CN111548393B - 一种线形肽分子及其应用 - Google Patents

一种线形肽分子及其应用 Download PDF

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CN111548393B
CN111548393B CN202010342952.7A CN202010342952A CN111548393B CN 111548393 B CN111548393 B CN 111548393B CN 202010342952 A CN202010342952 A CN 202010342952A CN 111548393 B CN111548393 B CN 111548393B
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周斌华
李保健
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Abstract

本发明涉及药物领域，具体的涉及一种线形肽分子及其应用。所述线性肽分子的氨基酸序列为：(Gly‑X‑Y‑Gly)n‑PTDs‑Ser‑Gly‑Gln‑Tyr‑Ala‑Ser‑Tyr‑His‑Cys‑Trp‑Cys‑Trp‑Arg‑Asp‑Pro‑Gly‑Arg‑Ser‑Gly‑Gly‑Ser‑Lys。本发明的线性肽分子与PDL1蛋白有较高的亲和力，与PDL1蛋白结合后可促进PDL1蛋白经溶酶体途径进行蛋白降解，减少细胞中的PDL1蛋白含量，从而有效地阻碍PD1与PDL1间的蛋白相互作用，抑制PD1/PDL1通路的活化。

Description

一种线形肽分子及其应用
技术领域
本发明涉及药物领域，具体的涉及一种线形肽分子及其应用。
背景技术
程序性死亡受体1(PD1)及其配体PDL1蛋白是机体免疫系统中的一对共抑制分子，其正常功能是防止T淋巴细胞被过度激活从而对机体的正常细胞产生损伤以及引起异常炎症反应。PD1主要表达于活化的T淋巴细胞、B淋巴细胞、NK细胞和单核细胞；PDL1蛋白诱导表达于T淋巴细胞、B淋巴细胞、树突细胞、巨噬细胞、骨髓来源的肥大细胞和非造血细胞，还有受炎症因子刺激应答的多种肿瘤细胞。当不同细胞上的PD1与PDL1结合后，PD1/PDL1通路激活，从而抑制已活化的T淋巴细胞和B淋巴细胞的增殖活性，减少细胞因子IL-2、IL-10和INF-γ的分泌，降低细胞毒性杀伤能力。当阻断PD1与PDL1的相互作用时，则可以抑制PD1/PDL1通路，同时解除T淋巴细胞和B淋巴细胞的活性抑制。因此，PD1/PDL1通路已经成为了当前免疫治疗领域中的重要靶标之一。
目前，靶向PD1/PDL1通路的上市药物只有单克隆抗体药物，譬如尼伏单抗(Nivolumab)和潘利珠单抗(Pembrolizumab)，其作用机制是通过直接阻碍PD1与PDL1间的蛋白相互作用。
单克隆抗体药物在临床应用中具有难以克服的自身局限性，如免疫源性副作用、渗透性差、费用昂贵等。因此，发展靶向PD1/PDL1通路的非抗体小分子药物方兴未艾，其相关报道尚少。如何利用小分子化合物有效地阻碍PD1与PDL1的相互作用，实现对机体的免疫调控并治疗相关疾病，是靶向PD1/PDL1通路的小分子药物研发的重要问题。
发明内容
本发明所要解决的背景技术中缺少利用小分子化合物有效地阻碍PD1与PDL1的相互作用，实现对机体的免疫调控并治疗相关疾病技术问题是提供一种线形肽分子及其应用。
本发明解决上述技术问题的技术方案如下：
本发明一方面提供了一种线形肽分子，所述线性肽分子的氨基酸序列为：
(Gly-X-Y-Gly)n-PTDs-Ser-Gly-Gln-Tyr-Ala-Ser-Tyr-His-Cys-Trp-Cys-Trp-Arg-Asp-Pro-Gly-Arg-Ser-Gly-Gly-Ser-Lys，其中：
X为Leu、Ala和Phe中的一种；
Y为Leu、Ala和Phe中的一种，且与X不相同；
PTDs为穿膜肽Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg、Arg7、Arg8和Arg-Arg-Gln-Arg-Arg-Thr-Ser-Lys-Leu-Met-Lys-Arg中的一种；
n为1或2或3或4；
氨基酸序列中，Gly表示甘氨酰，Leu表示亮氨酰，Arg表示精氨酰，Phe表示苯丙氨酰，Ala表示丙氨酰，Met表示甲硫氨酰，Ser表示丝氨酰，Gln表示谷氨酰胺，Tyr表示酪氨酰，His表示组氨酰，Cys表示胱氨酰，Trp表示色氨酰，Pro表示脯氨酰，Lys表示赖氨酰，Thr表示苏氨酰，Asp天冬氨酰。
本发明的有益效果是：本发明的线性肽分子与PDL1蛋白有较高的亲和力，与PDL1蛋白结合后可促进PDL1蛋白经溶酶体途径进行蛋白降解，减少细胞中的PDL1蛋白含量，从而有效地阻碍PD1与PDL1间的蛋白相互作用，抑制PD1/PDL1通路的活化。解决了缺少利用小分子化合物有效地阻碍PD1与PDL1的相互作用，实现对机体的免疫调控并治疗相关疾病技术问题。
本发明另一方面提供了一种诊断或治疗与PDL1蛋白降解相关疾病的药物，包括上述所述的线形肽分子。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，所述与PDL1蛋白降解相关疾病包括肿瘤、病毒感染和自身免疫性疾病。
本发明另一方面提供了一种诊断或治疗与PDL1蛋白降解相关疾病的药物，包括上述所述的线形肽分子在药学上可接受的盐。
在上述技术方案的基础上，本发明还可以做如下改进。
进一步，所述与PDL1蛋白降解相关疾病包括肿瘤、病毒感染和自身免疫性疾病。
与现有技术相比，本发明具有以下有益效果：
1、所述的线形肽分子阻碍PD1与PDL1相互作用的机制主要是通过促进PDL1蛋白的溶酶体降解，降低细胞中PDL1蛋白的含量，其比现有抗体药物直接阻断PD1与PDL1相互接触的作用效果更佳。
2、所述的线形肽分子分子量较小，易于自动化合成，生产成本低，应用前景广阔。
附图说明
图1为本发明所述线性肽分子与PDL1蛋白的亲和能力示意图，横坐标为时间，单位是秒；纵坐标为SPR角信号相应值，单位是RU；图中从上到下的PDP1的浓度分别为2.5μM、1.25μM、0.62μM、0.31μM和0.16μM。
图2为本发明所述线性肽分子的荧光标记分子对细胞中溶酶体的靶向性图；
图3为本发明ECL发光液显图；线性肽分子PDP1的浓度从左到右依次为0μM、0.1μM、1μM、10μM和20μM；
图4为本发明所述线性肽分子增加T淋巴细胞INF-γ的分泌图，纵坐标是T淋巴细胞INF-γ分泌量，横坐标依次是空白对照组、阳性对照尼伏单抗(Niv.)和不同浓度的线性肽分子PDP1；所述不同浓度的线性肽分子PDP1的浓度分别为1μM，10μM和20μM；
图5为本发明的质谱图，横坐标为质荷比，纵坐标为相对强度。
具体实施方式
以下结合附图对本发明的原理和特征进行描述，所举实例只用于解释本发明，并非用于限定本发明的范围。
实施例1、
一种线形肽分子，所述线性肽分子的氨基酸序列为：
(Gly-X-Y-Gly)n-PTDs-Ser-Gly-Gln-Tyr-Ala-Ser-Tyr-His-Cys-Trp-Cys-Trp-Arg-Asp-Pro-Gly-Arg-Ser-Gly-Gly-Ser-Lys，其中：
X为Leu、Ala和Phe中的一种；
Y为Leu、Ala和Phe中的一种，且与X不相同；
PTDs为穿膜肽Tyr-Gly-Arg-Lys-Lys-Arg-Arg-Gln-Arg-Arg-Arg、Arg7、Arg8和Arg-Arg-Gln-Arg-Arg-Thr-Ser-Lys-Leu-Met-Lys-Arg中的一种；
n为1或2或3或4；
氨基酸序列中，Gly表示甘氨酰，Leu表示亮氨酰，Arg表示精氨酰，Phe表示苯丙氨酰，Ala表示丙氨酰，Met表示甲硫氨酰，Ser表示丝氨酰，Gln表示谷氨酰胺，Tyr表示酪氨酰，His表示组氨酰，Cys表示胱氨酰，Trp表示色氨酰，Pro表示脯氨酰，Lys表示赖氨酰，Thr表示苏氨酰，Asp天冬氨酰。
本发明的多肽分子的所有氨基酸序列如下：
Figure BDA0002469097590000051
Figure BDA0002469097590000061
Figure BDA0002469097590000071
Figure BDA0002469097590000081
Figure BDA0002469097590000091
Figure BDA0002469097590000101
Figure BDA0002469097590000111
Figure BDA0002469097590000121
Figure BDA0002469097590000131
Figure BDA0002469097590000141
本发明的线形肽分子的合成步骤如下式1所示，包括以下步骤：
(1)以二氯树脂(250mg)为固相载体，与9-芴基甲氧基羰基(Fmoc)保护的首位氨基酸Lys(3eq.)和缩合剂N,N-二异丙基乙胺(DIEA，10eq.)在二氯甲烷(DCM)溶剂中室温反应过夜；反应结束后，取树脂经含20％哌啶的N,N-二甲基甲酰胺(DMF)溶液处理后，测定290nm的吸光度(A290)，以经验公式Loading Value(mmol/g)＝A290*1000稀释倍数/5253计算上载效率,其Loading Value以0.6～0.8之间为宜。
(2)用20％哌啶的DMF溶液脱去树脂上氨基酸的Fmoc保护基，从第二氨基酸Ser(3eq.)开始，用缩合剂N,N-二异丙基碳二亚胺(DIC，3eq.)和1-羟基苯并三唑(HOBt，3eq.)常温反应2～3小时，再用1,8-二氮杂环[5.4.0]十一碳-7-烯(DBU)/哌啶/DMF(体积比为2:5:93)脱除Fmoc保护基，重复上述脱保护、缩合、脱保护步骤，最终获得目标序列的肽链。
(3)脱除最末位氨基酸Gly的Fmoc保护基后，用含20％三氟乙酸的DCM溶液室温从固相载体上切下产物，浓缩得线性肽分子粗品。经半制备高效液相色谱纯化，冷冻干燥后得线性肽分子纯品(纯度为95.3％)。
将得到的线性肽分子(简称PDP1)纯品的分子量经如图5所示的高分辨质谱鉴定正确([M+2H]2+实测4113.0759，理论:4113.0762)。
Figure BDA0002469097590000151
为了证明线性肽分子纯品的性能，特做以下实验：
一、所述线性肽分子与PDL1蛋白亲和能力测试
利用表面等离子共振(SPR)技术评估所述线性肽分子与PDL1蛋白的亲和力能。SPR原理简单来说，金属的折射率与表面结合的分子质量成正比，而偏振光入射金属与其表等离子波发生共振时的入射角度(SPR角)随着金属的折射率变化而变化，可以通过SPR角的动态变化获得生物大分子与配体间相互作用的特异信号。因此，利用氨基偶联的方法将PDL1蛋白标记到GLH芯片上，随着不同浓度的所述线性肽分子流过芯片金属表面，实时检测SPR角的变化，根据Heterogeneous ligand模型计算出所述线性肽分子与PDL1蛋白相互作用的平衡解离常数KD值，以此评估所述线性肽分子与PDL1蛋白的亲和能力。
具体的，如图1所示，将PDL1蛋白用磷酸缓冲液(pH5.0)配成50μg/mL溶液，以25μL/min的流速标记活化的GLH芯片，使其相应信号达到4000RU。将所述线性肽分子PDP1用磷酸缓冲液倍半稀释配成2.5、1.25、0.62、0.31、0.16μM的系列浓度，以30μL/min的流速流过标记过PDL1蛋白的芯片，持续时间240秒；再将磷酸缓冲液以30μL/min的流速流过芯片，持续时间360秒；最后将0.42％的磷酸溶液以100μL/min的流速流过芯片，持续时间18秒。测定整个过程中SPR角的变化，使用ProteOn Manager软件扣除背景获得最终的SPR数据，并根据Heterogeneous ligand模型计算匹配的拟合曲线，算出所述线性肽分子PDP1与PDL1蛋白的平衡解离常数KD值如图1所示，KD＝1.018μM。显示出所述线性肽分子PDP1与PDL1蛋白间良好的结合能力。证明实验中PDP1均为实施例1合成的PDP1。
二、所述线性肽分子靶向细胞中溶酶体的测试
采用红色荧光分子罗丹明B(RhoB)标记所述线性肽分子，利用激光共聚焦显微镜实时观察荧光标记的所述线性肽分子在细胞中的分布情况，检测所述线性肽分子对细胞中溶酶体的靶向性。溶酶体是真核细胞中的一种细胞器，内含多种水解酶，是细胞分解各种外内源物质的重要场所。溶酶体为单层膜包被的囊状结构，在细胞中呈形态多样的小泡状，内部pH为5，与周围胞质(pH＝7.2)具有差异性，是实现所述线性肽分子靶向性的基础。
具体的，如图2所示，所述线性肽分子PDP1和RhoB(1.2eq.)在避光条件下，用缩合剂DIC(3eq.)和HOBt(3eq.)在DCM溶液中常温反应2～3小时；然后用碳酸钠水溶液萃取三次除去缩合剂，再用饱和氯化钠水溶液洗涤两次，最后合并DCM相减压蒸馏浓缩；将浓缩液冰浴冷却，逐滴加入冻乙醚，析出固体经高速离心沉淀，即得荧光标记的所述线性肽分子PDP1粗品，冻乙醚洗涤两次后配成10μM母液备用。在激光共聚焦显微镜实验中，1ⅹ104个/孔人乳腺癌MDA-MB-231细胞种在激光共聚焦测试小皿培养24小时后，将0.1μM荧光标记的所述线性肽分子PDP1与细胞避光孵育2小时，再以0.05μM溶酶体绿色荧光探针LysoTrackerGreen DND-26与细胞避光孵育10分钟，最后磷酸缓冲溶液洗涤三次，立即检测RhoB标记的所述线性肽分子(红色荧光)与溶酶体荧光探针(绿色荧光)的共定位情况。结果如图2所示，相比与RhoB，RhoB标记的所述线性肽分子PDP1的红色荧光与溶酶体荧光探针的绿色荧光达到了良好的共定位程度，表明所述线性肽分子PDP1在细胞中能够靶向溶酶体，以实现载运PDL1蛋白进入溶酶体进行蛋白降解的目的。
三、所述线性肽分子降低细胞中PDL1蛋白含量的测试
采用Western Blot法检测所述线性肽分子对细胞中PDL1蛋白含量的降解活性。选择高表达PDL1蛋白的MDA-MB-231肿瘤细胞作为检测模型，用强效细胞裂解液提取细胞膜和细胞质的总蛋白，通过Western Blot法检测其中PDL1蛋白含量的变化情况。
具体的，如图3所示，1ⅹ105个/孔人乳腺癌MDA-MB-231细胞种在6孔培养板培养24小时后，将不同浓度的所述线性肽分子PDP1与细胞孵育24小时，用强效细胞裂解液裂解细胞获得细胞总蛋白。经Bradford蛋白定量法确定细胞裂解液的蛋白浓度后，取含40μg蛋白的细胞裂解液与上样缓冲液混合，95℃变性10分钟，然后进行SDS-PAGE凝胶电泳分离，将凝胶分离的蛋白转移至PVDF膜，用PDL1抗体(Gene Tex)4℃孵育过夜，再以相应的辣根过氧化物酶标记二抗识别PDL1抗体，最后ECL发光液显影以检测细胞中PDL1蛋白的含量。结果如图3所示，以55kDa的内参α-tubulin蛋白为参考，50kDa的PDL1蛋白条带随着所述线性肽分子PDP1的用量增大而逐渐减少，说明细胞中PDL1蛋白的含量是随着所述线性肽分子PDP1的用量增大而减少，可见所述线性肽分子PDP1有效地降低了细胞中PDL1蛋白的含量。
四、所述线性肽分子增加T淋巴细胞INF-γ分泌的测试
采用常规的ELISA试剂盒测定所述线性肽分子对T淋巴细胞INF-γ分泌的影响，以永生化人T淋巴细胞系Jurkat细胞和高表达PDL1蛋白的MDA-MB-231细胞为测试模型。INF-γ主要由活化的T淋巴细胞和自然杀伤性细胞分泌，具有抗病毒、抗菌和免疫调节等生理作用，是T淋巴细胞自身活性的一个重要指标。通过检测Jurkat细胞和MDA-MB-231细胞共孵模型中所述线性肽分子对INF-γ分泌的影响，可验证所述线性肽分子促进PDL1蛋白溶酶体降解所介导的免疫调控活性。
具体的，如图4所示，MDA-MB-231细胞先经10μg/mL的丝裂霉素C处理1.5小时，再与不同浓度的所述线性肽分子PDP1孵育24小时后，以1ⅹ104个/孔的密度种在24孔培养板中培养4小时贴壁。随后5ⅹ105个/孔Jurkat细胞加入，与处理后的MDA-MB-231细胞在37℃共培养72小时。共孵育结束后，细胞培养上清经离心获得无细胞的上清液，根据INF-γ的ELISA试剂盒(华美生物)的测试操作步骤进行检测。结果如图4所示，与空白对照和阳性对照尼伏单抗(Niv.)相比，所述线性肽分子PDP1随着浓度的增加，其处理后的MDA-MB-231细胞与Jurkat细胞共孵育体系中上清液的INF-γ含量也逐渐增多，说明Jurkat细胞的细胞活性逐渐增强，所述线性肽分子PDP1通过促进肿瘤细胞中PDL1蛋白的降解在一定程度上解除了肿瘤细胞对T淋巴细胞活性的抑制作用，具有良好的应用前景。
以上所述仅为本发明的较佳实施例，并不用以限制本发明，凡在本发明的精神和原则之内，所作的任何修改、等同替换、改进等，均应包含在本发明的保护范围之内。
序列表
<110> 贵州民族大学
<120> 一种线形肽分子及其应用
<141> 2020-04-26
<160> 96
<170> SIPOSequenceListing 1.0
<210> 1
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 1
Gly Leu Phe Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
1 5 10 15
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
<210> 2
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 2
Gly Leu Phe Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
1 5 10 15
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
20 25 30
Lys
<210> 3
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Leu Phe Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 4
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Leu Phe Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 5
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Leu Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
1 5 10 15
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
<210> 6
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Leu Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
1 5 10 15
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
20 25 30
Lys
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Leu Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 8
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Leu Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
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Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Leu Ala Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
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Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
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<212> PRT
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Gly Leu Ala Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
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Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
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Lys
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Gly Leu Ala Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
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<212> PRT
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Gly Leu Ala Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
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Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
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Arg Ser Gly Gly Ser Lys
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Gly Phe Ala Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
1 5 10 15
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Ala Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
1 5 10 15
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
20 25 30
Lys
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<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Phe Ala Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 16
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 16
Gly Phe Ala Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 17
<211> 34
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 17
Gly Ala Phe Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
1 5 10 15
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
<210> 18
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
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Gly Ala Phe Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
1 5 10 15
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
20 25 30
Lys
<210> 19
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 19
Gly Ala Phe Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 20
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<212> PRT
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Gly Ala Phe Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 21
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Gly Ala Leu Gly Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr
1 5 10 15
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
20 25 30
Ser Lys
<210> 22
<211> 33
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 22
Gly Ala Leu Gly Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala
1 5 10 15
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
20 25 30
Lys
<210> 23
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 23
Gly Ala Leu Gly Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 24
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 24
Gly Ala Leu Gly Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 25
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 25
Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 26
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 26
Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 27
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 27
Gly Leu Phe Gly Gly Leu Phe Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 28
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 28
Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 29
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 29
Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 30
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 30
Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 31
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 31
Gly Phe Leu Gly Gly Phe Leu Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 32
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 32
Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 33
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 33
Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 34
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 34
Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 35
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 35
Gly Leu Ala Gly Gly Leu Ala Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 36
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 36
Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 37
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 37
Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 38
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 38
Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 39
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 39
Gly Phe Ala Gly Gly Phe Ala Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 40
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 40
Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 41
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 41
Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 42
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 42
Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 43
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 43
Gly Ala Phe Gly Gly Ala Phe Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 44
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 44
Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 45
<211> 38
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 45
Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Arg Arg Arg Arg Arg Arg
1 5 10 15
Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly
20 25 30
Arg Ser Gly Gly Ser Lys
35
<210> 46
<211> 37
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 46
Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Arg Arg Arg Arg Arg Ser
1 5 10 15
Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg
20 25 30
Ser Gly Gly Ser Lys
35
<210> 47
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 47
Gly Ala Leu Gly Gly Ala Leu Gly Tyr Gly Arg Lys Lys Arg Arg Gln
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 48
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 48
Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Gln Arg Arg Thr Ser Lys
1 5 10 15
Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 49
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 49
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 50
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 50
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 51
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 51
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 52
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 52
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 53
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 53
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 54
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 54
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 55
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 55
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 56
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 56
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 57
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 57
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 58
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 58
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 59
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 59
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 60
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 60
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 61
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 61
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 62
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 62
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 63
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 63
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 64
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 64
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 65
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 65
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 66
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 66
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 67
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 67
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 68
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 68
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 69
<211> 42
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 69
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp
20 25 30
Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 70
<211> 41
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 70
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Arg Arg
1 5 10 15
Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys Trp Cys Trp Arg
20 25 30
Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40
<210> 71
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 71
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Tyr Gly Arg Lys
1 5 10 15
Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 72
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 72
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Arg Arg Gln Arg
1 5 10 15
Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 73
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 73
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 74
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 74
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gly Leu Phe Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 75
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 75
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 76
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 76
Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly Gly Leu Phe Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50
<210> 77
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 77
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 78
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 78
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 79
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 79
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 80
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 80
Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly Gly Phe Leu Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50
<210> 81
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 81
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 82
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 82
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 83
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 83
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 84
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 84
Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly Gly Leu Ala Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50
<210> 85
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 85
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 86
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 86
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 87
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 87
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 88
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 88
Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly Gly Phe Ala Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50
<210> 89
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 89
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 90
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 90
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 91
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 91
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 92
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 92
Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly Gly Ala Phe Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50
<210> 93
<211> 46
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 93
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His
20 25 30
Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 94
<211> 45
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 94
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly
1 5 10 15
Arg Arg Arg Arg Arg Arg Arg Ser Gly Gln Tyr Ala Ser Tyr His Cys
20 25 30
Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser Lys
35 40 45
<210> 95
<211> 49
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 95
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly
1 5 10 15
Tyr Gly Arg Lys Lys Arg Arg Gln Arg Arg Arg Ser Gly Gln Tyr Ala
20 25 30
Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly Ser
35 40 45
Lys
<210> 96
<211> 50
<212> PRT
<213> 人工序列(Artificial Sequence)
<400> 96
Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly Gly Ala Leu Gly
1 5 10 15
Arg Arg Gln Arg Arg Thr Ser Lys Leu Met Lys Arg Ser Gly Gln Tyr
20 25 30
Ala Ser Tyr His Cys Trp Cys Trp Arg Asp Pro Gly Arg Ser Gly Gly
35 40 45
Ser Lys
50

Claims (3)

1.一种线形肽分子，其特征在于，所述线性肽分子的氨基酸序列为：
Gly-Leu-Phe-Gly-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Gly-Gln-Tyr-Ala-Ser-Tyr-His-Cys-Trp-Cys-Trp-Arg-Asp-Pro-Gly-Arg-Ser-Gly-Gl y-Ser-Lys。
2.一种药物，其特征在于，包括如权利要求1所述的线形肽分子。
3.一种药物，其特征在于，包括如权利要求1所述的线形肽分子在药学上可接受的盐。
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