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Thr Val Glu Leu Lys Lys Leu Asp Phe
885 890 895
Lys Ile Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Lys Leu Ser Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val Asn Phe Ser Ser Gln Leu Gly Thr Ile Val Phe
930 935 940
Gly Lys Asn Ser Ser His Phe Ile Gly Ser Gly Val Pro Leu Gly Leu
945 950 955 960
Ser Glu Glu Asp Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Glu Asn Val Leu Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Glu Arg Val His Gly Pro Ala Ser Leu Thr Lys
995 1000 1005
Asp Asp Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Pro Ile Asn Ser Thr Thr Asn Arg Lys Thr His Ile Asp
1025 1030 1035
Asp Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Ile Ile Leu Glu Ser Asn Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Glu Thr Phe Met Asp Lys Asn Thr Thr Ala Leu Gly
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Leu Asp Ala Glu
1100 1105 1110
Tyr Pro Asp Thr Ser Phe Phe Lys Thr Leu Phe Leu Pro Asp Ser
1115 1120 1125
Thr Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Ser Ser
1130 1135 1140
Gly Gln Arg Pro Ser Pro Lys Gln Leu Thr Ser Ser Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Ser Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Asn Ser Lys Ser Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Ser Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Lys Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Lys Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Thr Tyr Thr Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Lys Arg Ala Gly Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Ile Arg Glu Glu Ala Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Pro Gln Arg Gly Lys Arg Asp Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Lys Leu Glu Arg Gly
1340 1345 1350
Val Ile Leu Asn Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Phe Thr Gln Ile Glu Tyr Asn Lys Lys
1370 1375 1380
Glu Lys Arg Ala Ile Thr Gln Ser Phe Leu Ser Asp Cys Ser Met
1385 1390 1395
Arg Ser His Gly Ile Ile Gln Thr Asn Gly Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Lys Ile Pro Ser Gln Asp Asn Ser Ser His Leu Pro Ala Ser Ala
1430 1435 1440
Cys Ser Tyr Thr Phe Gly Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala
1460 1465 1470
Phe Leu Thr Leu Glu Met Ile Arg Gly Gln Gly Lys Ile Ser Thr
1475 1480 1485
Leu Gly Lys Ser Ala Thr Asn Pro Leu Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Ser Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Phe Leu Pro Lys Val His Val His Gln Glu Asp Phe Phe
1520 1525 1530
Pro Thr Lys Thr Ser Asn Gly Ser Pro Ala His Leu Asp Leu Arg
1535 1540 1545
Glu Glu Ile Phe Leu Gln Lys Thr Gln Gly Leu Val Lys Leu Asn
1550 1555 1560
Lys Val Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Trp Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Leu Ile Pro Arg Glu Glu Trp Lys
1595 1600 1605
Ser Leu Glu Lys Ser Gln Lys Ser Thr Ala Leu Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Pro Leu Asp Pro Cys Glu Asn Asn His Ser Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Lys Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Val Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Phe Gln
1670 1675 1680
Pro Glu Glu Asp Lys Ile Asp Tyr Asp Asp Thr Phe Ser Ile Glu
1685 1690 1695
Thr Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Asp Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Arg Ser Pro His
1730 1735 1740
Ala Leu Arg Asn Arg Ala Gln Asn Gly Asp Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Lys Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Ile Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Val His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys Arg Thr Asn Thr Leu Asn Ala Ala
1880 1885 1890
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Val Gly Ile Trp Arg Ile Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu Gln Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly Arg
2045 2050 2055
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Asp Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Ser Ile Met Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Ser Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Asn Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser His Leu
2210 2215 2220
Ser Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His Asn Trp
2285 2290 2295
Thr Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ala Leu Asp Pro Pro Leu
2315 2320 2325
Phe Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Ala His His
2330 2335 2340
Ile Ala Leu Arg Leu Glu Leu Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 29
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 29
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Ser Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Phe Gly Glu Arg Thr Gln Met Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Gly Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Ile Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Ala Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Phe Ser Ser Gln Leu Gly Thr Thr Val Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Gly Ser Gly Val Pro Leu Ser Leu
945 950 955 960
Ser Glu Arg Asn Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Lys Asn Val Ser Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Lys Arg Val His Gly Pro Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Ser Asn Asn Ser Thr Thr Asn Gly Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Ile Ile Leu Glu Ser Asp Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Glu Met Phe Met Asp Lys Asn Thr Thr Ala Leu Arg
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Pro Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1130 1135 1140
Gly Gln Gly Pro Ser Pro Lys Gln Leu Ile Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Ser Ser Arg Ser Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Phe Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Thr Tyr Ala Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Ala Glu Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Arg Arg Glu Glu Glu Asn Leu Glu Gly Leu Arg Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Glu Leu Glu Arg Gly
1340 1345 1350
Leu Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys
1370 1375 1380
Glu Lys Lys Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Pro Met
1385 1390 1395
Arg Asn His Gly Ile Thr Gln Met Asn Ser Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Lys Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Asn Tyr Thr Phe Arg Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala
1460 1465 1470
Ile Leu Thr Leu Glu Met Ile Arg Asn Gln Gly Lys Val Gly Ser
1475 1480 1485
Leu Gly Thr Ser Ala Thr Asn Ser Val Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Pro Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Lys Val His Ile His Gln Glu Asp Leu Phe
1520 1525 1530
Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Glu Glu Ile Leu Leu Gln Lys Thr Gln Gly Ala Ile Lys Trp Asn
1550 1555 1560
Lys Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Gly Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Gln Ile Pro Lys Glu Glu Trp Lys
1595 1600 1605
Ser Gln Glu Lys Ser Pro Lys Asn Thr Ala Phe Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Ser Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Arg Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Ala Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln
1670 1675 1680
Ser Glu Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Ile Glu
1685 1690 1695
Met Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Gly Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His
1730 1735 1740
Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
1880 1885 1890
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His
2045 2050 2055
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
2210 2215 2220
Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp
2285 2290 2295
Thr Leu Phe Leu Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
2315 2320 2325
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln
2330 2335 2340
Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 30
<211> 2356
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 30
Met Gln Ile Ala Leu Phe Thr Cys Phe Phe Leu Ser Leu Phe Asn Phe
1 5 10 15
Cys Ser Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asn Tyr Met Gln Ser Asp Leu Leu Ser Val Leu His Thr Asp Thr
35 40 45
Arg Phe Leu Pro Arg Met Pro Thr Ser Phe Pro Phe Asn Thr Ser Ile
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Tyr Met Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Thr Glu Val His Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Glu Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Lys Glu Gly Ser Leu Ser Lys Glu Arg
195 200 205
Thr Gln Met Leu His Gln Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Phe Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Thr Arg Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Ile Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Lys
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Trp Gln Lys Lys Asn Asn Glu Glu Met Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Leu Asp Ser Glu Met Asp Met Phe Thr Leu Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys Tyr Pro Lys
385 390 395 400
Thr Trp Ile His Tyr Ile Ser Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Ser Asp Asp Gly Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Ser Asn Gly Pro His Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Ile Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Thr Ile Gln His
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Arg Arg Leu Pro
500 505 510
Arg Gly Ile Lys His Val Lys Asp Leu Pro Ile Arg Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Pro Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Ile Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Asp Thr Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Thr Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Ile Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Lys Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Ser Thr Ser
725 730 735
Asp Tyr Tyr Glu Glu Ile Tyr Glu Asp Ile Pro Thr Gln Leu Val Asn
740 745 750
Asp Asn Asn Val Ile Glu Pro Arg Ser Phe Phe Gln Asn Ser Asn His
755 760 765
Pro Asn Thr Arg Lys Lys Lys Phe Lys Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Glu Pro Gln Phe Gly Glu Thr Ala Glu Met Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Asn Gln Glu Ala Ile
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Asp Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Lys Val Thr Gln Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Lys Ile Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Ser Asn
865 870 875 880
Lys Asn Leu Glu Thr Thr Ile Glu Val Lys Trp Lys Lys Leu Asp Leu
885 890 895
Gln Val Ser Ser Leu Pro Asn Asn Leu Met Thr Thr Pro Thr Ile Leu
900 905 910
Ser Asp Asn Leu Thr Ala Thr Ser Glu Lys Thr Asp Ser Ser Gly Ser
915 920 925
Pro Asp Met Pro Val His Phe Ser Ser Lys Leu Ser Thr Thr Ala Phe
930 935 940
Gly Lys Lys Ser Tyr Pro Leu Ile Gly Ser His Val Pro Leu Ser Ile
945 950 955 960
Ser Glu Arg Asn Ser Asp Ser Asn Leu Leu Asp Ala Thr Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Asp Asn Ile Ser Ser Met Glu Asn Asp
980 985 990
Arg Leu Leu Lys Glu Lys Arg Phe His Gly Ile Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Thr Leu Phe Lys Asp Asn Ile Ser Leu Met Lys Thr Asn
1010 1015 1020
Lys Thr Tyr Asn His Ser Thr Thr Asn Gly Lys Ala His Ile Asp
1025 1030 1035
Ser Pro Thr Ser Leu Ile Glu Asn Ser Thr Ala Val Leu Gln Asp
1040 1045 1050
Thr Ile Leu Lys Ile Asn Ser Glu Ile Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Gly Thr Leu Ser Gly Lys Asn Thr Thr Tyr Leu Arg
1070 1075 1080
Leu Asn His Met Leu Asn Arg Thr Thr Ser Ser Lys Asn Lys Glu
1085 1090 1095
Ile Phe His Gln Lys Asp Glu Asp Pro Val Pro Gln Asp Ala Glu
1100 1105 1110
Asn Thr Ile Met Pro Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Met Lys Arg Thr Asn Gly Asn Asn Ser Leu Asn Ser
1130 1135 1140
Glu Gln Gly Pro Ser Pro Lys Gln Leu Val Tyr Leu Met Leu Glu
1145 1150 1155
Lys Ser Val Lys Asn Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Ile Val Glu Gln Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Asp
1175 1180 1185
Met Val Phe Pro Ser Asn Met Ser Ile Phe Leu Thr Thr Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Met His Asn Gln Glu Lys Asn Ile Gln
1205 1210 1215
Glu Glu Ile Glu Lys Lys Glu Ala Leu Ile Glu Glu Lys Val Val
1220 1225 1230
Leu Pro Gln Val His Ile Ala Thr Gly Ser Lys Asn Phe Leu Lys
1235 1240 1245
Asp Ile Phe Phe Leu Gly Thr Arg Gln Asn Val Val Ser Leu Asp
1250 1255 1260
Glu Glu Ile Tyr Val Pro Val Leu Gln Asp Ile Arg Ser Ile Asn
1265 1270 1275
Asn Ser Thr Asn Thr Val Glu Ile His Met Ala His Phe Phe Lys
1280 1285 1290
Arg Arg Glu Asp Glu Asn Ser Glu Gly Leu Val Asn Lys Thr Arg
1295 1300 1305
Glu Met Val Lys Asn Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Lys Asn Ile Ile Thr Gln Arg Ser Lys Arg Ala Leu
1325 1330 1335
Gly Gln Phe Arg Leu Pro Leu Glu Glu Thr Glu Leu Glu Lys Gln
1340 1345 1350
Gln Ile Val Asn Asn Ala Ser Thr Gln Trp Pro Gln Thr Met Asn
1355 1360 1365
Tyr Leu Thr Gln Ser Ile Ile Thr Gln Ile Asp His Ser Lys Glu
1370 1375 1380
Gly Glu Lys Ser Ile Thr Gln Ser Ser Leu Ser Asp Ser Ser Met
1385 1390 1395
Ile Lys Lys Ser Thr Thr Gln Thr Asn Ser Ser Gly Leu His Ile
1400 1405 1410
Val Lys Thr Ser Ala Phe Pro Pro Ile Arg Pro Thr Asp Leu Lys
1415 1420 1425
Arg Ile Pro Phe Gln Asp Lys Phe Phe His Val Leu Ala Ser Ser
1430 1435 1440
Tyr Thr Tyr Asp Phe Lys Thr Lys Ser Ser Arg Ile Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Lys Glu Thr Lys Ile Asn Asn Ser Ser Leu Ala
1460 1465 1470
Ile Leu Pro Trp Glu Met Ile Ile Asn Gln Gly Lys Phe Ala Ser
1475 1480 1485
Pro Gly Thr Ser Asn Thr Asn Ser Val Thr Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Ile Val Leu Leu Lys Pro Val Leu Pro Glu Glu Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Gln Val Ser Ile His Glu Glu Glu Leu Leu
1520 1525 1530
Pro Thr Glu Thr Ser His Glu Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Lys Glu Val Phe Leu Gln Lys Thr Gln Gly Pro Ile Lys Trp Asn
1550 1555 1560
Lys Ala Lys Arg His Gly Glu Ser Pro Phe Leu Lys Gly Thr Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Asp Pro Leu Ala
1580 1585 1590
Trp Asp Asn His Tyr Ala Ala Gln Ile Pro Lys Asp Lys Trp Lys
1595 1600 1605
Ser Lys Glu Lys Ser Pro Glu Ile Thr Ser Ile Lys Arg Glu Asp
1610 1615 1620
Thr Ile Leu Ser Leu Asn Pro His Glu Asn Asn His Ser Ile Val
1625 1630 1635
Ala Ile Asn Glu Lys Gln Asn Trp Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Val Lys Gln Gly Gln Thr Gln Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Leu Ser Ala Leu Gln Ser Glu
1670 1675 1680
Gln Glu Ala Thr Asp Tyr Asp Asp Ala Ile Thr Ile Glu Thr Asn
1685 1690 1695
Glu Asp Phe Asp Ile Tyr Gly Glu Asp Ile Lys Gln Gly Pro Arg
1700 1705 1710
Ser Phe Gln Gln Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu
1715 1720 1725
Arg Leu Trp Asp Tyr Gly Met Ser Thr Ser Pro His Val Leu Arg
1730 1735 1740
Asn Arg Asp Gln Ser Gly Asn Ala Pro Gln Phe Lys Lys Val Val
1745 1750 1755
Phe Gln Glu Phe Thr Asp Gly Ser Phe Ser Gln Pro Leu Tyr Arg
1760 1765 1770
Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg
1775 1780 1785
Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys Asn Gln Ala
1790 1795 1800
Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Lys Glu
1805 1810 1815
Asp Gln Arg Gln Gly Glu Glu Pro Arg Arg Asn Phe Val Lys Pro
1820 1825 1830
Asn Glu Thr Lys Ile Tyr Phe Trp Lys Val Gln His His Met Ala
1835 1840 1845
Pro Thr Glu Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser
1850 1855 1860
Asp Val Asp Leu Glu Arg Asp Met His Ser Gly Leu Ile Gly Pro
1865 1870 1875
Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg
1880 1885 1890
Gln Val Ala Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp
1895 1900 1905
Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Val Glu Arg Asn Cys
1910 1915 1920
Lys Thr Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Leu Lys Glu
1925 1930 1935
Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp Thr Leu
1940 1945 1950
Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu
1955 1960 1965
Leu Ser Met Gly Ser Asn Glu Asn Ile Gln Ser Ile His Phe Ser
1970 1975 1980
Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala
1985 1990 1995
Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu
2000 2005 2010
Pro Ser Arg Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu
2015 2020 2025
His Leu Gln Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Lys
2030 2035 2040
Gln Cys Gln Ile Pro Leu Gly Met Ala Ser Gly Ser Ile Arg Asp
2045 2050 2055
Phe Gln Ile Thr Ala Ser Gly His Tyr Gly Gln Trp Ala Pro Asn
2060 2065 2070
Leu Ala Arg Leu His His Ser Gly Ser Ile Asn Ala Trp Ser Thr
2075 2080 2085
Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Thr Pro Met
2090 2095 2100
Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser
2105 2110 2115
Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly
2120 2125 2130
Lys Lys Trp Leu Ser Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met
2135 2140 2145
Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ser
2150 2155 2160
Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr
2165 2170 2175
His Ser Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys
2180 2185 2190
Asp Leu Asn Ser Cys Ser Ile Pro Leu Gly Met Glu Asn Lys Val
2195 2200 2205
Ile Ser Asp Thr Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met
2210 2215 2220
Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu Gln Gly
2225 2230 2235
Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asp Pro Lys Glu Trp
2240 2245 2250
Leu Gln Val Asp Leu Gln Lys Thr Met Lys Val Thr Gly Ile Ile
2255 2260 2265
Thr Gln Gly Val Lys Ser Leu Phe Thr Ser Met Phe Val Lys Glu
2270 2275 2280
Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr His Ile
2285 2290 2295
Leu His Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser
2300 2305 2310
Ser Thr Pro Met Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg
2315 2320 2325
Tyr Leu Arg Ile His Pro Gln Ile Trp Glu His Gln Ile Ala Leu
2330 2335 2340
Arg Leu Glu Ile Leu Gly Cys Glu Ala Gln Gln Leu Tyr
2345 2350 2355
<210> 31
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 31
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Phe Gly Glu Arg Thr Gln Met Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Gly Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Ile Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Ala Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Phe Ser Ser Gln Leu Gly Thr Thr Val Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Gly Ser Gly Val Pro Leu Ser Leu
945 950 955 960
Ser Glu Arg Asn Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Lys Asn Val Ser Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Lys Arg Val His Gly Pro Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Ser Asn Asn Ser Thr Thr Asn Gly Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Ile Ile Leu Glu Ser Asp Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Glu Met Phe Met Asp Lys Asn Thr Thr Ala Leu Arg
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Pro Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1130 1135 1140
Gly Gln Gly Pro Ser Pro Lys Gln Leu Ile Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Ser Ser Arg Ser Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Phe Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Ala Tyr Ala Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Ala Glu Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Arg Arg Glu Glu Glu Asn Leu Glu Gly Leu Arg Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Glu Leu Glu Arg Gly
1340 1345 1350
Leu Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Asp Tyr Asn Lys Lys
1370 1375 1380
Glu Lys Lys Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Pro Met
1385 1390 1395
Arg Asn His Gly Ile Thr Gln Met Asn Ser Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Arg Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Asn Tyr Thr Phe Arg Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala
1460 1465 1470
Ile Leu Thr Leu Glu Met Ile Arg Asn Gln Gly Lys Val Gly Ser
1475 1480 1485
Leu Gly Thr Ser Ala Thr Asn Ser Val Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Pro Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Lys Val His Ile His Gln Glu Asp Leu Phe
1520 1525 1530
Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Glu Glu Ile Leu Leu Gln Lys Thr Gln Gly Ala Ile Lys Trp Asn
1550 1555 1560
Lys Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Gly Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Gln Ile Pro Lys Glu Glu Trp Lys
1595 1600 1605
Ser Gln Glu Lys Ser Pro Lys Asn Thr Ala Phe Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Ser Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Arg Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Ala Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln
1670 1675 1680
Ser Glu Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Ile Glu
1685 1690 1695
Met Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Gly Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His
1730 1735 1740
Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
1880 1885 1890
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His
2045 2050 2055
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
2210 2215 2220
Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp
2285 2290 2295
Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
2315 2320 2325
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln
2330 2335 2340
Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 32
<211> 2359
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 32
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Trp Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Thr Gln Ala Met
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Val Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Pro Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Phe Gly Glu Arg Thr Gln Met Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Gly Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Ile Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Ala Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Phe Ser Ser Gln Leu Gly Thr Thr Val Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Gly Ser Gly Val Pro Leu Ser Leu
945 950 955 960
Ser Glu Arg Asn Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Lys Asn Val Ser Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Lys Arg Ala His Gly Pro Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Ser Asn Asn Ser Thr Thr Asn Gly Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Thr Ile Leu Glu Ser Asp Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Glu Met Phe Met Asp Lys Asn Thr Thr Ala Leu Arg
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Pro Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1130 1135 1140
Gly Gln Gly Pro Ser Pro Lys Gln Leu Ile Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Ser Ser Arg Asn Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val Gln Glu Asn Asp Thr His Asn Gln Glu Lys Lys Phe Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Leu Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Ala Tyr Ala Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Ala Glu Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Arg Arg Glu Glu Glu Asn Leu Glu Gly Leu Arg Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Glu Leu Glu Lys Gly
1340 1345 1350
Leu Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Asp Tyr Asn Lys Lys
1370 1375 1380
Glu Lys Lys Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Pro Met
1385 1390 1395
Arg Ser His Gly Ile Thr Gln Met Asn Ser Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Arg Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Asn Tyr Thr Phe Arg Glu Arg Ser Ser Gly Val Gln Glu Ser
1445 1450 1455
Ser His Phe Leu Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala
1460 1465 1470
Ile Leu Thr Leu Glu Met Ile Arg Asn Gln Arg Lys Val Gly Ser
1475 1480 1485
Leu Gly Thr Ser Ala Thr Asn Ser Val Met Tyr Lys Lys Leu Glu
1490 1495 1500
Asn Thr Val Leu Leu Lys Pro Gly Leu Pro Glu Ala Ser Gly Lys
1505 1510 1515
Val Glu Leu Leu Pro Lys Val His Ile His Gln Glu Asp Leu Phe
1520 1525 1530
Pro Thr Glu Thr Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met
1535 1540 1545
Glu Glu Ile Leu Leu Gln Lys Thr Gln Gly Ala Ile Lys Trp Asn
1550 1555 1560
Lys Ala Asn Arg Pro Gly Lys Val Pro Phe Leu Lys Gly Ala Thr
1565 1570 1575
Glu Ser Ser Glu Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala
1580 1585 1590
Trp Asp Asn Gln Tyr Ala Thr Gln Ile Pro Lys Glu Glu Trp Lys
1595 1600 1605
Ser Gln Glu Lys Ser Pro Lys Asn Thr Ala Phe Lys Thr Lys Asp
1610 1615 1620
Thr Ile Leu Ser Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala
1625 1630 1635
Ala Ile Asn Glu Gly Gln Asp Arg Pro Gln Arg Glu Ala Thr Trp
1640 1645 1650
Ala Lys Gln Gly Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro
1655 1660 1665
Val Leu Lys Arg His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln
1670 1675 1680
Ser Glu Gln Glu Glu Ile Asp Tyr Asp Asp Thr Ile Ser Ile Glu
1685 1690 1695
Met Lys Arg Glu Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln
1700 1705 1710
Gly Pro Arg Ser Phe Gln Lys Arg Thr Arg His Tyr Phe Ile Ala
1715 1720 1725
Ala Val Glu Arg Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His
1730 1735 1740
Val Leu Arg Asn Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys
1745 1750 1755
Lys Val Val Phe Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro
1760 1765 1770
Leu Tyr Arg Gly Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro
1775 1780 1785
Tyr Ile Arg Ala Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys
1790 1795 1800
Asn Gln Ala Ser Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser
1805 1810 1815
Tyr Glu Glu Asp Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe
1820 1825 1830
Val Lys Pro Asn Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His
1835 1840 1845
His Met Ala Pro Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala
1850 1855 1860
Tyr Phe Ser Asp Val Asp Leu Glu Lys Asp Met His Ser Gly Leu
1865 1870 1875
Ile Gly Pro Leu Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala
1880 1885 1890
His Gly Arg Gln Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr
1895 1900 1905
Ile Phe Asp Glu Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu
1910 1915 1920
Arg Asn Cys Arg Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr
1925 1930 1935
Phe Lys Glu Asn Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met
1940 1945 1950
Asp Thr Leu Pro Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg
1955 1960 1965
Trp Tyr Leu Leu Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile
1970 1975 1980
His Phe Ser Gly His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr
1985 1990 1995
Lys Met Ala Val Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val
2000 2005 2010
Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu
2015 2020 2025
Ile Gly Glu His Leu His Ala Gly Met Ser Thr Leu Phe Leu Val
2030 2035 2040
Tyr Ser Lys Gln Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His
2045 2050 2055
Ile Arg Asp Phe Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp
2060 2065 2070
Ala Pro Lys Leu Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala
2075 2080 2085
Trp Ser Thr Lys Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu
2090 2095 2100
Ala Pro Met Ile Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln
2105 2110 2115
Lys Phe Ser Ser Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser
2120 2125 2130
Leu Asp Gly Lys Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly
2135 2140 2145
Thr Leu Met Val Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys
2150 2155 2160
His Asn Ile Phe Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu
2165 2170 2175
His Pro Thr His Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu
2180 2185 2190
Met Gly Cys Asp Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu
2195 2200 2205
Ser Lys Ala Ile Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe
2210 2215 2220
Thr Asn Met Phe Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His
2225 2230 2235
Leu Gln Gly Arg Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro
2240 2245 2250
Lys Glu Trp Leu Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr
2255 2260 2265
Gly Ile Thr Thr Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr
2270 2275 2280
Val Lys Glu Phe Leu Ile Ser Ser Ser Gln Asp Gly His His Trp
2285 2290 2295
Thr Leu Phe Phe Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn
2300 2305 2310
Gln Asp Ser Phe Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu
2315 2320 2325
Leu Thr Arg Tyr Leu Arg Ile His Pro Gln Ser Trp Val His Gln
2330 2335 2340
Ile Ala Leu Arg Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu
2345 2350 2355
Tyr
<210> 33
<211> 2355
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 33
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Ser Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu His Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Glu Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Pro Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Arg
195 200 205
Thr Gln Thr Leu His Glu Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asp Ser Leu Met Gln Asp Thr
225 230 235 240
Asp Ser Ala Ser Ala Gln Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Glu Glu Asp Tyr Asp Asn
355 360 365
Asp Leu Asp Asp Ser Glu Met Asp Val Leu Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Thr Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Ser Pro Leu His Ser Gly Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Leu Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Leu Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Met Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Met Gln Arg Phe Leu Pro Asn Ala Ala Gly Val Gln Pro Gln
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Val Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Arg Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Thr Tyr Glu Asp Ile Ser Thr Tyr Leu Leu Ser
740 745 750
Glu Asn Asn Val Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Lys Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Ile Asp Pro Gln Phe Gly Glu Arg Thr Gln Met Leu
785 790 795 800
Lys Val Gln Ser Val Ser Ser Ser Asp Leu Leu Met Leu Leu Gly Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Thr
820 825 830
Tyr Glu Ala Ile Pro Asp Asp His Ser Pro Gly Ala Ile Asp Ser Asn
835 840 845
Glu Gly Pro Ser Glu Val Ala His Leu Arg Pro Glu Leu His His Ser
850 855 860
Gly Asp Ile Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Asn Leu Gly Thr Thr Ile Ala Val Glu Leu Lys Lys Leu Asp Leu
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Leu Met Thr Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Glu Lys Thr Gly Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Phe Asp Ser Gln Leu Asp Thr Thr Val Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Gly Ser Gly Val Pro Leu Ser Leu
945 950 955 960
Ser Glu Gly Asn Asn Asp Ser Lys Leu Leu Glu Ala Ala Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Leu Gly Lys Asn Val Ser Ser Met Glu Ser Asp
980 985 990
Arg Leu Phe Lys Glu Lys Arg Ala His Gly Pro Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Asn Ile Ser Leu Val Lys Thr Asn
1010 1015 1020
Lys Ala Ser Asn Asn Ser Thr Thr Asn Arg Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Thr Leu Leu Ile Glu Asn Ser Thr Ser Val Trp Gln Asp
1040 1045 1050
Thr Ile Leu Glu Ser Asp Thr Glu Phe Gln Glu Val Thr Ser Leu
1055 1060 1065
Ile His Asp Lys Met Phe Met Asp Lys Asn Thr Thr Ala Leu Arg
1070 1075 1080
Leu Asn His Val Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val His Gln Lys Lys Glu Gly Pro Val Pro Pro Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Ile Lys Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1130 1135 1140
Gly Gln Gly Pro Ser Pro Lys Gln Leu Ile Ser Leu Gly Ser Glu
1145 1150 1155
Lys Ser Val Lys Asp Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Glu Asp Glu Phe Thr Lys Asp Thr Gly Leu Lys Glu
1175 1180 1185
Met Ile Phe Pro Ser Ser Arg Asn Ile Phe Leu Thr Asn Leu Ala
1190 1195 1200
Asn Val His Glu Asn Asp Thr His Asn Gln Glu Lys Lys Ile Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Val Tyr Thr Val Thr Gly Thr Lys Asn Phe Met Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Leu Asp
1250 1255 1260
Glu Gly Ala Tyr Ala Pro Val Leu Gln Asp Thr Arg Ser Leu Asn
1265 1270 1275
Asp Ser Ala Asn Arg Thr Glu Ile His Met Ala His Phe Ser Lys
1280 1285 1290
Lys Arg Glu Glu Glu Asn Leu Glu Gly Leu Arg Asn Gln Thr Lys
1295 1300 1305
Gln Met Val Glu Lys Tyr Pro Ser Thr Thr Arg Met Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Val Ile Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Ile Glu Leu Glu Lys Gly
1340 1345 1350
Leu Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
Tyr Leu Thr Gln Gly Thr Leu Thr Gln Ile Asp Tyr Asn Lys Lys
1370 1375 1380
Glu Lys Lys Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Met
1385 1390 1395
Arg Ser His Gly Ile Thr Gln Met Asn Ser Ser Ala Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ala Phe Pro Ser Ile Arg Pro Thr Asp Leu Thr
1415 1420 1425
Arg Ile Pro Ser Gln Asp Asn Ser Ser His Leu Leu Ala Ser Ala
1430 1435 1440
Cys Arg Lys Lys Ser Ser Gly Val Gln Glu Ser Ser His Phe Leu
1445 1450 1455
Gln Gly Ala Lys Arg Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu
1460 1465 1470
Glu Met Ile Gly Asn Gln Arg Lys Val Gly Ser Leu Gly Thr Ser
1475 1480 1485
Ala Thr Asn Ser Val Met Tyr Lys Lys Leu Glu Asn Thr Val Leu
1490 1495 1500
Leu Lys Pro Gly Leu Pro Glu Ala Ser Gly Lys Val Glu Leu Leu
1505 1510 1515
Pro Lys Val His Ile His Gln Glu Asp Leu Phe Pro Thr Glu Thr
1520 1525 1530
Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met Glu Glu Ile Leu
1535 1540 1545
Leu Gln Lys Thr Gln Gly Ala Ile Lys Trp Asn Lys Ala Asn Arg
1550 1555 1560
Pro Gly Lys Val Pro Phe Leu Lys Gly Ala Thr Glu Ser Ser Glu
1565 1570 1575
Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala Trp Asp Asn Gln
1580 1585 1590
Tyr Ala Thr Gln Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu Lys
1595 1600 1605
Ser Pro Glu Asn Thr Ala Phe Lys Thr Lys Asp Thr Ile Leu Ser
1610 1615 1620
Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu
1625 1630 1635
Gly Gln Asp Arg Pro Gln Arg Glu Ala Thr Trp Ala Lys Gln Gly
1640 1645 1650
Gly Thr Gly Arg Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg
1655 1660 1665
His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Ser Asp Gln Glu
1670 1675 1680
Glu Ile Asp Tyr Asp Asp Thr Ile Ser Thr Glu Met Lys Arg Glu
1685 1690 1695
Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Gly Pro Arg Ser
1700 1705 1710
Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg
1715 1720 1725
Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn
1730 1735 1740
Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe
1745 1750 1755
Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly
1760 1765 1770
Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala
1775 1780 1785
Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys Asn Gln Ala Ser
1790 1795 1800
Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp
1805 1810 1815
Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn
1820 1825 1830
Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro
1835 1840 1845
Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp
1850 1855 1860
Val Asp Leu Glu Lys Asp Met His Ser Gly Leu Ile Gly Pro Leu
1865 1870 1875
Leu Ile Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln
1880 1885 1890
Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu
1895 1900 1905
Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg
1910 1915 1920
Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn
1925 1930 1935
Tyr Arg Phe His Ala Ile Asn Gly Tyr Val Met Asp Thr Leu Pro
1940 1945 1950
Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1955 1960 1965
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly
1970 1975 1980
His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Val
1985 1990 1995
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro
2000 2005 2010
Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His
2015 2020 2025
Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Lys Gln
2030 2035 2040
Cys Gln Thr Pro Leu Gly Met Ala Ser Gly His Ile Arg Asp Phe
2045 2050 2055
Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu
2060 2065 2070
Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
2075 2080 2085
Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
2090 2095 2100
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser
2105 2110 2115
Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys
2120 2125 2130
Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val
2135 2140 2145
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe
2150 2155 2160
Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His
2165 2170 2175
Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp
2180 2185 2190
Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
2195 2200 2205
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe
2210 2215 2220
Ala Thr Trp Ser Pro Ser Gln Ala Arg Leu His Leu Gln Gly Arg
2225 2230 2235
Thr Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu
2240 2245 2250
Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Ile Thr Thr
2255 2260 2265
Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
2270 2275 2280
Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr Leu Phe Phe
2285 2290 2295
Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe
2300 2305 2310
Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr
2315 2320 2325
Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
2330 2335 2340
Leu Glu Val Leu Gly Cys Glu Ala Gln Gln Leu Tyr
2345 2350 2355
<210> 34
<211> 2355
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 34
Met Gln Ile Glu Leu Ser Thr Cys Phe Phe Leu Cys Leu Leu Arg Phe
1 5 10 15
Cys Phe Ser Ala Thr Arg Arg Tyr Tyr Leu Gly Ala Val Glu Leu Ser
20 25 30
Trp Asp Tyr Met Gln Ser Asp Leu Leu Gly Glu Leu Pro Val Asp Thr
35 40 45
Arg Phe Pro Pro Arg Val Pro Arg Ser Phe Pro Phe Asn Thr Ser Val
50 55 60
Met Tyr Lys Lys Thr Val Phe Val Glu Phe Thr Asp His Leu Phe Asn
65 70 75 80
Ile Ala Lys Pro Arg Pro Pro Trp Met Gly Leu Leu Gly Pro Thr Ile
85 90 95
Gln Ala Glu Val Tyr Asp Thr Val Val Ile Thr Leu Lys Asn Met Ala
100 105 110
Ser His Pro Val Ser Leu His Ala Val Gly Val Ser Tyr Trp Lys Ala
115 120 125
Ser Glu Gly Ala Glu Tyr Asp Asp Gln Thr Ser Gln Arg Glu Lys Glu
130 135 140
Asp Asp Lys Val Phe Pro Gly Gly Ser His Thr Tyr Val Trp Gln Val
145 150 155 160
Leu Lys Glu Asn Gly Pro Met Ala Ser Asp Pro Leu Cys Leu Thr Tyr
165 170 175
Ser Tyr Leu Ser His Val Asp Leu Val Lys Asp Leu Asn Ser Gly Leu
180 185 190
Ile Gly Ala Leu Leu Val Cys Arg Glu Gly Ser Leu Ala Lys Glu Lys
195 200 205
Thr Gln Thr Leu His Lys Phe Val Leu Leu Phe Ala Val Phe Asp Glu
210 215 220
Gly Lys Ser Trp His Ser Glu Thr Lys Asn Ser Leu Met Gln Asp Arg
225 230 235 240
Asp Ala Ala Ser Ala Arg Ala Trp Pro Lys Met His Thr Val Asn Gly
245 250 255
Tyr Val Asn Arg Ser Leu Pro Gly Leu Ile Gly Cys His Arg Lys Ser
260 265 270
Val Tyr Trp His Val Ile Gly Met Gly Thr Thr Pro Glu Val His Ser
275 280 285
Ile Phe Leu Glu Gly His Thr Phe Leu Val Arg Asn His Arg Gln Ala
290 295 300
Ser Leu Glu Ile Ser Pro Ile Thr Phe Leu Thr Ala Gln Thr Leu Leu
305 310 315 320
Met Asp Leu Gly Gln Phe Leu Leu Phe Cys His Ile Ser Ser His Gln
325 330 335
His Asp Gly Met Glu Ala Tyr Val Lys Val Asp Ser Cys Pro Glu Glu
340 345 350
Pro Gln Leu Arg Met Lys Asn Asn Glu Glu Ala Glu Asp Tyr Asp Asp
355 360 365
Asp Leu Ala Asp Ser Glu Met Asp Val Val Arg Phe Asp Asp Asp Asn
370 375 380
Ser Pro Ser Phe Ile Gln Ile Arg Ser Val Ala Lys Lys His Pro Lys
385 390 395 400
Thr Trp Val His Tyr Ile Ala Ala Glu Glu Glu Asp Trp Asp Tyr Ala
405 410 415
Pro Ser Val Leu Ala Pro Asp Asp Arg Ser Tyr Lys Ser Gln Tyr Leu
420 425 430
Asn Asn Gly Pro Gln Arg Ile Gly Arg Lys Tyr Lys Lys Val Arg Phe
435 440 445
Met Ala Tyr Thr Asp Glu Thr Phe Lys Thr Arg Glu Ala Ile Gln Tyr
450 455 460
Glu Ser Gly Ile Leu Gly Pro Leu Leu Tyr Gly Glu Val Gly Asp Thr
465 470 475 480
Leu Leu Ile Ile Phe Lys Asn Gln Ala Ser Arg Pro Tyr Asn Ile Tyr
485 490 495
Pro His Gly Ile Thr Asp Val Arg Pro Leu Tyr Ser Arg Arg Leu Pro
500 505 510
Lys Gly Val Lys His Leu Lys Asp Phe Pro Ile Leu Pro Gly Glu Ile
515 520 525
Phe Lys Tyr Lys Trp Thr Val Thr Val Glu Asp Gly Pro Thr Lys Ser
530 535 540
Asp Pro Arg Cys Leu Thr Arg Tyr Tyr Ser Ser Phe Ile Asn Met Glu
545 550 555 560
Arg Asp Leu Ala Ser Gly Leu Ile Gly Pro Leu Leu Ile Cys Tyr Lys
565 570 575
Glu Ser Val Asp Gln Arg Gly Asn Gln Ile Met Ser Asp Lys Arg Asn
580 585 590
Val Ile Leu Phe Ser Val Phe Asp Glu Asn Gln Ser Trp Tyr Leu Thr
595 600 605
Glu Asn Ile Gln Arg Phe Leu Pro Asn Pro Ala Gly Val Gln Leu Glu
610 615 620
Asp Pro Glu Phe Gln Ala Ser Asn Ile Met His Ser Ile Asn Gly Tyr
625 630 635 640
Val Phe Asp Ser Leu Gln Leu Ser Val Cys Leu His Glu Val Ala Tyr
645 650 655
Trp Tyr Ile Leu Ser Ile Gly Ala Gln Thr Asp Phe Leu Ser Val Phe
660 665 670
Phe Ser Gly Tyr Thr Phe Lys His Lys Met Val Tyr Glu Asp Thr Leu
675 680 685
Thr Leu Phe Pro Phe Ser Gly Glu Thr Val Phe Met Ser Met Glu Asn
690 695 700
Pro Gly Leu Trp Ile Leu Gly Cys His Asn Ser Asp Phe Arg Asn Arg
705 710 715 720
Gly Met Thr Ala Leu Leu Lys Val Ser Ser Cys Asp Lys Asn Thr Gly
725 730 735
Asp Tyr Tyr Glu Asp Ser Tyr Glu Asp Ile Ser Thr Tyr Leu Leu Ser
740 745 750
Lys Asn Asn Ala Ile Glu Pro Arg Ser Phe Ser Gln Asn Ser Arg His
755 760 765
Pro Ser Thr Arg Gln Lys Gln Phe Asn Ala Thr Thr Ile Pro Glu Asn
770 775 780
Asp Ile Glu Lys Thr Asp Pro Trp Phe Ala His Arg Thr Pro Met Pro
785 790 795 800
Lys Val Gln Asn Val Ser Ser Ser Asp Leu Leu Met Leu Leu Arg Gln
805 810 815
Ser Pro Thr Pro His Gly Leu Ser Leu Ser Asp Leu Gln Glu Ala Lys
820 825 830
Tyr Glu Thr Phe Ser Asp Asp Pro Ser Pro Gly Ala Ile Asp Ser Asn
835 840 845
Asn Ser Leu Ser Glu Met Thr His Leu Arg Pro Gln Leu His His Ser
850 855 860
Gly Asp Met Val Phe Thr Pro Glu Pro Gly Leu Gln Leu Arg Leu Asn
865 870 875 880
Glu Lys Leu Gly Thr Thr Val Ala Thr Glu Leu Lys Lys Leu Asp Phe
885 890 895
Lys Val Ser Ser Ser Ser Asn Asn Leu Ile Ser Ser Pro Thr Ile Pro
900 905 910
Ser Asp Asn Leu Ala Ala Gly Thr Asp Asn Thr Ser Ser Leu Gly Pro
915 920 925
Pro Asn Met Pro Val His Tyr Asp Ser Gln Leu Asp Thr Thr Leu Phe
930 935 940
Gly Lys Lys Ser Ser Pro Leu Ile Glu Ser Gly Gly Pro Leu Ser Leu
945 950 955 960
Ser Glu Glu Asn Asn Asp Ser Lys Leu Leu Glu Ser Gly Leu Met Asn
965 970 975
Ser Gln Glu Ser Ser Trp Gly Lys Asn Val Ser Ser Thr Glu Ser Gly
980 985 990
Arg Leu Phe Lys Glu Lys Arg Ala His Gly Pro Ala Leu Leu Thr Lys
995 1000 1005
Asp Asn Ala Leu Phe Lys Val Ser Ile Ser Leu Leu Lys Thr Asn
1010 1015 1020
Lys Thr Ser Asn Asn Ser Ala Thr Asn Arg Lys Thr His Ile Asp
1025 1030 1035
Gly Pro Ser Leu Leu Ile Glu Asn Ser Pro Ser Val Trp Gln Asn
1040 1045 1050
Thr Ile Leu Glu Ser Asp Thr Glu Phe Gln Lys Val Thr Pro Leu
1055 1060 1065
Ile His Asp Arg Met Leu Met Asp Lys Asn Thr Thr Ala Leu Arg
1070 1075 1080
Leu Asn His Met Ser Asn Lys Thr Thr Ser Ser Lys Asn Met Glu
1085 1090 1095
Met Val Gln Gln Lys Lys Glu Gly Pro Ile Pro Pro Asp Ala Glu
1100 1105 1110
Asn Pro Asp Met Ser Phe Phe Lys Met Leu Phe Leu Pro Glu Ser
1115 1120 1125
Ala Asn Trp Ile Gln Arg Thr His Gly Lys Asn Ser Leu Asn Ser
1130 1135 1140
Gly Gln Gly Pro Ser Pro Lys Gln Leu Val Ser Leu Gly Pro Glu
1145 1150 1155
Lys Ser Val Glu Gly Gln Asn Phe Leu Ser Glu Lys Asn Lys Val
1160 1165 1170
Val Val Gly Lys Gly Glu Phe Thr Lys Asp Val Gly Leu Lys Glu
1175 1180 1185
Met Val Phe Pro Ser Ser Arg Asn Leu Phe Leu Thr Asn Leu Asp
1190 1195 1200
Asn Leu His Glu Asn Asn Thr His Asn Gln Glu Lys Lys Ile Gln
1205 1210 1215
Glu Glu Ile Glu Arg Lys Glu Thr Leu Ile Gln Glu Asn Val Val
1220 1225 1230
Leu Pro Gln Ile His Thr Val Thr Gly Thr Lys Asn Phe Met Lys
1235 1240 1245
Asn Leu Phe Leu Leu Ser Thr Arg Gln Asn Val Glu Gly Ser Tyr
1250 1255 1260
Glu Gly Ala Tyr Ala Pro Val Leu Gln Asp Phe Arg Ser Leu Asn
1265 1270 1275
Asp Ser Thr Asn Arg Thr Lys Lys His Met Ala His Phe Ser Lys
1280 1285 1290
Lys Gly Glu Glu Glu Asn Leu Glu Gly Leu Gly Asn Gln Thr Lys
1295 1300 1305
Gln Ile Val Glu Lys Tyr Pro His Thr Thr Arg Ile Ser Pro Asn
1310 1315 1320
Pro Ser Gln Gln Asn Phe Val Thr Gln Arg Gly Lys Arg Ala Leu
1325 1330 1335
Lys Gln Phe Arg Leu Pro Leu Glu Glu Thr Glu Leu Glu Lys Arg
1340 1345 1350
Leu Ile Val Asp Asp Thr Ser Thr Gln Trp Ser Lys Asn Met Lys
1355 1360 1365
His Leu Thr Pro Ser Thr Leu Thr Gln Ile Asp Tyr Asn Glu Lys
1370 1375 1380
Glu Lys Gly Ala Ile Thr Gln Ser Pro Leu Ser Asp Cys Leu Thr
1385 1390 1395
Arg Ser His Ser Ile Thr Gln Ala Asn Arg Ser Pro Leu Pro Ile
1400 1405 1410
Ala Lys Val Ser Ser Phe Pro Ser Ile Arg Pro Ile Asp Leu Thr
1415 1420 1425
Arg Val Leu Phe Gln Asp Asn Ser Ser His Leu Pro Ala Pro Ser
1430 1435 1440
Tyr Arg Lys Lys Asp Ser Gly Val Gln Glu Ser Ser His Phe Leu
1445 1450 1455
Gln Gly Ala Lys Lys Asn Asn Leu Ser Leu Ala Ile Leu Thr Leu
1460 1465 1470
Glu Met Ile Gly Asp Gln Arg Glu Val Gly Ser Leu Gly Thr Ser
1475 1480 1485
Ala Thr Asn Ser Val Thr Tyr Lys Lys Val Glu Asn Thr Val Leu
1490 1495 1500
Leu Lys Pro Gly Leu Pro Lys Thr Ser Gly Lys Val Glu Leu Leu
1505 1510 1515
Pro Lys Val His Ile Tyr Gln Lys Asp Leu Phe Pro Thr Glu Thr
1520 1525 1530
Ser Asn Gly Ser Pro Gly His Leu Asp Leu Met Glu Gly Ser Leu
1535 1540 1545
Leu Gln Glu Thr Glu Gly Ala Ile Lys Trp Asn Glu Ala Asn Arg
1550 1555 1560
Pro Gly Lys Ile Pro Phe Leu Arg Gly Ala Thr Glu Ser Ser Ala
1565 1570 1575
Lys Thr Pro Ser Lys Leu Leu Gly Pro Leu Ala Trp Asp Asn His
1580 1585 1590
Tyr Gly Thr Gln Ile Pro Lys Glu Glu Trp Lys Ser Gln Glu Lys
1595 1600 1605
Ser Pro Glu Asn Thr Ala Phe Lys Lys Lys Asp Thr Ile Leu Ser
1610 1615 1620
Leu Asn Pro Cys Glu Ser Asn His Ala Ile Ala Ala Ile Asn Glu
1625 1630 1635
Gly Gln Asn Lys Pro Gln Ile Glu Val Thr Trp Ala Lys Gln Gly
1640 1645 1650
Gly Thr Glu Arg Leu Cys Ser Gln Asn Pro Pro Val Leu Lys Arg
1655 1660 1665
His Gln Arg Glu Ile Thr Leu Thr Thr Leu Gln Ser Asp Gln Glu
1670 1675 1680
Glu Ile Asp Tyr Asp Asp Thr Ile Ser Val Glu Met Lys Lys Glu
1685 1690 1695
Asp Phe Asp Ile Tyr Gly Glu Asp Glu Asn Gln Ser Pro Arg Ser
1700 1705 1710
Phe Gln Lys Lys Thr Arg His Tyr Phe Ile Ala Ala Val Glu Arg
1715 1720 1725
Leu Trp Asp Tyr Gly Met Ser Ser Ser Pro His Val Leu Arg Asn
1730 1735 1740
Arg Ala Gln Ser Gly Ser Val Pro Gln Phe Lys Lys Val Val Phe
1745 1750 1755
Gln Glu Phe Thr Asp Gly Ser Phe Thr Gln Pro Leu Tyr Arg Gly
1760 1765 1770
Glu Leu Asn Glu His Leu Gly Leu Leu Gly Pro Tyr Ile Arg Ala
1775 1780 1785
Glu Val Glu Asp Asn Ile Met Val Thr Phe Lys Asn Gln Ala Ser
1790 1795 1800
Arg Pro Tyr Ser Phe Tyr Ser Ser Leu Ile Ser Tyr Glu Glu Asp
1805 1810 1815
Gln Arg Gln Gly Ala Glu Pro Arg Lys Asn Phe Val Lys Pro Asn
1820 1825 1830
Glu Thr Lys Thr Tyr Phe Trp Lys Val Gln His His Met Ala Pro
1835 1840 1845
Thr Lys Asp Glu Phe Asp Cys Lys Ala Trp Ala Tyr Phe Ser Asp
1850 1855 1860
Val Asp Leu Glu Lys Asp Val His Ser Gly Leu Ile Gly Pro Leu
1865 1870 1875
Leu Val Cys His Thr Asn Thr Leu Asn Pro Ala His Gly Arg Gln
1880 1885 1890
Val Thr Val Gln Glu Phe Ala Leu Phe Phe Thr Ile Phe Asp Glu
1895 1900 1905
Thr Lys Ser Trp Tyr Phe Thr Glu Asn Met Glu Arg Asn Cys Arg
1910 1915 1920
Ala Pro Cys Asn Ile Gln Met Glu Asp Pro Thr Phe Lys Glu Asn
1925 1930 1935
Tyr Arg Phe His Ala Ile Asn Gly Tyr Ile Met Asp Thr Leu Pro
1940 1945 1950
Gly Leu Val Met Ala Gln Asp Gln Arg Ile Arg Trp Tyr Leu Leu
1955 1960 1965
Ser Met Gly Ser Asn Glu Asn Ile His Ser Ile His Phe Ser Gly
1970 1975 1980
His Val Phe Thr Val Arg Lys Lys Glu Glu Tyr Lys Met Ala Val
1985 1990 1995
Tyr Asn Leu Tyr Pro Gly Val Phe Glu Thr Val Glu Met Leu Pro
2000 2005 2010
Ser Lys Ala Gly Ile Trp Arg Val Glu Cys Leu Ile Gly Glu His
2015 2020 2025
Leu His Ala Gly Met Ser Thr Leu Phe Leu Val Tyr Ser Asn Lys
2030 2035 2040
Cys Gln Thr Pro Leu Gly Met Ala Ser Gly Arg Ile Arg Asp Phe
2045 2050 2055
Gln Ile Thr Ala Ser Gly Gln Tyr Gly Gln Trp Ala Pro Lys Leu
2060 2065 2070
Ala Arg Leu His Tyr Ser Gly Ser Ile Asn Ala Trp Ser Thr Lys
2075 2080 2085
Glu Pro Phe Ser Trp Ile Lys Val Asp Leu Leu Ala Pro Met Ile
2090 2095 2100
Ile His Gly Ile Lys Thr Gln Gly Ala Arg Gln Lys Phe Ser Ser
2105 2110 2115
Leu Tyr Ile Ser Gln Phe Ile Ile Met Tyr Ser Leu Asp Gly Lys
2120 2125 2130
Lys Trp Gln Thr Tyr Arg Gly Asn Ser Thr Gly Thr Leu Met Val
2135 2140 2145
Phe Phe Gly Asn Val Asp Ser Ser Gly Ile Lys His Asn Ile Phe
2150 2155 2160
Asn Pro Pro Ile Ile Ala Arg Tyr Ile Arg Leu His Pro Thr His
2165 2170 2175
Tyr Ser Ile Arg Ser Thr Leu Arg Met Glu Leu Met Gly Cys Asp
2180 2185 2190
Leu Asn Ser Cys Ser Met Pro Leu Gly Met Glu Ser Lys Ala Ile
2195 2200 2205
Ser Asp Ala Gln Ile Thr Ala Ser Ser Tyr Phe Thr Asn Met Phe
2210 2215 2220
Ala Thr Trp Ser Pro Ser Lys Ala Arg Leu His Leu Gln Gly Arg
2225 2230 2235
Ser Asn Ala Trp Arg Pro Gln Val Asn Asn Pro Lys Glu Trp Leu
2240 2245 2250
Gln Val Asp Phe Gln Lys Thr Met Lys Val Thr Gly Ile Thr Thr
2255 2260 2265
Gln Gly Val Lys Ser Leu Leu Thr Ser Met Tyr Val Lys Glu Phe
2270 2275 2280
Leu Ile Ser Ser Ser Gln Asp Gly His His Trp Thr Leu Phe Phe
2285 2290 2295
Gln Asn Gly Lys Val Lys Val Phe Gln Gly Asn Gln Asp Ser Phe
2300 2305 2310
Thr Pro Val Val Asn Ser Leu Asp Pro Pro Leu Leu Thr Arg Tyr
2315 2320 2325
Leu Arg Ile His Pro Gln Ser Trp Val His Gln Ile Ala Leu Arg
2330 2335 2340
Met Glu Val Leu Gly Cys Glu Ala Gln Glu Leu Tyr
2345 2350 2355
<210> 35
<211> 446
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 35
Met Val Ser Gln Pro Arg Gly Leu Ala Leu Leu Cys Phe Leu Leu Gly
1 5 10 15
Leu Gln Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His
20 25 30
Ser Val Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu
35 40 45
Arg Pro Gly Ser Leu Glu Arg Glu Cys Arg Glu Glu Gln Cys Ser Phe
50 55 60
Glu Glu Ala Arg Glu Ile Phe Lys Asn Thr Glu Arg Thr Lys Gln Phe
65 70 75 80
Trp Ile Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln
85 90 95
Asn Gly Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys
100 105 110
Pro Glu Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Asp Gln
115 120 125
Leu Ile Cys Met Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp
130 135 140
His Ala Glu Ala Arg Arg Ser Cys Arg Cys His Glu Gly Tyr Thr Leu
145 150 155 160
Gln Ala Asp Gly Val Ser Cys Thr Pro Thr Val Glu Tyr Pro Cys Gly
165 170 175
Lys Ile Pro Val Leu Glu Lys Arg Asn Asp Ser Asn Pro Gln Gly Arg
180 185 190
Ile Val Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala
195 200 205
Ala Leu Lys Leu Asn Gly Glu Leu Leu Cys Gly Gly Thr Leu Leu Asp
210 215 220
Thr Thr Trp Val Val Ser Ala Ala His Cys Phe Asp Arg Ile Arg Ser
225 230 235 240
Trp Lys Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu
245 250 255
Asp Gly Asp Glu Gln Glu Arg Gln Val Ala Gln Ile Ile Ile Pro Asp
260 265 270
Lys Tyr Val Pro Arg Lys Thr Asp His Asp Ile Ala Leu Leu Arg Leu
275 280 285
Arg Arg Pro Val Ala Phe Thr Asp His Val Val Pro Leu Cys Leu Pro
290 295 300
Glu Lys Ala Phe Ser Glu Arg Thr Leu Ala Phe Ile Arg Phe Ser Ser
305 310 315 320
Val Ser Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu
325 330 335
Leu Met Ala Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu
340 345 350
Gln Ser Arg Arg Arg Ala Gly Ser Pro Ala Ile Thr Glu Asn Met Phe
355 360 365
Cys Ala Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser
370 375 380
Gly Gly Pro His Ala Thr Lys Phe Gln Gly Thr Trp Tyr Leu Thr Gly
385 390 395 400
Val Val Ser Trp Gly Glu Gly Cys Ala Ala Glu Gly His Phe Gly Val
405 410 415
Tyr Thr Arg Val Ser Gln Tyr Ile Glu Trp Leu His Arg Leu Met Ser
420 425 430
Ser Glu Pro His Ser Gly Gly Leu Leu Arg Ala Pro Leu Pro
435 440 445
<210> 36
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 36
Met Ala Ser Arg Gly Leu Ala Leu Leu Cys Leu Leu Leu Gly Leu Gln
1 5 10 15
Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Gln Ala His Ser Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Trp Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Arg Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Lys Asn Glu Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Pro Glu
100 105 110
Gly Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Lys Ser Gln Leu Ile
115 120 125
Cys Met Asn Asp Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Glu Ala Gly Arg Ser Cys Trp Cys His Glu Gly Tyr Ala Leu Gln Ala
145 150 155 160
Asp Gly Val Ser Cys Thr Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Val Leu Glu Lys Arg Asn Asp Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Met Leu
195 200 205
Lys Leu Asn Gly Ala Leu Leu Cys Gly Gly Thr Leu Leu Asp Thr Thr
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Arg Ile Arg Ser Trp Arg
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Gln Asp Glu Gly
245 250 255
Asp Glu Gln Glu Arg Gln Val Ala Gln Val Ile Val Pro Asp Lys Tyr
260 265 270
Val Pro Gly Lys Thr Asp His Asp Leu Ala Leu Leu Arg Leu Ala Arg
275 280 285
Pro Val Ala Leu Ser Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Arg Thr Leu Ala Phe Val Arg Phe Ser Ala Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Arg Val Leu Met
325 330 335
Ala Ile Gln Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu Gln Ser
340 345 350
Arg Arg Arg Pro Gly Ser Pro Ala Ile Thr Asp Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Phe Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Ala Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Arg Tyr Thr Ala Trp Leu His Arg Leu Met Gly Ser Pro
420 425 430
Pro Ser Ser Gly Gly Leu Leu Arg Ala Pro Leu Pro
435 440
<210> 37
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 37
Met Gln Ala Arg Gly Leu Leu Leu Leu Cys Phe Leu Leu Gln Leu Gln
1 5 10 15
Gly Pro Leu Gly Ala Val Phe Ile Thr Gln Glu Glu Ala His Ser Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Trp Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Leu Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Lys Ser Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Val Tyr Thr Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Thr Cys Gln Asp His Leu Gln Ser Tyr Ile Cys Phe Cys Leu Leu
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Lys Asn Lys Asn Glu Gln Leu Ile
115 120 125
Cys Ala Asn Glu Asn Gly Gly Cys Asp Gln Tyr Cys Thr Asp His Pro
130 135 140
Gly Thr Lys Arg Thr Cys Arg Cys His Glu Asp Tyr Val Leu Gln Pro
145 150 155 160
Asp Glu Val Ser Cys Lys Pro Lys Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Val Leu Glu Lys Arg Asn Ser Ser Ser Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Val Leu
195 200 205
Lys Ile Asn Gly Ala Leu Leu Cys Gly Ala Val Leu Leu Asp Thr Thr
210 215 220
Trp Ile Val Ser Ala Ala His Cys Phe Asp Asn Ile Arg Ser Trp Arg
225 230 235 240
Asn Ile Thr Val Val Met Gly Glu His Asp Phe Ser Glu Lys Asp Gly
245 250 255
Thr Glu Gln Val Arg Arg Val Thr Gln Val Ile Ile Pro Asp Lys Tyr
260 265 270
Ile Pro Gly Lys Ile Asp His Asp Ile Ala Leu Leu Arg Leu His Arg
275 280 285
Pro Val Thr Phe Thr Asp Tyr Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Asn Thr Leu Ala Arg Ile Arg Phe Ser Arg Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Ile Glu Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu His Ala
340 345 350
Lys His Ser Pro Asn Thr Pro Lys Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Met Asp Gly Thr Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr His Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Val Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Thr Asp Trp Leu Ile Arg Leu Met Asp Ser Lys
420 425 430
Leu Gln Val Gly Val Ile Phe Arg Val Pro Leu Leu
435 440
<210> 38
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 38
Met Ala Pro Arg Ala Leu Ser Leu Leu Cys Leu Leu Leu Gly Leu Gln
1 5 10 15
Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His Gly Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Arg Ser Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Asp Gln Leu Ile
115 120 125
Cys Val Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Glu Ala Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Thr Leu Leu Ala
145 150 155 160
Asp Gly Val Ser Cys Thr Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Val Leu Glu Lys Arg Asn Ala Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Leu Leu
195 200 205
Thr Leu Asn Gly Ala Leu Leu Cys Gly Gly Thr Leu Leu Asp Thr Ser
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Arg Ser Trp Arg
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu Asp Gly
245 250 255
Asp Glu Gln Glu Arg Gln Val Ala Gln Val Ile Ile Pro Asp Lys Tyr
260 265 270
Val Pro Gly Lys Thr Asp His Asp Ile Ala Leu Leu Arg Leu Arg Arg
275 280 285
Pro Val Ala Leu Thr Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Arg Thr Leu Ala Tyr Ile Arg Phe Ser Arg Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu Gln Ser
340 345 350
Arg Arg Arg Ala Asp Ser Pro Arg Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Thr Glu Trp Leu Ser Arg Leu Met His Ser Glu
420 425 430
Pro Arg Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 39
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 39
Met Ala Pro Arg Ala Leu Ser Leu Leu Cys Leu Leu Leu Gly Leu Gln
1 5 10 15
Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His Gly Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Arg Asn Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Asp Gln Leu Ile
115 120 125
Cys Val Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Glu Ala Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Thr Leu Leu Ala
145 150 155 160
Asp Gly Val Ser Cys Ala Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Ile Leu Glu Lys Arg Asn Ala Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Leu Leu
195 200 205
Thr Leu Asn Gly Ala Leu Leu Cys Gly Gly Thr Leu Leu Asp Thr Ser
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Lys Ser Trp Arg
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu Asp Gly
245 250 255
Asp Glu Gln Glu Arg Gln Val Ala Gln Val Ile Ile Pro Asp Lys Tyr
260 265 270
Val Pro Gly Lys Thr Asp His Asp Ile Ala Leu Leu Arg Leu Arg Arg
275 280 285
Pro Val Ala Leu Thr Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Arg Thr Leu Ala Tyr Ile Arg Phe Ser Arg Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Glu Gln Ser
340 345 350
Arg Arg Arg Ala Asp Ser Pro Arg Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Thr Glu Trp Leu Ser Arg Leu Met His Ser Glu
420 425 430
Pro Arg Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 40
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 40
Met Ala Ser Gln Ala Leu Arg Leu Leu Cys Leu Leu Leu Gly Leu Gln
1 5 10 15
Gly Ser Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His Gly Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Arg Asn Thr Glu Arg Thr Lys Gln Phe Trp Ile
65 70 75 80
Ser Tyr Asn Asp Gly Asp Gln Cys Ala Ser Asn Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Glu Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110
Asp Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asn Asp Gln Leu Ile
115 120 125
Cys Val Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Glu Ala Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Ser Leu Leu Ala
145 150 155 160
Asp Gly Val Ser Cys Ala Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Ile Leu Glu Lys Arg Asn Ala Ser Asn Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Lys Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Ala Leu Leu
195 200 205
Thr Leu Asn Gly Ala Leu Leu Cys Gly Gly Thr Leu Ile Asp Thr Ser
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Lys Ser Trp Arg
225 230 235 240
Asn Leu Thr Val Val Leu Gly Glu His Asp Leu Ser Glu Glu Asp Gly
245 250 255
Asp Glu Gln Glu Arg Arg Val Ala Gln Val Ile Ile Pro Asp Thr Tyr
260 265 270
Val Pro Gly Thr Thr Asp His Asp Ile Ala Leu Leu Arg Leu Arg Arg
275 280 285
Pro Val Ala Leu Thr Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Ala Phe Ser Glu Arg Thr Leu Ala Tyr Val Arg Phe Ser Arg Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Ile Asp Val Pro Arg Leu Met Thr Gln Asp Cys Leu Gln Gln Ser
340 345 350
Arg Arg Arg Ala Asp Ser Pro Arg Ile Thr Glu Asn Met Phe Cys Ala
355 360 365
Gly Tyr Leu Asp Gly Ser Lys Asp Ala Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Val Val
385 390 395 400
Ser Trp Gly Glu Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Thr Glu Trp Leu Ser Arg Leu Met His Ser Glu
420 425 430
Pro Arg Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 41
<211> 444
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 重组凝血因子序列
<400> 41
Met Val Ser Gln Ala Leu Arg Leu Leu Cys Leu Leu Leu Gly Leu Gln
1 5 10 15
Gly Cys Leu Ala Ala Val Phe Ile Thr Gln Glu Glu Ala His Gly Val
20 25 30
Leu His Arg Gln Arg Arg Ala Asn Ser Phe Leu Glu Glu Leu Arg Pro
35 40 45
Gly Ser Leu Glu Arg Glu Cys Lys Glu Glu Gln Cys Ser Phe Glu Glu
50 55 60
Ala Arg Glu Ile Phe Lys Asp Leu Glu Arg Thr Lys Leu Phe Trp Ile
65 70 75 80
Ser Tyr Ser Asp Gly Asp Gln Cys Ala Ser Ser Pro Cys Gln Asn Gly
85 90 95
Gly Ser Cys Lys Asp Gln Leu Gln Ser Tyr Ile Cys Phe Cys Leu Pro
100 105 110
Ala Phe Glu Gly Arg Asn Cys Glu Thr Asn Lys Asp Asp Gln Leu Ile
115 120 125
Cys Val Asn Glu Asn Gly Gly Cys Glu Gln Tyr Cys Ser Asp His Ala
130 135 140
Gly Ala Lys Arg Ser Cys Arg Cys His Glu Gly Tyr Ser Leu Leu Ala
145 150 155 160
Asp Gly Val Ser Cys Met Pro Thr Val Glu Tyr Pro Cys Gly Lys Ile
165 170 175
Pro Ile Leu Glu Lys Arg Asn Ala Ser Lys Pro Gln Gly Arg Ile Val
180 185 190
Gly Gly Arg Val Cys Pro Lys Gly Glu Cys Pro Trp Gln Val Leu Leu
195 200 205
Leu Val Asn Gly Ala Gln Leu Cys Gly Gly Thr Leu Ile Asn Thr Ile
210 215 220
Trp Val Val Ser Ala Ala His Cys Phe Asp Lys Ile Lys Asn Trp Arg
225 230 235 240
Asn Leu Thr Ala Val Leu Gly Glu His Asp Leu Ser Glu His Asp Gly
245 250 255
Asp Glu Gln Ser Arg Arg Val Ala Gln Val Ile Ile Pro Ser Thr Tyr
260 265 270
Val Pro Gly Thr Thr Asn His Asp Ile Ala Leu Leu Arg Leu His Arg
275 280 285
Pro Val Val Leu Thr Asp His Val Val Pro Leu Cys Leu Pro Glu Arg
290 295 300
Thr Phe Ser Glu Arg Thr Leu Ala Phe Val Arg Phe Ser Leu Val Ser
305 310 315 320
Gly Trp Gly Gln Leu Leu Asp Arg Gly Ala Thr Ala Leu Glu Leu Met
325 330 335
Ala Leu Asn Val Pro Arg Leu Met Thr Gln Asp Cys Leu Gln Gln Ser
340 345 350
Arg Lys Val Gly Asp Ser Pro Asn Ile Thr Glu Tyr Met Phe Cys Ala
355 360 365
Gly Tyr Ser Asp Gly Ser Lys Asp Ser Cys Lys Gly Asp Ser Gly Gly
370 375 380
Pro His Ala Thr Arg Tyr Arg Gly Thr Trp Tyr Leu Thr Gly Ile Val
385 390 395 400
Ser Trp Gly Gln Gly Cys Ala Ala Val Gly His Phe Gly Val Tyr Thr
405 410 415
Arg Val Ser Gln Tyr Ile Glu Trp Leu Gln Lys Leu Met His Ser Glu
420 425 430
Pro Arg Pro Gly Val Leu Leu Arg Ala Pro Phe Pro
435 440
<210> 42
<211> 461
<212> PRT
<213> 智人(homo sapiens)
<400> 42
Met Gln Arg Val Asn Met Ile Met Ala Glu Ser Pro Gly Leu Ile Thr
1 5 10 15
Ile Cys Leu Leu Gly Tyr Leu Leu Ser Ala Glu Cys Thr Val Phe Leu
20 25 30
Asp His Glu Asn Ala Asn Lys Ile Leu Asn Arg Pro Lys Arg Tyr Asn
35 40 45
Ser Gly Lys Leu Glu Glu Phe Val Gln Gly Asn Leu Glu Arg Glu Cys
50 55 60
Met Glu Glu Lys Cys Ser Phe Glu Glu Ala Arg Glu Val Phe Glu Asn
65 70 75 80
Thr Glu Arg Thr Thr Glu Phe Trp Lys Gln Tyr Val Asp Gly Asp Gln
85 90 95
Cys Glu Ser Asn Pro Cys Leu Asn Gly Gly Ser Cys Lys Asp Asp Ile
100 105 110
Asn Ser Tyr Glu Cys Trp Cys Pro Phe Gly Phe Glu Gly Lys Asn Cys
115 120 125
Glu Leu Asp Val Thr Cys Asn Ile Lys Asn Gly Arg Cys Glu Gln Phe
130 135 140
Cys Lys Asn Ser Ala Asp Asn Lys Val Val Cys Ser Cys Thr Glu Gly
145 150 155 160
Tyr Arg Leu Ala Glu Asn Gln Lys Ser Cys Glu Pro Ala Val Pro Phe
165 170 175
Pro Cys Gly Arg Val Ser Val Ser Gln Thr Ser Lys Leu Thr Arg Ala
180 185 190
Glu Thr Val Phe Pro Asp Val Asp Tyr Val Asn Ser Thr Glu Ala Glu
195 200 205
Thr Ile Leu Asp Asn Ile Thr Gln Ser Thr Gln Ser Phe Asn Asp Phe
210 215 220
Thr Arg Val Val Gly Gly Glu Asp Ala Lys Pro Gly Gln Phe Pro Trp
225 230 235 240
Gln Val Val Leu Asn Gly Lys Val Asp Ala Phe Cys Gly Gly Ser Ile
245 250 255
Val Asn Glu Lys Trp Ile Val Thr Ala Ala His Cys Val Glu Thr Gly
260 265 270
Val Lys Ile Thr Val Val Ala Gly Glu His Asn Ile Glu Glu Thr Glu
275 280 285
His Thr Glu Gln Lys Arg Asn Val Ile Arg Ile Ile Pro His His Asn
290 295 300
Tyr Asn Ala Ala Ile Asn Lys Tyr Asn His Asp Ile Ala Leu Leu Glu
305 310 315 320
Leu Asp Glu Pro Leu Val Leu Asn Ser Tyr Val Thr Pro Ile Cys Ile
325 330 335
Ala Asp Lys Glu Tyr Thr Asn Ile Phe Leu Lys Phe Gly Ser Gly Tyr
340 345 350
Val Ser Gly Trp Gly Arg Val Phe Asn Lys Gly Arg Ser Ala Ser Val
355 360 365
Leu Gln Tyr Leu Arg Val Pro Leu Val Asp Arg Ala Thr Cys Leu Arg
370 375 380
Ser Thr Lys Phe Thr Ile Tyr Asn Asn Met Phe Cys Ala Gly Phe His
385 390 395 400
Glu Gly Gly Arg Asp Ser Cys Gln Gly Asp Ser Gly Gly Pro His Val
405 410 415
Thr Glu Val Glu Gly Thr Ser Phe Leu Thr Gly Ile Ile Ser Trp Gly
420 425 430
Glu Glu Cys Ala Met Lys Gly Lys Tyr Gly Ile Tyr Thr Lys Val Ser
435 440 445
Arg Tyr Val Asn Trp Ile Lys Glu Lys Thr Lys Leu Thr
450 455 460
Claims (20)
1.一种分离的核酸分子，其包含：
编码fIX蛋白质的核酸序列，所述fIX蛋白质包含与SEQ ID NO:1(An96 fIX Padua)的残基47-462或SEQ ID NO:2(An97 fIX Padua)的残基47-461至少95％相同的氨基酸序列；
编码fVIII蛋白质的核酸序列，所述fVIII蛋白质包含与SEQ ID NO:3(An84 fVIIIBDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)中的任一个的残基20-1458至少98％相同的氨基酸序列；或
编码fVII蛋白质的核酸序列，所述fVII蛋白质包含与SEQ ID NO:7(An81 fVII)或SEQID NO:8(An61 fVII)的残基21-444至少98％相同的氨基酸序列。
2.如权利要求1所述的分离的核酸分子，其中：
所述fIX蛋白质包含以SEQ ID NO:1(An96 fIX Padua)的残基47-462或SEQ ID NO:2(An97 fIX Padua)的残基47-461示出的氨基酸序列；
所述fVIII蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIIIBDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)中的任一个的残基20-1458示出的氨基酸序列；或
所述fVII蛋白质包含以SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)的残基21-444示出的氨基酸序列。
3.如权利要求1所述的分离的核酸分子，其中：
所述核酸序列编码与信号肽和前肽连接的fIX蛋白质，所述fIX蛋白质包含与SEQ IDNO:1(An96 fIX Padua)或SEQ ID NO:2(An97 fIX Padua)至少95％相同的氨基酸序列；
所述核酸序列编码与信号肽连接的fVIII蛋白质，所述fVIII蛋白质包含与SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)中的任一个至少98％相同的氨基酸序列；或
所述核酸序列编码与信号肽连接的fVII蛋白质，所述fVII蛋白质包含与SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)中的任一个至少98％相同的氨基酸序列。
4.如权利要求1所述的分离的核酸分子，其中：
所述与信号肽和前肽连接的fIX蛋白质包含以SEQ ID NO:1(An96 fIX Padua)或SEQID NO:2(An97 fIX Padua)示出的氨基酸序列；
所述与信号肽连接的fVIII蛋白质包含以SEQ ID NO:3(An84 fVIII BDD)、SEQ ID NO:4(An63 fVIII BDD)、SEQ ID NO:5(An96 fVIII BDD)或SEQ ID NO:6(An97 fVIII BDD)中的任一个示出的氨基酸序列；或
所述与信号肽连接的fVII蛋白质包含以SEQ ID NO:7(An81 fVII)或SEQ ID NO:8(An61 fVII)中的任一个示出的氨基酸序列。
5.如权利要求1-4中任一项所述的分离的核酸分子，其中所述核酸序列是cDNA序列。
6.根据前述权利要求中任一项所述的核酸分子，其中
所述编码fIX蛋白质的核酸序列包含以SEQ ID NO:9的核苷酸139-1389或SEQ ID NO:10的核苷酸139-1386示出的序列；
所述编码fVIII蛋白质的核酸序列包含以SEQ ID NO:11-14中任一个的核苷酸58-4377示出的序列；或
所述编码fVII蛋白质的核酸序列包含以SEQ ID NO:15或SEQ ID NO:16的核苷酸61-1335示出的序列。
7.如权利要求6所述的核酸分子，其中
所述编码fIX蛋白质的核酸序列包含以SEQ ID NO:9或SEQ ID NO:10示出的序列；
所述编码fVIII蛋白质的核酸序列包含以SEQ ID NO:11-14中的任一个示出的序列；或
所述编码fVII蛋白质的核酸序列包含以SEQ ID NO:15或SEQ ID NO:16示出的序列。
8.一种载体，其包含与启动子可操作连接的如权利要求1-7中任一项所述的重组核酸分子。
9.如权利要求8所述的载体，其中所述载体是病毒载体。
10.如权利要求9所述的载体，其中所述病毒载体是AAV载体、慢病毒载体或逆转录病毒载体。
11.一种分离的fIX、fVIII或fVII蛋白质，其由如权利要求1-10中任一项所述的核酸分子或载体编码。
12.如权利要求XX所述的分离的fIX、fVIII或fVII蛋白质，其中所述fIX、fVIII或fVII蛋白质是成熟的fIX、fVIII或fVII蛋白质。
13.一种包含如权利要求1-10中任一项所述的核酸分子或载体的宿主细胞。
14.一种生产fIX、fVIII或fVII蛋白质的方法，其包括：
在足以表达所述核酸分子或表达载体以生产所述fIX、fVIII或fVII蛋白质的体外条件下孵育如权利要求13所述的宿主细胞；和
纯化所述fIX、fVIII或fVII蛋白质。
15.如权利要求14所述的经纯化的fIX、fVIII或fVII蛋白质。
16.一种组合物，其包含在药学上可接受的载体中的如权利要求1-12或15中任一项所述的核酸分子、载体或蛋白质。
17.一种在有需要的受试者中诱导血液凝结的方法，其包括向所述受试者给予治疗有效量的如权利要求1-12或15-16中任一项所述的核酸分子、载体、蛋白质或组合物。
18.一种治疗患有凝血障碍的受试者的方法，其包括选择患有所述凝血障碍的受试者，并且向所述受试者给予治疗有效量的如权利要求1-12或15-16中任一项所述的核酸分子、载体、蛋白质或组合物。
19.如权利要求18所述的方法，其中所述凝血障碍是：
血友病A，并且向所述受试者给予包含所述编码fVIII蛋白质的核酸分子的载体；
血友病B，并且向所述受试者给予包含所述编码fIX蛋白质的核酸分子的载体；或
先天性前转变素缺乏症，并且向所述受试者给予包含所述编码fVII蛋白质的核酸分子的载体。
20.如权利要求1-12或15-16中任一项所述的核酸分子、载体、蛋白质或组合物在有需要的受试者中诱导血液凝结和/或治疗患有凝血障碍的受试者的用途。
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| WO2022094493A2 (en) * | 2020-10-30 | 2022-05-05 | Expression Therapeutics, Llc | Clotting factor variants and their use |
| WO2022226048A1 (en) * | 2021-04-21 | 2022-10-27 | The Children's Hospital Of Philadelphia | Immune tolerance induction and eradication of anti-drug antibodies (ada) to therapeutic factor viii |
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| WO2008127702A2 (en) | 2007-04-13 | 2008-10-23 | Catalyst Biosciences, Inc. | Modified factor vii polypetides and uses thereof |
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| WO2010114948A2 (en) | 2009-04-02 | 2010-10-07 | University Of Florida Research Foundation, Inc. | An inducible system for highly efficient production of recombinant adeno-associated virus (raav) vectors |
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| WO2016168728A2 (en) | 2015-04-16 | 2016-10-20 | Emory University | Recombinant promoters and vectors for protein expression in liver and use thereof |
| EP3622065A1 (en) * | 2017-05-09 | 2020-03-18 | Emory University | Clotting factor variants and their use |
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