CN113880915A - 用于修复黏膜损伤或皮肤创伤的多肽及其应用 - Google Patents
用于修复黏膜损伤或皮肤创伤的多肽及其应用 Download PDFInfo
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- CN113880915A CN113880915A CN202110747197.5A CN202110747197A CN113880915A CN 113880915 A CN113880915 A CN 113880915A CN 202110747197 A CN202110747197 A CN 202110747197A CN 113880915 A CN113880915 A CN 113880915A
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Abstract
本发明涉及用于修复黏膜损伤或皮肤创伤的新型多肽及其应用，本发明的多肽与已知多肽无同源性，而且能够在体内和体外均稳定存在，具有调控干细胞增殖和分化修复黏膜损伤或皮肤创伤的效果；以及涉及所述新型多肽通过调控干细胞增殖和分化修复黏膜损伤或皮肤创伤的用途，以及用于预防、减轻或治疗胃肠疾病的用途。
Description
技术领域
本发明涉及用于修复黏膜损伤或皮肤创伤的新型多肽及其应用，本发明的多肽与已知多肽无同源性，而且能够在体内和体外均稳定存在，具有调控干细胞增殖和分化，修复黏膜损伤或皮肤损伤的效果；以及涉及所述新型多肽通过调控干细胞增殖和分化修复黏膜损伤或皮肤创伤的用途，以及用于预防、减轻或治疗胃肠疾病的用途。
背景技术
皮肤创伤和/或黏膜损伤是很多疾病的共同病理特征。皮肤创伤或皮肤损伤是指正常皮肤(组织)在外界致伤因子如外科手术、外力、热、电流、化学物质、低温以及机体内在因素如局部血液供应障碍等作用下所导致的损害。皮肤损伤常伴有皮肤完整性的破坏以及一定量正常组织的丢失，同时，皮肤的正常功能受损。也称为伤口或者创伤。目前有包括碱性成纤维生长因子、表皮生长因子、血小板生长因子、粒-巨噬细胞集落刺激因子及生长激素等蛋白质/多肽药物具有明显的修复创面、护肤、抗皱和防衰老作用，但这些蛋白质/多肽药物的氨基酸序列较长导致制备成本高、稳定性较差等缺点，因而其应用受到了一定的限制。
人体黏膜是指呼吸系统、消化系统、生殖泌尿系统等腔道或囊状肌性器官的内层，是仅次于皮肤的人体第二大屏障，包括口腔、咽、气管、食道、胃、肠道、阴道、膀胱等，这些器官的管壁或囊壁均有共同的分层规律，又具有与其功能相适应的特点，其胚胎起源、组织结构、病理过程、临床表现、愈后等均有共同特点。
慢性胃炎是一种胃黏膜慢性炎症，是消化内科的常见病和多发病，临床上将不同原因引起的胃黏膜慢性炎症(即在病理上表现为单核细胞和淋巴细胞浸润)和(或)腺体萎缩性病变称为慢性胃炎。以胃黏膜上皮和腺体萎缩为特征的慢性萎缩性胃炎(chronicatrophic gastrifis,CAG)，其起病隐匿、病程长、症状无特异性、难以治愈，在慢性胃炎中占11％～31％，好发于中老年人群，发病和年龄有一定的关联但与性别没有关系，发病缓慢且病势缠绵，迁延难愈，治疗棘手。慢性萎缩性胃炎是胃癌发生发展重要阶段被视为胃癌前病变，1978年世界卫生组织％WHO)已将CAG列为癌前状态，其常伴假幽门腺化生和肠上皮化生，或不典型增生阶段等癌前病变。尤其是伴有弥漫的肠上皮化生或不典型增生者，癌变可能性更大，业界大多数专业人士都赞同通过慢性浅表性胃炎、萎缩性胃炎、肠上皮化生、异型增生、肠型胃癌这样的发展模式。故早期准确的诊断和治疗对慢性萎缩性胃炎患者有着重要的意义。目前现代医学治疗本病主要以改善症状、手术介入为主，在腺体萎缩、肠化生方面尚无良策。CAG为慢性胃炎转变为胃癌的重要阶段，积极治疗CAG对预防其癌变、降低胃癌发病率有着深远意义。寻求萎缩性胃炎的有效治疗方法，是更好地开展胃癌预防的重要措施之一。
黏膜组织的损伤临床上会导致慢性胃炎和消化道溃疡等胃肠道疾病。黏膜上皮的修复有修复(restitution)和再生(regeneration或renewal)两种不同的机制(Cur.Med.Chem.,2008,15,3133-3144)：修复或恢复一般在损伤后几分钟内就开始，通过细胞迁移快速修复浅表病变；再生是通过干细胞和祖细胞的分化和增殖持续再生，持续数天至数月。
表皮生长因子(EGF)是一种由53个氨基酸残基组成的多肽，广泛存在于多种组织器官和体液中，其可促进上皮细胞增殖从而对皮肤起到保护作用。表皮生长因子主要是促进皮肤组织细胞的增殖与生长，使新生的细胞替代衰老的细胞，从而起到抗衰老和护肤保健等功能。表皮生长因子已经被报道具有修复创面作用，因皮肤创面需要消毒、清创时，会应用含碘或双氧水的消毒剂，EGF在此条件下不稳定。生长因子与胃肠吻合口愈合有关(J.Surgical Res.2014；17:202-210)，但是EGF经胃肠口服给药时，进入体内后会发生降解，不能达到治疗效果。
因此，需要一种体内外稳定、能够治疗皮肤和/或黏膜损伤，特别是胃肠道黏膜损伤的肽类物质。
发明内容
为了克服现有技术的不足和缺陷，本发明的目的在于提供一类新型多肽。
第一方面，本发明提供式(I)的化合物或其生理学上相容的盐，其中所述式(I)的化合物如下：
H-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Val-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-OH(I)
其中
Xaa1为Pro、Gly、Ala或缺失；
Xaa2为Ala、Leu、Ile、Gly、Cys、Ser或缺失；
Xaa3为Ala、Pro、Gly、Leu、Ile、Cys、Ser或缺失；
Xaa4为Glu、Gln、Asp、Asn、Leu、Ile、Val或缺失；
Xaa5为Pro、Gly、Ala、Val或缺失；
Xaa6为Pro、Gly或Ala；
Xaa7为Leu、Phe、Val、Ala、Tyr、Glu、Lys、Asp、Ile、Met或缺失；
Xaa8为Val、Leu、Gln、Ile、Met或缺失；
Xaa9为Lys、Arg、His、Asp、Val或缺失；
Xaa10为Glu、Gln、Asp、Asn或缺失；以及
Xaa11为Glu、Asp、Asn、Gln或缺失，
条件是：Xaa1、Xaa2、Xaa3、Xaa4、Xaa5、Xaa7、Xaa8、Xaa9、Xaa10和Xaa11中至多有9个是缺失的。
在一实施方案中，Xaa5为Pro。
在一实施方案中，Xaa6为Pro。
在一实施方案中，Xaa7为Leu。
在一实施方案中，式(I)化合物具有以下式(II)结构，
H-Xaa1-Xaa2-Xaa3-Xaa4-Pro-Val-Pro-Leu-Xaa8-Xaa9-Xaa10-Xaa11-OH(II)，
其中
Xaa1为Pro、Gly、Ala或缺失；
Xaa2为Ala、Leu、Ile、Gly、Cys、Ser或缺失；
Xaa3为Ala、Pro、Gly、Leu、Ile、Cys、Ser或缺失；
Xaa4为Glu、Gln、Asp、Asn、Leu、Ile、Val或缺失；
Xaa8为Val、Leu、Gln、Ile、Met或缺失；
Xaa9为Lys、Arg、His、Asp、Val或缺失；
Xaa10为Glu、Gln、Asp、Asn或缺失；以及
Xaa11为Glu、Asp、Asn、Gln或缺失。
在一实施方案中，式(I)或(II)中的Xaa1为Pro或缺失；优选为Pro。
在一实施方案中，式(I)或(II)中的Xaa2为Ala或缺失；优选为Ala。
在一实施方案中，式(I)或(II)中的Xaa3为Ala、Gly或缺失；优选为Ala。
在一实施方案中，式(I)或(II)中的Xaa4为Glu、Gln、Asp或缺失；优选为Glu、Asp或Gln。
在一实施方案中，式(I)或(II)中的Xaa8为Val或缺失；优选为Val。
在一实施方案中，式(I)或(II)中的Xaa9为Lys、Arg或缺失；优选为Lys或缺失。
在一实施方案中，式(I)或(II)中的Xaa10为Glu、Gln或缺失；优选为Gln。
在一实施方案中，式(I)或(II)中的Xaa11为Asp或缺失；优选为Asp。
在一实施方案中，式(I)或(II)中的Xaa1、Xaa2、Xaa3和Xaa4中有一个是缺失的；或者有两个是缺失的；或者有三个是缺失的；或者都是缺失的。
在一实施方案中，式(I)或(II)中的Xaa8、Xaa9、Xaa10和Xaa11中有一个是缺失的；或者有两个是缺失的；或者有三个是缺失的；或者都是缺失的。
在一实施方案中，所述化合物选自本发明化合物1-73中任一个。
在一实施方案中，所述化合物选自：
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物1)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys(化合物3)；
Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物10)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu(化合物26)；
Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物27)；
Ala-Glu-Pro-Val-Pro-Leu(化合物30)；
Glu-Pro-Val-Pro-Leu(化合物31)；
Pro-Val-Pro-Leu(化合物32)；
Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物28)；
Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物11)；
Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物48)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp(化合物57)；或
Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物38)。
为方便起见，在本申请中描述本发明的化合物时，省略左侧的H和右侧的OH。
在一实施方案中，所述化合物为Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物1)。
第二方面，本发明提供一种修复黏膜损伤的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐或使黏膜损伤与本发明的化合物或其生理学上相容的盐接触。在一实施方案中，所述修复是通过调控干细胞增殖和分化进行的。
在一实施方案中，所述黏膜损伤是消化系统、呼吸系统等腔道内黏膜损伤。
消化系统黏膜损伤与口腔、食道、胃肠疾病相关，所述口腔疾病包括口腔溃疡、口腔炎、牙龈炎、牙周炎等；所述食道疾病包括食管炎、食管溃疡等；所述胃肠疾病包括慢性胃炎、慢性萎缩性胃炎、急性胃炎、胃十二指肠溃疡、功能性胃肠道疾病、消化不良、癌前病变、消化系统肿瘤、胃肠道出血、胃食管返流疾病、急慢性肠炎、溃疡性结肠炎、克罗恩病和放化疗引起的黏膜损伤，但不限于此。
在优选的实施方案中，所述消化道黏膜包括胃黏膜和肠黏膜。在优选的实施方案中，慢性胃炎包括慢性萎缩性胃炎。在优选的实施方案中，所述黏膜损伤是由刺激性物质或药物、应激状态引起的胃黏膜损伤。所述刺激性物质如盐酸、乙醇或酒精等，所述药物例如非类固醇类抗炎药阿司匹林或吲哚美辛等。
本发明提供一种预防、减轻或治疗消化道疾病或消除炎症水肿的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐。所述消化道疾病包括口腔、食道、胃肠疾病相关，所述口腔疾病包括口腔溃疡、口腔炎、牙龈炎、牙周炎等；所述食道疾病包括食管炎、食管溃疡等；所述胃肠疾病包括慢性胃炎、慢性萎缩性胃炎、急性胃炎、胃十二指肠溃疡、功能性胃肠道疾病、消化不良、癌前病变、消化系统肿瘤、胃肠道出血、胃食管返流疾病、急慢性肠炎、溃疡性结肠炎、克罗恩病和放化疗引起的黏膜损伤；但不限于此。在一实施方案中，所述消化道疾病的预防、减轻或治疗是通过调控干细胞增殖和分化进行的。所述方法通过本发明的化合物或其生理学上相容的盐对胃黏膜或肠黏膜等消化道黏膜起到保护作用或修复胃黏膜或肠黏膜等消化道黏膜的损伤，从而起到预防、减轻或治疗胃肠疾病的作用。
本发明提供一种修复黏膜或皮肤创面的方法，所述方法包括对受试者给予本发明的化合物或其生理学上相容的盐。在一实施方案中，所述黏膜或皮肤创面的修复包括调控干细胞增殖和分化。
在上述本发明的方法中，本发明的化合物或其生理学上相容的盐是通过口服、注射、皮下等方式给药的。
第三方面，本发明提供一种修复皮肤创伤的方法，所述方法包括使皮肤创伤与本发明的化合物或其生理学上相容的盐接触。在优选的实施方案中，所述皮肤创伤与表皮炎症、机械及手术创面、烧伤及烫伤、溃疡、瘘管、褥疮、放化疗引起的皮肤损伤相关，但不限于此。在一实施方案中，所述皮肤创伤是指正常皮肤在外界致伤因子如外科手术、外力、热、电流、化学物质、低温以及机体内在因素如局部血液供应障碍等作用下所导致的损害。在一实施方案中，所述皮肤创伤常伴有皮肤完整性的破坏以及一定量正常组织的丢失。在另一实施方案中，所述皮肤创伤包括皮肤的正常功能受损。在一实施方案中，所述皮肤创伤的恢复是通过调控干细胞增殖和分化进行的。
本发明提供一种促进HaCAT细胞增殖的方法，所述方法包括使所述细胞与本发明的化合物或其生理学上相容的盐接触。
第四方面，本发明提供一种使损伤的血管再生的方法，所述方法包括使损伤的血管与本发明的化合物或其生理学上相容的盐接触。在优选的实施方案中，所述损伤的血管包括消化道黏膜损伤和皮肤创伤导致的血管损伤。
第五方面，本发明提供一种药物、食品、保健品或化妆品、日用品组合物，所述组合物包括本发明的化合物或其生理学上相容的盐以及生理学上可接受的载体。在一实施方案中，所述生理学上可接受的载体包括药学上可接受的载体或化妆品可接受的载体。所述药物食品、保健品或化妆品、日用品组合物可以按照制剂学或化妆品常规技术制备，包括将作为活性成分的本发明的化合物与载体混合，按照常规技术制成所需要的剂型。可以根据需要，将本发明的组合物配制成口服施用制剂、黏膜施用制剂、注射制剂、吸入制剂和外用制剂。
本发明的多肽与已知多肽无同源性，便于人工多肽合成以获得高纯度多肽，与表皮生长因子多肽相比本发明的多肽由于仅由至多12个氨基酸残基组成在体内稳定，而且本发明的多肽能促进干细胞增殖分化，特别是能促进胃类器官的增殖和分化，参与并调控胃上皮干细胞的增殖和分化，从而可对胃肠干细胞，表皮干细胞损伤进行修复，具有显著的减轻诸如慢性胃炎及消化道溃疡的胃肠疾病病理发展、消除炎症水肿、促进消化道黏膜损伤修复和皮肤创伤修复、缩短创面愈合时间、调解免疫功能等作用。此外，本发明的多肽用于体表皮肤创面时即使经碘制剂或双氧水消毒之后也能够起作用或者在人工胃液、人工肠液等中也能稳定存在，而表皮生长因子用于体表皮肤时，经碘制剂或双氧水消毒之后结构会破坏，不能发挥作用。
附图说明
图1示出了多肽固相合成步骤的示意图。
图2示出了化合物1对乙醇诱导的小鼠胃溃疡的抗溃疡作用。
图3示出了化合物1对促进胃类器官的增殖和分化的结果。
图4示出了化合物1对促进胃类器官的分化的结果。
图5示出了化合物1对慢性萎缩性胃炎小鼠的治疗作用。
图6示出了化合物1对慢性萎缩性胃炎大鼠胃上皮干细胞的影响。
图7示出了化合物1对慢性萎缩性胃炎大鼠的治疗作用。
图8示出了化合物1对HaCAT细胞的促增殖作用。
图9示出了斑马鱼肠下血管面积分析部位示意图。
图10示出了经本发明化合物处理后的斑马鱼肠下血管面积典型图。
图11示出了经本发明化合物处理后的斑马鱼肠下血管分支数。
具体实施方式
术语“生理学上相容的盐”是指生理学上相容的(即药理学上可接受的)并且对将被施用本发明化合物的个体基本上无毒的盐形式。本发明化合物的生理学上相容的盐包括由适宜的、无毒的有机或无机酸或无机碱形成的常规的和化学计量的酸加成盐或碱加成盐。
术语“受试者”是指动物，优选为哺乳动物，最优选为人。具体地讲，术语“受试者”涉及具有皮肤创伤和/或黏膜损伤的哺乳动物或人。本领域技术人员应理解，本发明的皮肤创伤和/或黏膜损伤的修复可出于美容目的(即非治疗性目的)和治疗性目的施用。为此，本申请的术语“皮肤损伤”还包括出于美容目的修复的皮肤损伤例如，皱纹(例如紫外线照射导致的皱纹)、皮肤纹、裂缝、肿块、大毛孔(例如与附件结构如汗腺管、皮脂腺或毛囊相关的)，或不平或粗糙，皮肤失去弹性(功能性皮肤弹性蛋白丧失和/或失活)、下垂(包括眼部和下颌浮肿)、皮肤硬度丧失、皮肤紧实度丧失、皮肤变形后的回复能力丧失、变色(包括黑眼圈)、斑疱、肤色灰黄、色素过量皮肤区域例如老年斑和雀斑、角质物、异常的分化、过度角质化、弹性组织变性、胶原蛋白的破坏，以及皮肤角质，真皮，表皮层，皮肤血管系统(例如毛细血管扩张或多叉血管)，以及皮下组织，特别是靠近皮肤的皮下组织中的其它组织变化。
以下是结合具体试验对本发明的说明，并不是对本发明保护范围的限制。
表1书写中所使用到试剂、溶剂的英文名或缩写
| 英文名或缩写 | 中文名 |
| HBTU | 苯并三氮唑-N,N,N',N'-四甲基脲六氟磷酸盐 |
| Methanol | 甲醇 |
| Tert-Butyl methyl ether | 甲基叔丁基醚 |
| Ethanol | 乙醇 |
| AA | 氨基酸 |
实施例1：多肽的化学合成
多肽化合物的合成采用常规固相合成方法，经过树脂溶胀、取代、脱保护、洗涤、氨基酸溶解、氨基酸活化和缩合过程、洗涤、再脱保护多个循环过程，以及最后裂解和侧链脱保护。
多肽固相合成步骤示意图参见图1。图1中，Cl-2-Cl-Resin表示2-氯三苯甲基氯树脂(2-Chlorotrityl Chloride Resin)；Fmoc-Aa(n)等表示9-芴基甲氧基羰基的氨基酸；DIPEA为N,N-二异丙基乙胺；DCM为二氯甲烷；PIP为哌啶；DMF为N,N-二甲基甲酰胺；HOBt为1-羟基苯并三唑；DIC为N,N'-二异丙基碳二亚胺；TFA为三氟乙酸；TIPS为三异丙基硅烷。
以下以化合物1(Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp)为例，示出化合物1的合成和纯化的方法，所述方法包括步骤1、全保护肽树脂的制备；2、切割、脱保护；3、纯化(换盐)冻干。
步骤1、全保护肽树脂的制备
(1)树脂溶胀：称取2-Chlorotrityl Chloride Resin 2.0192g(S＝0.73mmol/g)，加入到有筛板的合成管中，用40ml二氯甲烷溶胀30min，抽滤除去二氯甲烷。
(2)制备Fmoc-Asp(OtBu)-树脂：按树脂、Fmoc-Asp(OtBu)-OH、DIPEA，以1：1.5：1.65的摩尔比分别称取Fmoc-Asp(OtBu)-OH、DIPEA，溶解于二氯甲烷20ml中，加入合成管中。室温N2鼓泡震荡1～3小时，直接向反应液中加入甲醇2ml封闭30min。然后分别用二甲基甲酰胺洗涤4次，25ml/次，抽干树脂。
(3)脱除Fmoc保护基：向反应器中加入20％哌啶-DMF(v/v)溶液20ml，N2鼓泡反应20min，抽干；然后用二甲基甲酰胺洗涤6次，25ml/次，3分钟/次，抽干，茚三酮法检测Fmoc脱除结果。
(4)氨基酸预活化：在250ml圆底烧瓶中加入4.38mmol的Fmoc保护的氨基酸、5.26mmol HOBt、4.60mmol DIC，用1：1的DCM-DMF(v/v)20ml溶解，-5-0℃冰浴搅拌下预活化30～60min。
(5)氨基酸连接：将已活化的保护氨基酸溶液倒入反应器中，补加适量的DCM清洗用具。室温下N2鼓泡反应1～3小时，茚三酮法检测氨基酸连接是否完全，若完全，抽干。树脂用二甲基甲酰胺洗涤4次，25ml/次，3min/次，抽干。每一种氨基酸、缩合剂的用量及具体反应时间见表2。
(6)第一个氨基酸缩合完成后，重复步骤(3)～(5)，按照氨基酸顺序延长肽链至最后一个氨基酸偶联完毕。
(7)树脂肽用二氯甲烷洗涤6次，25ml/次，3min/次，抽干。
表2氨基酸、缩合剂的用量
| 氨基酸名称 | AA/eq | 氨基酸用量/g | HOBt/g | DIPEA/g | DIC/g |
| Fmoc-L-Asp(OtBu)-OH | 2.19 | 0.90 | 0 | 0.31 | 0 |
| Fmoc-L-Gln(Trt)-OH | 4.38 | 2.67 | 0.71 | 0.57 | 0.58 |
| Fmoc-L-Lys(Boc)-OH | 4.38 | 2.05 | 0.71 | 0.57 | 0.58 |
| Fmoc-L-Val-OH | 4.38 | 1.49 | 0.71 | 0.57 | 0.58 |
| Fmoc-L-Leu-OH | 4.38 | 1.55 | 0.71 | 0.57 | 0.58 |
| Fmoc-L-Pro-OH | 4.38 | 1.48 | 0.71 | 0.57 | 1.16 |
| Fmoc-L-Val-OH | 4.38 | 1.49 | 0.71 | 0.57 | 0.58 |
| Fmoc-L-Pro-OH | 4.38 | 1.48 | 0.71 | 0.57 | 1.16 |
| Fmoc-L-Glu(OtBu)-OH.H<sub>2</sub>O | 4.38 | 1.94 | 0.71 | 0.57 | 1.16 |
| Fmoc-L-Ala-OH.H<sub>2</sub>O | 4.38 | 1.44 | 0.71 | 0.57 | 1.16 |
| Fmoc-L-Ala-OH.H<sub>2</sub>O | 4.38 | 1.44 | 0.71 | 0.57 | 1.16 |
| Fmoc-L-Pro-OH | 4.38 | 1.48 | 0.71 | 0.57 | 1.16 |
步骤2、切割、脱保护
(1)在步骤1的合成管中，加入切割剂(TFA:TIPS:H2O＝95:2.5:2.5，v/v)50ml，N2鼓泡反应1.5-3小时。
(2)切割反应完成后，将切割剂抽滤至250ml圆底烧瓶中。真空浓缩至原切割剂体积的三分之一后，加入10倍现有体积的甲基叔丁基醚，搅拌30min。将所得混合溶剂过滤，并用30ml甲基叔丁基醚分别清洗3次后，将所得粗肽产品置于砂芯漏斗在通风橱中N2吹干，使溶剂挥发至粗肽为粉末状。得到粗肽1.87g，粗产率85.1％。
步骤3、纯化(换盐)和冻干
采用以下色谱参数条件A，对步骤2中获得的粗肽进行HPLC纯化。具体而言，用水和/或乙腈溶解步骤2中获得的粗肽，并经0.45μm滤膜过滤；进样；用乙腈-水流动相梯度洗脱；收集目的肽洗脱液；最后进行旋蒸浓缩。
色谱参数条件A：
色谱柱：YMC-Actus Triart C18 30*250mm；
洗脱液A：0.1％(v/v)TFA/H2O；
洗脱液B：乙腈；
流速25ml/min；
紫外检测波长220nm；
表3梯度洗脱条件
| 时间min | 洗脱液A(％) | 洗脱液B(％) |
| 0 | 90 | 10 |
| 30 | 75 | 25 |
接着采用以下色谱参数条件B利用HPLC法对上述步骤所获得的产品进行换盐，得到最终的肽化合物1。具体而言，使用95％A1+5％B平衡色谱柱；然后进样；接着采用95％A2+5％B平衡色谱柱；用A1和B梯度洗脱；收集目的肽洗脱液；最后旋蒸浓缩并且冷冻干燥，得到化合物1(纯化收率73.3％，纯度100％)。化合物1的结构经MS、1H-NMR确认。
色谱参数条件B：
色谱柱：YMC-Actus Triart C18 30*250mm
洗脱液A1：0.1M乙酸
洗脱液A2:0.025M乙酸+0.1M乙酸铵
洗脱液B：乙腈
流速25ml/min
紫外检测波长220nm
表4梯度洗脱条件
| 时间min | 洗脱液A1(％) | 洗脱液B(％) |
| 0 | 95 | 5 |
| 5 | 95 | 5 |
| 35 | 70 | 30 |
以与合成化合物1类似的方式，合成其他化合物。结果参见表5和说明书其他部分。
表5合成的化合物
注释：双电荷代表质谱出1/2目标峰，三电荷代表质谱出1/3目标峰；N/A代表称量有难度，未计实际重量。
化合物1:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.27(d,J＝7.6Hz,1H),8.21(d,J＝7.8Hz,1H),8.09(d,J＝7.5Hz,1H),8.03(d,J＝7.9Hz,1H),7.99(d,J＝7.4Hz,1H),7.94(dd,J＝16.7,8.0Hz,2H),7.58(d,J＝6.3Hz,1H),7.51(d,J＝8.6Hz,1H),7.16(s,1H),6.70(s,1H),4.48(dd,J＝13.3,7.9Hz,1H),4.39(dd,J＝8.2,4.2Hz,1H),4.35–4.21(m,6H),4.18–4.03(m,3H),3.71–3.47(m,5H),2.93–2.69(m,4H),2.45–2.32(m,2H),2.25(t,J＝7.7Hz,2H),2.08(t,J＝7.9Hz,2H),2.01–1.93(m,3H),1.93–1.84(m,14H,AcOH),1.84–1.76(m,3H),1.75–1.57(m,8H),1.54–1.39(m,5H),1.36–1.27(m,2H),1.21–1.10(m,6H),0.91–0.74(m,18H).
化合物3:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys醋酸盐
1H NMR(600MHz,DMSO)δ8.22–8.13(m,2H),8.10(s,1H),7.98(d,J＝7.6Hz,1H),7.92(d,J＝8.4Hz,1H),7.72(s,1H),7.59(s,1H),4.52–4.43(m,1H),4.39–4.19(m,6H),4.12–4.04(m,1H),3.89(d,J＝5.9Hz,1H),3.67–3.46(m,6H),2.85(dt,J＝10.2,6.8Hz,1H),2.80–2.73(m,1H),2.69(s,2H),2.21(t,J＝7.4Hz,2H),2.03–1.76(m,14H,AcOH),1.73(d,J＝5.5Hz,1H),1.70–1.61(m,4H),1.61–1.52(m,3H),1.47(s,4H),1.26(s,2H),1.20–1.12(m,6H),0.91–0.83(m,9H),0.83–0.77(m,9H).
化合物4:Pro-Ala-Ala-Glu-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,D2O)δ4.45–4.16(m,10H),4.04(d,J＝8.1Hz,1H),3.93–3.76(m,3H),3.67–3.58(m,1H),3.42–3.28(m,2H),2.94(t,J＝7.4Hz,2H),2.72(qd,J＝16.4,6.0Hz,2H),2.45–2.27(m,5H),2.27–2.16(m,1H),2.11–1.86(m,17H,AcOH),1.84–1.47(m,8H),1.45–1.25(m,8H),0.91(d,J＝6.8Hz,3H),0.89–0.73(m,15H).
化合物5:Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,D2O+D3COD)δ4.66–4.62(m,2H),4.40(dd,J＝8.1,5.9Hz,1H),4.35–4.21(m,6H),4.03–3.98(m,2H),3.92–3.81(m,2H),3.78–3.71(m,1H),3.62(dt,J＝10.3,7.1Hz,1H),3.39–3.30(m,2H),2.96–2.87(m,4H),2.51–2.35(m,3H),2.32(t,J＝7.6Hz,2H),2.26–2.19(m,1H),2.10–1.91(m,14H,AcOH),1.91–1.78(m,2H),1.78–1.71(m,1H),1.70–1.58(m,3H),1.53(d,J＝3.6Hz,3H),1.42–1.34(m,2H),1.33(d,J＝7.2Hz,3H),1.30(d,J＝7.2Hz,3H),0.94–0.88(m,6H),0.88–0.83(m,9H),0.82–0.79(m,3H).
化合物8:Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.30–8.24(m,3H),8.15(d,J＝7.3Hz,1H),8.11–8.03(m,2H),7.94(d,J＝7.4Hz,1H),7.88(d,J＝8.0Hz,1H),7.80(t,J＝9.4Hz,2H),7.59(d,J＝6.4Hz,1H),7.17(s,1H),6.70(s,1H),4.44–3.99(m,10H),3.82–3.57(m,7H),2.94–2.69(m,5H),2.47–2.41(m,1H),2.41–2.32(m,1H),2.21(t,J＝7.9Hz,2H),2.08(t,J＝7.9Hz,2H),2.03–1.79(m,11H,AcOH),1.78–1.26(m,14H),1.19(dd,J＝6.9,4.7Hz,6H),0.87–0.76(m,18H).
化合物9:Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu
1H NMR(600MHz,DMSO)δ8.43(d,J＝7.6Hz,1H),8.29–8.23(m,2H),8.22–8.14(m,2H),7.81(d,J＝8.5Hz,1H),7.75(d,J＝7.9Hz,1H),4.32–4.08(m,5H),3.78–3.69(m,4H),3.63(dd,J＝16.4,5.6Hz,1H),2.98–2.86(m,2H),2.22(t,J＝7.9Hz,2H),2.07–1.92(m,2H),1.92–1.86(m,1H),1.79–1.64(m,4H),1.62–1.54(m,1H),1.50–1.40(m,2H),1.19(dd,J＝7.0,1.3Hz,6H),0.86–0.78(m,12H).
化合物10:Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.28(d,J＝7.7Hz,1H),8.14(d,J＝7.8Hz,1H),8.07(d,J＝7.4Hz,1H),8.04(d,J＝8.0Hz,1H),8.00(d,J＝7.3Hz,1H),7.95(t,2H),7.58(d,J＝6.3Hz,1H),7.50(d,J＝8.7Hz,1H),7.17(d,J＝15.3Hz,2H),6.76(s,1H),6.70(s,1H),4.45(q,J＝13.6,7.9Hz,1H),4.39(dd,J＝8.3,4.1Hz,1H),4.33–4.20(m,6H),4.20–4.09(m,2H),4.09–4.02(m,1H),3.69–3.47(m,5H),2.86(dt,J＝10.2,6.7Hz,1H),2.80–2.62(m,3H),2.46–2.40(m,1H),2.37(dd,J＝15.5,2.7Hz,1H),2.14–2.03(m,4H),2.02–1.76(m,16H,AcOH),1.75–1.39(m,13H),1.39–1.22(m,2H),1.22–1.11(m,6H),1.00–0.68(m,18H).
化合物11:Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.26(d,J＝7.6Hz,1H),8.19(d,J＝7.7Hz,1H),8.09(d,J＝7.7Hz,1H),8.04(d,J＝7.5Hz,1H),7.96(t,J＝7.4Hz,2H),7.87(d,J＝7.0Hz,1H),7.60(d,J＝6.4Hz,1H),7.37(d,J＝8.9Hz,1H),7.17(s,1H),6.70(s,1H),4.70(q,J＝14.2,7.0Hz,1H),4.37–4.21(m,7H),4.16–4.10(m,2H),4.09–4.03(m,1H),3.74–3.67(m,2H),3.68–3.59(m,4H),3.49–3.45(m,1H),2.99–2.84(m,3H),2.80–2.71(m,2H),2.63(dd,J＝16.5,7.5Hz,1H),2.46–2.25(m,4H),2.07(t,J＝7.9Hz,2H),2.05–1.76(m,20H,AcOH),1.74–1.58(m,6H),1.56–1.42(m,5H),1.32(d,J＝8.0Hz,2H),1.18(d,J＝7.0Hz,3H),1.14(d,J＝7.1Hz,3H),0.88–0.74(m,18H).
化合物12:Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.29(d,J＝7.5Hz,1H),8.17(d,J＝7.7Hz,1H),8.09(d,J＝7.4Hz,1H),8.03(d,J＝7.2Hz,1H),7.96(d,J＝7.6Hz,1H),7.90(d,J＝8.7Hz,1H),7.86(d,J＝7.9Hz,1H),7.73(d,J＝8.5Hz,1H),7.58(d,J＝6.4Hz,1H),7.25–7.19(m,4H),7.18–7.12(m,2H),6.71(s,1H),4.54–4.44(m,2H),4.37(q,J＝8.3Hz,1H),4.33–4.21(m,5H),4.19–4.10(m,2H),4.09–4.02(m,1H),3.64–3.53(m,5H),3.51–3.45(m,2H),3.00(dd,J＝9.6Hz,1H),2.89–2.82(m,2H),2.80–2.71(m,3H),2.46–2.36(m,2H),2.24(t,J＝7.4Hz,2H),2.08(t,J＝8.0Hz,2H),2.00–1.70(m,18H,AcOH),1.69–1.64(m,2H),1.63–1.56(m,2H),1.55–1.47(m,3H),1.34(s,2H),1.16(t,J＝6.9Hz,6H),0.87–0.76(m,12H).
化合物26:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu醋酸盐
1H NMR(600MHz,DMSO)δ8.25(s,1H),8.09(d,J＝7.5Hz,1H),7.94(d,J＝7.6Hz,1H),7.89(d,J＝8.3Hz,2H),4.53–4.46(m,1H),4.39(dd,J＝8.3,4.2Hz,1H),4.34(dd,J＝8.4,3.8Hz,1H),4.31–4.19(m,3H),4.13(dd,J＝15.1,7.7Hz,1H),3.71–3.49(m,5H),2.94–2.77(m,2H),2.33–2.20(m,2H),2.06–1.77(m,13H,AcOH),1.77–1.56(m,6H),1.46(t,J＝7.3Hz,2H),1.25–1.11(m,6H),0.95–0.76(m,12H).
化合物27:Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,D2O)δ4.61(dd,J＝9.6,4.4Hz,1H),4.44–4.22(m,8H),4.09–3.99(m,2H),3.85–3.72(m,2H),3.69–3.57(m,2H),2.94(t,J＝7.4Hz,2H),2.79–2.63(m,2H),2.43–2.16(m,7H),2.09–1.74(m,19H,AcOH),1.73–1.47(m,7H),1.48–1.13(m,6H),1.00–0.79(m,21H).
化合物28:Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.28(d,J＝7.8Hz,1H),8.13–7.87(m,3H),7.57(d,J＝6.4Hz,1H),7.50(d,J＝8.7Hz,1H),7.15(s,1H),6.69(s,1H),4.40–4.31(m,2H),4.29–4.21(m,2H),4.19–4.02(m,3H),3.67–3.60(m,1H),3.59–3.53(m,2H),2.92–2.85(m,1H),2.80–2.70(m,3H),2.47–2.38(m,1H),2.38–2.31(m,1H),2.08(t,J＝7.9Hz,2H),2.04–1.76(m,14H,AcOH),1.74–1.41(m,11H),1.41–1.14(m,2H),0.91–0.74(m,18H).
化合物30:Ala-Glu-Pro-Val-Pro-Leu醋酸盐
1H NMR(600MHz,DMSO)δ8.29(d,J＝7.1Hz,1H),7.89(d,J＝8.6Hz,1H),7.79(d,J＝8.0Hz,1H),4.54(d,J＝5.4Hz,1H),4.42–4.38(m,1H),4.37–4.28(m,2H),4.09(dd,J＝14.2,8.5Hz,1H),3.66–3.46(m,5H),2.28(t,J＝7.4Hz,2H),2.13–1.71(m,16H,AcOH),1.71–1.58(m,2H),1.53–1.32(m,2H),1.18(d,J＝6.9Hz,3H),0.90–0.83(m,9H),0.80(d,J＝6.6Hz,3H).
化合物31:Glu-Pro-Val-Pro-Leu醋酸盐
1H NMR(600MHz,DMSO)δ7.94–7.86(m,2H),4.44(dd,J＝8.3,4.5Hz,1H),4.37–4.27(m,2H),4.13(q,J＝7.6Hz,1H),3.74–3.69(m,1H),3.66–3.42(m,4H),2.40–2.25(m,2H),2.06–1.58(m,17H,AcOH),1.46(t,J＝7.3Hz,2H),0.89–0.84(m,9H),0.81(d,J＝6.5Hz,3H).
化合物32:Pro-Val-Pro-Leu醋酸盐
1H NMR(600MHz,DMSO)δ8.15(d,J＝9.0Hz,1H),7.91(d,J＝8.0Hz,1H),4.35(dt,J＝10.1,5.2Hz,2H),4.22–4.02(m,1H),3.67–3.59(m,2H),3.56(q,J＝13.2,9.3Hz,1H),2.96–2.88(m,1H),2.86–2.76(m,1H),2.05–1.59(m,11H,AcOH),1.59–1.42(m,2H),0.91–0.72(m,12H).
化合物34:Pro-Ala-Ala-Glu-Pro-Val醋酸盐
1H NMR(600MHz,DMSO)δ8.01(d,J＝7.3Hz,1H),7.14(d,J＝7.8Hz,1H),4.49(q,J＝6.8Hz,1H),4.31–4.22(m,3H),3.75(dd,J＝7.8,4.7Hz,1H),3.70–3.61(m,2H),2.88–2.81(m,1H),2.81–2.75(m,1H),2.27–2.13(m,2H),2.01–1.64(m,18H,AcOH),1.58(p,J＝6.9Hz,2H),1.17(dd,J＝10.2,7.1Hz,6H),0.78(dd,J＝6.9,3.5Hz,6H).
化合物35:Pro-Ala-Ala-Glu-Pro醋酸盐
1H NMR(600MHz,DMSO)δ8.28(s,1H),8.12(d,J＝7.5Hz,1H),7.90(d,J＝7.7Hz,1H),4.49(dd,J＝13.7,7.7Hz,1H),4.35–4.13(m,3H),3.76–3.50(m,3H),2.97–2.79(m,2H),2.33–2.18(m,2H),2.16–1.77(m,10H,AcOH),1.73–1.58(m,4H),1.26–1.13(m,6H).
化合物45:Ala-Glu-Pro-Val醋酸盐
1H NMR(600MHz,DMSO)δ8.36(d,J＝7.4Hz,1H),7.46(d,J＝8.0Hz,1H),4.65–4.53(m,1H),4.35(dd,J＝8.6,3.4Hz,1H),3.89(dd,J＝7.9,5.4Hz,1H),3.74–3.53(m,3H),2.38–2.19(m,2H),2.05–1.64(m,10H,AcOH),1.27–1.17(m,3H),0.83(d,J＝7.1Hz,6H).
化合物48:Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.33(d,J＝7.6Hz,1H),8.27(d,1H),8.21(t,J＝5.8Hz,1H),8.10(d,J＝7.5Hz,1H),8.05–7.97(m,2H),7.93(d,J＝8.5Hz,1H),7.57(d,J＝6.4Hz,1H),7.51(d,J＝8.8Hz,1H),7.16(s,1H),6.70(s,1H),4.53–4.47(m,1H),4.38(dd,J＝8.2,4.2Hz,1H),4.35–4.20(m,5H),4.18–4.09(m,2H),4.06(s,1H),3.75–3.50(m,8H),2.93–2.69(m,5H),2.45–2.41(m,1H),2.41–2.30(m,1H),2.25(t,J＝7.3Hz,2H),2.08(t,J＝7.9Hz,2H),2.01–1.76(m,15H,AcOH),1.74–1.53(m,8H),1.53–1.40(m,4H),1.33(d,J＝7.2Hz,2H),1.20(t,J＝9.0Hz,3H),0.91–0.73(m,18H).
化合物50:Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Lys-Gln-Asn醋酸盐
1H NMR(600MHz,DMSO)δ8.49(d,J＝7.8Hz,1H),8.17–8.06(m,2H),8.05–7.99(m,2H),7.97(d,J＝7.7Hz,1H),7.92(d,J＝8.7Hz,1H),7.59(s,1H),7.54(d,J＝8.8Hz,1H),7.37(d,J＝6.9Hz,1H),7.10(s,1H),6.68(d,J＝15.7Hz,2H),4.48(d,J＝5.1Hz,1H),4.39(dd,J＝8.1,4.3Hz,1H),4.35–4.19(m,6H),4.17–4.10(m,1H),4.05–3.97(m,2H),3.67–3.48(m,6H),2.92–2.78(m,2H),2.78–2.66(m,3H),2.44–2.34(m,1H),2.33–2.20(m,3H),2.07(t,J＝7.8Hz,2H),2.01–1.76(m,15H,AcOH),1.75–1.62(m,6H),1.62–1.53(m,3H),1.49–1.29(m,6H),1.19–1.12(m,6H),0.91–0.73(m,18H).
化合物51:Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Val-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.51(d,J＝7.6Hz,1H),8.08(d,J＝7.3Hz,1H),8.03–7.96(m,2H),7.95–7.89(m,2H),7.78(d,J＝8.9Hz,1H),7.75–7.69(m,1H),7.61(d,J＝8.8Hz,1H),7.18(s,1H),6.68(s,1H),4.51(d,J＝5.4Hz,1H),4.40(dd,J＝8.2,4.2Hz,1H),4.35–4.12(m,10H),4.01–3.95(m,1H),3.69–3.51(m,4H),3.09(d,J＝6.4Hz,2H),2.45–2.40(m,1H),2.39–2.34(m,1H),2.27(dd,J＝13.4,6.7Hz,2H),2.21–2.13(m,1H),2.06(t,J＝8.0Hz,2H),2.02–1.75(m,18H,AcOH),1.75–1.58(m,5H),1.44(t,J＝7.3Hz,2H),1.22(d,J＝7.1Hz,3H),1.16(d,J＝7.0Hz,3H),0.88(d,J＝6.7Hz,3H),0.85(dd,J＝6.5,2.7Hz,6H),0.83–0.77(m,15H).
化合物52:Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.28(s,1H),8.17(d,J＝8.0Hz,1H),8.09(d,J＝7.5Hz,1H),7.99–7.92(m,2H),7.87(dd,J＝16.4,8.8Hz,2H),7.68(d,J＝8.5Hz,1H),7.57(d,J＝6.1Hz,1H),7.17(s,1H),6.70(s,1H),4.50–4.45(m,1H),4.44–4.35(m,2H),4.32–4.21(m,4H),4.18–4.10(m,3H),4.08–3.99(m,1H),3.66–3.49(m,6H),2.90–2.82(m,1H),2.82–2.72(m,3H),2.46–2.30(m,2H),2.27–2.23(m,1H),2.07(t,J＝7.9Hz,2H),2.01–1.76(m,19H,AcOH),1.75–1.60(m,5H),1.60–1.45(m,5H),1.39–1.25(m,2H),1.20–1.10(m,6H),0.88(d,J＝6.6Hz,3H),0.86–0.76(m,15H).
化合物56:Pro-Ile-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.27(d,J＝7.8Hz,1H),8.17(d,J＝7.3Hz,1H),8.10(d,J＝9.4Hz,1H),8.05–7.97(m,2H),7.92(q,J＝13.5,8.1Hz,2H),7.57(d,J＝6.3Hz,1H),7.51(d,J＝8.8Hz,1H),7.16(s,1H),6.70(s,1H),4.54–4.45(m,1H),4.39(dd,J＝8.3,4.2Hz,1H),4.35–4.22(m,5H),4.21–4.09(m,3H),4.10–4.00(m,1H),3.67–3.48(m,6H),3.41–3.16(m,4H),2.95–2.86(m,1H),2.81–2.68(m,3H),2.47–2.41(m,1H),2.41–2.32(m,1H),2.25(t,J＝7.6Hz,2H),2.08(t,J＝7.9Hz,2H),2.02–1.75(m,19H,AcOH),1.75–1.55(m,9H),1.54–1.36(m,5H),1.33(d,J＝7.0Hz,2H),1.15(d,J＝7.1Hz,3H),0.89–0.784(m,8H),0.82–0.76(m,14H).
化合物57:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.31(d,J＝7.8Hz,1H),8.20(d,J＝7.8Hz,1H),8.09(d,J＝7.5Hz,1H),8.03(t,J＝7.7Hz,2H),7.96–7.87(m,2H),7.58(d,J＝6.3Hz,1H),7.49(d,J＝8.8Hz,1H),4.49(q,J＝5.3Hz,1H),4.39(dd,J＝8.2,4.4Hz,1H),4.35–4.20(m,7H),4.19–4.12(m,2H),4.10–4.00(m,1H),3.67–3.49(m,7H),2.91–2.84(m,2H),2.84–2.70(m,4H),2.46–2.38(m,1H),2.38–2.33(m,1H),2.29–2.18(m,4H),2.04–1.76(m,19H,AcOH),1.76–1.55(m,8H),1.55–1.41(m,5H),1.32(s,2H),1.21–1.11(m,6H),0.94–0.73(m,18H).
化合物58:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asn-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.28(d,J＝7.1Hz,1H),8.19(d,J＝7.7Hz,1H),8.09(d,J＝7.5Hz,1H),8.04(d,J＝7.7Hz,1H),8.00–7.89(m,3H),7.50(d,J＝8.6Hz,1H),7.44(d,J＝6.0Hz,1H),7.30(s,1H),6.80(s,1H),4.56–4.46(m,2H),4.38(dd,J＝8.1,4.3Hz,1H),4.35–4.20(m,6H),4.18–4.12(m,1H),4.04–4.00(m,1H),3.66–3.49(m,6H),2.93–2.84(m,1H),2.83–2.71(m,3H),2.43–2.31(m,3H),2.25(t,J＝8.0Hz,2H),2.04–1.57(m,26H,AcOH),1.56–1.46(m,3H),1.46–1.43(m,2H),1.35–1.27(m,2H),1.20–1.10(m,6H),0.86(dd,J＝14.8,7.9Hz,9H),0.81–0.76(m,9H).
化合物60:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu醋酸盐
1H NMR(600MHz,DMSO)δ8.51(d,J＝8.0Hz,1H),8.17(d,J＝7.8Hz,1H),8.10(d,J＝7.4Hz,1H),8.04(d,J＝6.2Hz,2H),7.96(d,J＝7.7Hz,1H),7.93(d,J＝8.5Hz,1H),7.52(d,J＝8.8Hz,1H),7.34(d,J＝6.6Hz,1H),7.11(s,1H),6.71(s,1H),4.48(d,J＝5.4Hz,1H),4.39(dd,J＝8.1,4.3Hz,1H),4.34–4.18(m,7H),4.18–4.10(m,1H),4.07–3.99(m,1H),3.83(q,J＝12.8,6.5Hz,2H),3.69–3.48(m,7H),2.92–2.83(m,1H),2.81–2.62(m,4H),2.31–2.02(m,7H),2.01–1.75(m,22H,AcOH),1.74–1.25(m,16H),1.20–1.11(m,6H),0.91–0.83(m,9H),0.81–0.76(m,9H).
化合物62:Pro-Ala-Ile-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ8.31–8.23(m,1H),8.20(d,J＝7.5Hz,1H),8.03(d,J＝7.7Hz,2H),7.99(d,J＝7.6Hz,1H),7.93–7.85(m,2H),7.57(d,J＝6.6Hz,1H),7.51(d,J＝8.1Hz,1H),7.16(s,1H),6.70(s,1H),4.49(d,J＝5.5Hz,1H),4.41–4.20(m,6H),4.19–4.00(m,5H),3.71–3.61(m,2H),3.61–3.47(m,4H),2.91–2.73(m,4H),2.45–2.39(m,1H),2.39–2.29(m,1H),2.24(t,J＝7.1Hz,2H),2.07(t,J＝7.9Hz,2H),2.02–1.76(m,20H,AcOH),1.74–1.47(m,12H),1.47–1.29(m,5H),1.16(d,J＝6.9Hz,3H),1.04(d,J＝8.4Hz,1H),0.89–0.84(m,8H),0.83–0.72(m,16H).
化合物66:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Arg-Gln-Asp醋酸盐
1H NMR(600MHz,DMSO)δ9.30(s,1H),8.39(d,J＝8.7Hz,1H),8.19(d,J＝7.9Hz,1H),8.09(d,J＝7.4Hz,1H),8.03(d,J＝8.1Hz,1H),7.98(d,J＝7.0Hz,1H),7.96–7.89(m,3H),7.52(d,J＝8.9Hz,1H),7.11(s,1H),6.69(s,1H),4.49(d,J＝5.3Hz,1H),4.39(dd,J＝8.2,4.3Hz,1H),4.34(d,J＝4.3Hz,1H),4.31–4.21(m,5H),4.20–4.10(m,3H),3.68–3.49(m,6H),3.13(d,J＝6.1Hz,1H),3.00–2.93(m,1H),2.92–2.85(m,1H),2.83–2.76(m,1H),2.41–2.32(m,1H),2.25(t,J＝8.2Hz,2H),2.09–2.03(m,2H),2.02–1.76(m,20H,AcOH),1.74–1.70(m,1H),1.69–1.56(m,7H),1.55–1.39(m,4H),1.22–1.11(m,6H),0.93–0.83(m,9H),0.83–0.77(m,9H).
化合物73:Val-Pro-Leu-Val醋酸盐
1H NMR(600MHz,MeOD)δ4.54–4.49(m,1H),4.40(dd,J＝9.2,6.0Hz,1H),4.18(d,J＝5.0Hz,1H),3.99(d,J＝5.3Hz,1H),3.69(dd,J＝10.7,5.0Hz,1H),3.65–3.58(m,1H),2.32–2.20(m,2H),2.19–2.01(m,3H),2.00–1.86(m,4H,AcOH),1.85–1.75(m,1H),1.69–1.54(m,2H),1.12(d,J＝7.0Hz,3H),1.03–1.01(m,3H),0.95(d,J＝6.6Hz,3H),0.93–0.89(m,9H).
实施例2：多肽(化合物1)对乙醇诱导的小鼠胃溃疡模型的抗溃疡作用
1、实验动物：SPF级C57BL/6小鼠，成都药康生物科技有限公司，动物许可证号：SCXK(川)2020-034
2、方法：实验动物适应性喂养后，小鼠按随机分组法分成4组，每组10只，即：对照组(空白组)、模型组(无水乙醇造模)、阳性药物组(替普瑞酮160mg/kg)，化合物1组(1mg/kg)。动物分组后，对照组及模型组给予纯水治疗外，其它给药组给予相应药物治疗，每天一次，连续8天。第7天给药后所有动物禁食不禁水24h，于第8天给药30min后对各组(除对照组外)小鼠经口灌胃给予0.15mL的无水乙醇造模，1h后CO2过量吸入处死动物，结扎胃贲门和夹闭幽门，摘取全胃。向胃体内注入1％甲醛溶液1mL，结扎贲门，取出胃后即放入1％甲醛溶液中固定25min。沿胃大弯剪开，生理盐水清洗干净胃内容物，平铺后计算溃疡指数。溃疡指数计算方法：条索状损伤长度大于1mm者，测量其长度，每毫米计1分；若其宽度大于1mm，将计分按宽度的毫米数加倍；长度小于1mm计0.5分，将计分相加得出该动物的溃疡指数。
3、结果：
在小鼠乙醇诱导的胃溃疡模型中，化合物1每天一次连续8天经口灌胃可显著使小鼠胃溃疡指数降低，且效果优于阳性药物组(表6)，结果表明化合物1治疗胃溃疡作用显著。实验结果参见图2。
表6.受试药对乙醇致胃溃疡小鼠溃疡指数的影响
注：与对照组相比，##P<0.01；与模型组相比，*P<0.05，**P<0.01
实施例3：实施例1获得的部分多肽样品对乙醇诱导的小鼠胃溃疡模型的抗溃疡作用
1、实验动物：SPF级C57BL/6小鼠，成都药康生物科技有限公司，动物许可证号：SCXK(川)2020-034
2、方法：
实验动物适应性喂养后，实验前1天给药后所有动物开始禁食不禁水24h。造模前实验小鼠随机分组：空白组5只、模型组10只、各给药组每组10只，除空白组及模型组灌胃给予纯化水以外，给药组均按照0.2mg/kg的给药剂量灌胃给予不同受试样品，给药1小时后，各组小鼠经口灌胃给予0.9ml/kg的无水乙醇造模，1h后利用脱颈法处死动物，结扎胃贲门和夹闭幽门，摘取全胃。向胃体内注入1％甲醛溶液1mL，结扎贲门，取出胃后即放入1％甲醛溶液中。浸泡30min后取出胃组织，沿胃大弯剪开，使用生理盐水冲洗干净胃内容物，平铺后观察并测定小鼠胃黏膜的损伤，计算溃疡指数和溃疡抑制率。
溃疡指数计算方法：条索状损伤长度大于1mm者，测量其长度，每毫米计1分；若其宽度大于1mm，将计分按宽度的毫米数加倍；长度小于1mm计0.5分，将计分相加得出该动物的溃疡指数。
溃疡抑制率＝(模型组溃疡指数-给药组溃疡指数)/模型组溃疡指数×100％；
相对溃疡抑制率＝(测试化合物溃疡抑制率)/(化合物1溃疡抑制率)。
3、结果：表7示出了本发明化合物的相对溃疡抑制率
表7小鼠乙醇造模单次给药抗溃疡活性
*注释：
每个化合物的抗溃疡作用经多批试验完成。为便于比较，抗溃疡活性以相对溃疡抑制率(每批试验都以化合物1作为对照组)的平均值表示。
相对溃疡抑制率＝(测试化合物溃疡抑制率)/(化合物1溃疡抑制率)
相对溃疡抑制率>1.20，表示为“++++”；
相对溃疡抑制率为0.9-1.20，表示为“+++”；
相对溃疡抑制率为0.6–0.9，表示为“++”；
相对溃疡抑制率为0.3–0.6，表示为“+”；
0<相对溃疡抑制率<0.3，表示为“/”(极低活性)；
相对溃疡抑制率<0，表示为“-”；
ND表示未与化合物1进行对比。
实施例4：化合物1对小鼠胃类器官的影响
方法：用健康野生型小鼠的胃窦上皮组织进行类器官(organoid)培养，体视镜下将小鼠胃窦上皮层与肌肉层分离，剪成0.5mm左右大小的小块，放入到2.5mM的EDTA/DPBS中4℃条件下进行消化，约1h。将消化后的胃腺上皮细胞过滤离心并弃掉上清，所得的细胞沉淀重悬于基质胶中，在培养皿中加入含生长因子的类器官培养基中进行培养，对照组除生长因子外不加入受试药物，实验组在与对照组相同培养条件加入化合物1，用倒置显微镜观察拍照其在Day1、Day3、Day5和Day7时成球和生长状况，观察化合物1对类器官生长的影响。
结果：与对照组相比，随着时间的推移，在含有化合物1的培养基中类器官的生长速率明显加快，通过对类器官直径进行定量分析，结果表明化合物1处理的类器官体积明显大于对照组(参见图3，图3中与对照组相比，*代表p<0.05)，可以显著促进类器官的增殖(统计数据也均有显著性差异)。提取化合物1处理的类器官RNA，通过实时荧光定量PCR检测分化相关的基因表达发现，内分泌细胞标志物SST和Gastrin、颈部粘液细胞标志物TFF2的mRNA水平明显上升(参见图4)。这些结果表明多肽化合物1能促进胃类器官的增殖和分化，说明化合物1参与并调控胃上皮干细胞的增殖和分化。
实施例5：化合物1对小鼠慢性萎缩性胃炎模型的治疗作用
方法：小鼠(Lgr5-GFP-CreERT小鼠)慢性萎缩性胃炎采用MNNG(N-甲基-N-硝基-N-亚硝基胍)联合雷尼替丁造模法：小鼠自由饮用含有MNNG(100mg/ml)的水溶液，同时每日固定时间给小鼠按照150mg/kg的剂量灌胃雷尼替丁(8mg/ml)水溶液，持续20周。造模20周后在小鼠饮用普通蒸馏水基础上，每日灌胃化合物1(5mg/kg)，给药2周后观察化合物1对慢性萎缩性胃炎的治疗效果。
结果：组织染色结果显示，模型组小鼠的胃体部和胃窦部腺体结构紊乱，伴随着胃酸细胞(H+-K+-ATPase阳性)细胞数目的减少，并且胃窦部的粘膜上皮高度下降。通过2周的化合物1治疗，与模型组相比，化合物1组小鼠的胃腺结构恢复正常，胃酸细胞数目显著增多，胃窦部粘膜高度基本恢复至正常状态，结果参见图5。这些结果表明化合物1能够促进小鼠慢性萎缩性胃炎的修复。
在慢性萎缩性胃炎中，上皮的修复过程需要干细胞的参与。我们通过免疫荧光染色技术检测胃上皮干细胞(Lgr5+和AQP5+)的改变。实验结果表明，与对照组相比，模型组的干细胞数目显著减少；与模型组相比，化合物1治疗组的增殖活跃的干细胞数目(PCNA阳性的Lgr5+细胞和Ki67阳性的AQP5+细胞)也存在显著增加，统计结果均存在显著性差异，结果参见参看图6。
实施例6：化合物1对慢性萎缩性胃炎大鼠的治疗作用
1、实验动物
SPF级SD大鼠85只，雌雄各半，体重160-280g，由斯贝福(北京)生物技术有限公司提供，许可证编号：SCXK(京)2016-0002。
2、实验方法
SD大鼠85只，适应性喂养1周后，随机分为空白对照组10只和慢性萎缩性胃炎造模组(简称CAG组)75只。空白对照组给予每日灌胃去离子水5ml/kg，正常饮食，自由饮水。CAG组给予每日灌胃120μg/mL的MNNG(N-甲基-N-硝基-N-亚硝基胍)水溶液，5ml/kg，自由食用0.03％雷尼替丁饲料，自由饮用2％水杨酸钠自由饮水。第15周起每周禁食18小时后灌胃高热淀粉糊(5ml/kg，60-70℃)，且当日不再灌胃MNNG，余处理同前。第18周起，每2周分别随机取非空白组雌雄大鼠各2只，取胃粘膜，病理切片观察至模型成功(固有腺体减少+肠化)，造模过程死亡19只大鼠。造模第25周将成模大鼠随机分为3组，模型组、化合物1高剂量组(3mg/kg)、化合物1低剂量组(1mg/kg)。正常对照组和模型组每日灌胃等量生理盐水，其它各组灌胃给予相应药物，给药8周。
试验期间每周定期检测大鼠体重变化，测定摄食量与饮水量，观察大鼠活动状态等。给药8周后，大鼠禁食不禁水24小时，10％水合氯醛3.5ml/kg腹腔注射麻醉。摘离全胃，迅速沿大弯侧剪开，生理盐水漂洗后，取全小弯侧及近大弯侧上至食管端下至十二指肠端的胃黏膜组织，于10％中性福尔马林液固定，常规石蜡包埋切片，常规HE染色，进行病理结果分析。
所有数据均采用SPSS23软件进行处理。计量资料以Shapiro-Wilk检验进行正态性检验，若符合正态分布，以均数加减标准差
表示，多组间均值比较，采用单因素方差分析(One-way ANOVA)，方差齐者用LSD法进行组间比较，方差不齐者采用Dunnett’s T3法进行组间比较，P<0.05表示差异具有统计学意义。若不符合正态分布，进行秩和检验，多组间比较采用Kruskal-Wallis检验，组间两两比较采用Mann-Whitney检验。等级资料同非正态分布检验方法。P<0.05表示差异具有统计学意义。
3、结果
3.1大鼠一般情况
正常组大鼠体毛顺滑浓密，毛色洁白有光泽。活动度较高，对饲养笼搬动、投喂食水等活动以及声响反应度高。精神状态佳，灌胃、称重等操作时情绪稳定。模型组大鼠体毛枯槁稀疏，易脱落，毛色晦暗偏米黄。活动度低，喜蜷卧，对饲养笼搬动、投喂食水等活动以及声响反应度低，精神状态萎靡，灌胃、称重等操作时容易出现情绪波动以及抓咬撕挠实验操作者行为，化合物1低、高剂量组均有不同程度改善大鼠活动度、反应性等整体状态。
3.2大鼠体重情况
给药8周后，各组雌鼠体重无明显差异。与正常组相比，模型组雄鼠体重明显减轻，有统计学意义(P＜0.05)；与模型组相比，化合物1低剂量组、高剂量组,雄鼠体重明显升高，有统计学意义(P＜0.05)，其余各给药组体重差异无统计学意义，见表8。
表8.各组给药8周后体重(g)
| 组别 | 动物数量 | 雌鼠体重(均值) | 雄鼠体重(均值) |
| 空白对照组 | 10 | 364 | 602 |
| 模型组 | 12 | 369 | 446<sup>#</sup> |
| 化合物1高 | 14 | 396 | 637<sup>*</sup> |
| 化合物1低 | 14 | 374 | 532<sup>*</sup> |
注：#与正常组相比有显著性差异(P＜0.05)；*与模型组相比有显著性差异(P＜0.05)。
3.3病理结果
大鼠胃黏膜病理切片显微镜下观察：正常组大鼠黏膜各层结构清晰，腺体排列紧密、整齐，黏膜层未见慢性炎症；模型组大鼠胃黏膜见炎细胞浸润，黏膜肌增生，固有层腺体不同程度减少，排列稀疏不规则，部分腺体扩张，未见肠上皮化生，少数见异型增生。与正常组相比，模型组炎症及萎缩评分明显增高(P＜0.05)；与模型组相比，化合物1低、高剂量组可显著改善大鼠胃黏膜炎症、萎缩程度(P<0.05)。结果参见图7。
实施例7：化合物1对HaCAT细胞增殖的促进作用
方法：将HaCAT细胞浓度调整为1.0×105～5.0×105/mL进行传代培养，于37℃，5％CO2条件下培养24～36小时用于生物学活性检测。用胰酶消化并收集细胞，用无血清培养基配成浓度2.5×104/mL接种于96孔细胞培养板中，每孔100μL，即2500个细胞/孔，于37℃，5％CO2条件下培养过夜。再加入50μL用无血清培养基配制化合物溶液，使化合物1终浓度为0.4ug/mL；同时设置EGF对照组，即加入50μL用无血清培养基配制的重组人表皮生长因子(EGF)溶液，终浓度为100ng/mL；模型对照组，即加入等体积的无血清培养基。于37℃，5％CO2条件下培养72小时，采用
试剂盒检测HaCAT细胞株增殖情况。
结果：如图8所示，0.4μg/mL化合物1对HaCAT细胞具有显著的促增殖作用，表明化合物1对于表皮生长和皮肤损伤修复有较好的作用。图8中，与模型对照组相比，*代表p<0.05，**代表p<0.01。
实施例8：化合物1及化合物26对斑马鱼血管损伤的修复作用
方法：转基因血管绿色荧光斑马鱼(Fli-1)的血管被绿色荧光蛋白标记，在荧光显微镜下清晰可见(图9，图9中虚线框(原图为黄色)为分析部位肠下血管，箭头(原图为白色)指向为肠下血管分支)，成为观察血管变化的模式生物。Fli-1斑马鱼，以自然成对交配繁殖方式进行。随机选取受精后1天的Fli-1斑马鱼于6孔板中，每孔(实验组)30尾。正常对照组用标准稀释水处理斑马鱼，其余各实验组水溶给予辛伐他汀诱导3小时建立斑马鱼微血管缺失模型。3小时后，所有组别水溶液替换为标准稀释水，终止辛伐他汀诱导。受试药物组分别静脉注射给予化合物1(500ng/尾)或化合物26(500ng/尾)，28℃处理2天。每组随机选取10尾斑马鱼置于荧光显微镜下拍照，用NIS-Elements D 3.20高级图像处理软件分析并采集数据，分析肠下血管分支数。
结果：模型组可见肠下血管分支数量减少。化合物1和化合物26静脉注射可以显著逆转辛伐他汀造成的肠下微血管缺失，恢复斑马鱼肠下血管的分支数量。表明化合物1和化合物26可以促进血管的损伤后修复(图10和11)。图11中，与模型对照组比较，**p<0.01，***p<0.001。
实施例9：部分多肽样品的胃、肠稳定性试验
方法：取待测样品(化合物1、化合物26、化合物27、化合物28及EGF)各1mg，加水1ml溶解。取样品溶液100ul，加水900ul，混匀，作为对照品溶液。取样品溶液各100ul，分别加人工胃液(W)、人工肠液(X)、聚维酮碘溶液(I)、过氧化氢溶液(O)900ul，37℃恒温水浴1小时，放冷，滤过，作为供试品溶液，用高效液相色谱法分别检测处理前及处理后的样品峰面积,试验结果以样品的峰面积进行对比计算。以水稀释后不做任何处理的原液作为对照，对比统计其他供试品溶液相应位置的峰面积(含量)变化情况。
表9多肽样品的胃、肠稳定性试验
| 编号 | W保留％ | X保留％ | I保留％ | O保留％ |
| 化合物1 | 96 | 0 | 101 | 100 |
| 化合物26 | 100 | 103 | 101 | 102 |
| 化合物27 | 97 | 0 | 100 | 101 |
| 化合物28 | 96 | 0 | 99 | 99 |
| EGF | 0 | 0 | 0 | 0 |
注：W表示人工胃液，X表示人工肠液，I表示聚维酮碘溶液，O表示过氧化氢溶液
结果：如表9所示，4个供试品(化合物1、26、27和28)对人工胃液(W)、聚维酮碘溶液(I)和过氧化氢溶液(O)都100％保留，说明很稳定；化合物26对人工肠液(X)也极其的稳定；EGF在胃液和肠液里都没有保留，说明在胃液和肠液中不稳定，聚维酮碘溶液和过氧化氢溶液消毒后涂抹EGF外用也会被破坏。
实施例10：化合物1对阿司匹林诱导的大鼠胃溃疡的影响
方法：SD大鼠适应性喂养后，按Excel完全随机分组法分成3组(每组10只)，即：对照组、模型组、化合物1(0.3mg/kg)组。动物分组后，开始给予相应处理(对照组及模型组给予同体积纯化水，化合物1组给予相应药物治疗)，每天一次，连续8天。第7天给药后，所有动物禁食不禁水24h。第8天除对照组外，化合物1组及模型组大鼠给药(或水)30min后经口灌胃给予250mg/kg阿司匹林溶液造模。造模4h后，处死动物，结扎贲门和夹闭幽门，摘取全胃。向胃体内注入l％甲醛溶液8mL，结扎幽门，取出胃后即放入l％甲醛溶液中固定，30min后沿胃大弯剪开，生理盐水清洗干净胃内容物，将胃平铺后，观察并拍摄胃全景照片，测定溃疡面积。
结果：每天1次连续8天经口灌胃给予化合物1(0.3mg/kg)对阿司匹林诱导胃溃疡模型大鼠的体重变化无明显影响，化合物1减少了阿司匹林诱导的胃溃疡模型大鼠胃部出血点，显著降低大鼠胃溃疡面积。表10示出了化合物1对阿司匹林诱导的大鼠胃溃疡的影响。
表10化合物1对阿司匹林诱导的大鼠胃溃疡的影响。
| 组别/给药 | 溃疡面积(mm<sup>2</sup>) |
| 对照组： | 7.42±7.32 |
| 模型组： | 140.36±82.40<sup>##</sup> |
| 化合物1组： | 20.55+10.45** |
注：##与对照组相比，p<0.01；**与模型组相比，p<0.01
尽管本发明披露了上述实施例，但本发明的实施方式并不限于上述实施例，其他的任何未背离本发明的改变、修饰、替代、组合、简化，均应为等效的置换方式均包含在本发明的保护范围之内。
序列表
<110> 四川好医生攀西药业有限责任公司
<120> 用于修复黏膜损伤或皮肤创伤的多肽及其应用
<130> F21W0932PCT
<141> 2021-07-01
<150> CN202010619687.2
<151> 2020-07-01
<160> 73
<170> SIPOSequenceListing 1 .0
<210> 1
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物1序列
<400> 1
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 2
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物2序列
<400> 2
Gly Ala Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 3
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物3序列
<400> 3
Pro Ala Ala Glu Pro Val Pro Leu Val Lys
1 5 10
<210> 4
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物4序列
<400> 4
Pro Ala Ala Glu Gly Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 5
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物5序列
<400> 5
Pro Ala Ala Glu Pro Val Gly Leu Val Lys Gln Asp
1 5 10
<210> 6
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物6序列
<400> 6
Pro Ala Ala Glu Pro Val Gly Ala Val Lys Gln Asp
1 5 10
<210> 7
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物7序列
<400> 7
Pro Ala Ala Glu Pro Val Gly Val Val Lys Gln Asp
1 5 10
<210> 8
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物8序列
<400> 8
Pro Ala Ala Glu Gly Val Gly Leu Val Lys Gln Asp
1 5 10
<210> 9
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物9序列
<400> 9
Pro Ala Ala Glu Gly Val Gly Leu
1 5
<210> 10
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物10序列
<400> 10
Pro Ala Ala Gln Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 11
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物11序列
<400> 11
Pro Ala Ala Asp Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 12
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物12序列
<400> 12
Pro Ala Ala Glu Pro Val Pro Phe Val Lys Gln Asp
1 5 10
<210> 13
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物13序列
<400> 13
Pro Ala Ala Glu Pro Val Pro Tyr Val Lys Gln Asp
1 5 10
<210> 14
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物14序列
<400> 14
Pro Ala Ala Glu Pro Val Gly Leu Val Lys
1 5 10
<210> 15
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物15序列
<400> 15
Pro Ala Ala Glu Pro Val Gly Val Val Lys
1 5 10
<210> 16
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物16序列
<400> 16
Pro Ala Ala Glu Pro Val Ala Leu Val Lys
1 5 10
<210> 17
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物17序列
<400> 17
Pro Ala Ala Glu Pro Val Ala Val Val Lys
1 5 10
<210> 18
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物18序列
<400> 18
Pro Ala Ala Glu Ala Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 19
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物19序列
<400> 19
Pro Ala Ala Glu Pro Val Ala Leu Val Lys Gln Asp
1 5 10
<210> 20
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物20序列
<400> 20
Pro Ala Ala Glu Ala Val Ala Leu Val Lys Gln Asp
1 5 10
<210> 21
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物21序列
<400> 21
Ala Ala Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 22
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物22序列
<400> 22
Pro Ala Ala Glu Pro Val Pro Phe Val Lys
1 5 10
<210> 23
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物23序列
<400> 23
Pro Ala Ala Glu Pro Val Pro Tyr Val Lys
1 5 10
<210> 24
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物24序列
<400> 24
Pro Ala Ala Glu Pro Val Gly Phe Val Lys
1 5 10
<210> 25
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物25序列
<400> 25
Pro Ala Ala Glu Pro Val Ala Phe Val Lys
1 5 10
<210> 26
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物26序列
<400> 26
Pro Ala Ala Glu Pro Val Pro Leu
1 5 10
<210> 27
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物27序列
<400> 27
Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 28
<211> 8
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物28序列
<400> 28
Pro Val Pro Leu Val Lys Gln Asp
1 5
<210> 29
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物29序列
<400> 29
Pro Ala Ala Glu Pro Val Pro
1 5
<210> 30
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物30序列
<400> 30
Ala Glu Pro Val Pro Leu
1 5
<210> 31
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物31序列
<400> 31
Glu Pro Val Pro Leu
1 5
<210> 32
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物32序列
<400> 32
Pro Val Pro Leu
1
<210> 33
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物33序列
<400> 33
Ala Ala Glu Pro Val Pro Leu
1 5
<210> 34
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物34序列
<400> 34
Pro Ala Ala Glu Pro Val
1 5
<210> 35
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物35序列
<400> 35
Pro Ala Ala Glu Pro
1 5
<210> 36
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物36序列
<400> 36
Pro Ala Ala Glu
1
<210> 37
<211> 11
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物37序列
<400> 37
Ala Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 38
<211> 9
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物38序列
<400> 38
Glu Pro Val Pro Leu Val Lys Gln Asp
1 5
<210> 39
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物39序列
<400> 39
Val Pro Leu Val Lys Gln Asp
1 5
<210> 40
<211> 6
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物40序列
<400> 40
Pro Leu Val Lys Gln Asp
1 5
<210> 41
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物41序列
<400> 41
Pro Ala Ala Glu Pro Val Pro Ile Val Lys
1 5 10
<210> 42
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物42序列
<400> 42
Pro Ala Ala Glu Pro Val Pro Val Val Lys
1 5 10
<210> 43
<211> 10
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物43序列
<400> 43
Pro Ala Ala Glu Pro Val Pro Met Val Lys
1 5 10
<210> 44
<211> 5
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物44序列
<400> 44
Ala Glu Pro Val Pro
1 5
<210> 45
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物45序列
<400> 45
Ala Glu Pro Val
1
<210> 46
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物46序列
<400> 46
Pro Ala Ala Asn Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 47
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物47序列
<400> 47
Pro Ala Ala Leu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 48
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物48序列
<400> 48
Pro Ala Gly Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 49
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物49序列
<400> 49
Pro Ala Pro Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 50
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物50序列
<400> 50
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Gln Asn
1 5 10
<210> 51
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物51序列
<400> 51
Pro Ala Ala Glu Pro Val Pro Leu Val Val Gln Asp
1 5 10
<210> 52
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物52序列
<400> 52
Pro Ala Ala Glu Pro Val Pro Val Val Lys Gln Asp
1 5 10
<210> 53
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物53序列
<400> 53
Pro Ala Ala Glu Pro Val Pro Ile Val Lys Gln Asp
1 5 10
<210> 54
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物54序列
<400> 54
Pro Ala Ala Glu Pro Val Pro Met Val Lys Gln Asp
1 5 10
<210> 55
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物55序列
<400> 55
Pro Leu Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 56
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物56序列
<400> 56
Pro Ile Ala Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 57
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物57序列
<400> 57
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Glu Asp
1 5 10
<210> 58
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物58序列
<400> 58
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Asn Asp
1 5 10
<210> 59
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物59序列
<400> 59
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Asp Asp
1 5 10
<210> 60
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物60序列
<400> 60
Pro Ala Ala Glu Pro Val Pro Leu Val Lys Gln Glu
1 5 10
<210> 61
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物61序列
<400> 61
Pro Ala Leu Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 62
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物62序列
<400> 62
Pro Ala Ile Glu Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 63
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物63序列
<400> 63
Pro Ala Ala Glu Pro Val Pro Leu Leu Lys Gln Asp
1 5 10
<210> 64
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物64序列
<400> 64
Pro Ala Ala Glu Pro Val Pro Leu Ile Lys Gln Asp
1 5 10
<210> 65
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物65序列
<400> 65
Pro Ala Ala Glu Pro Val Pro Leu Met Lys Gln Asp
1 5 10
<210> 66
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物66序列
<400> 66
Pro Ala Ala Glu Pro Val Pro Leu Val Arg Gln Asp
1 5 10
<210> 67
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物67序列
<400> 67
Pro Ala Ala Val Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 68
<211> 7
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物68序列
<400> 68
Val Pro Leu Val Lys Gln Asp
1 5
<210> 69
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物69序列
<400> 69
Gly Ala Ala Val Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 70
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物70序列
<400> 70
Gly Ala Gly Val Pro Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 71
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物71序列
<400> 71
Gly Ala Gly Val Gly Val Pro Leu Val Lys Gln Asp
1 5 10
<210> 72
<211> 12
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物72序列
<400> 72
Pro Ala Ala Glu Pro Val Ala Phe Val Lys Gln Asp
1 5 10
<210> 73
<211> 4
<212> PRT
<213> 人工序列(Artificial Sequence)
<220>
<223> 化合物73序列
<400> 73
Val Pro Leu Val
1
Claims (24)
1.式(I)的化合物或其生理学上相容的盐，其中所述式(I)的化合物如下：
H-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Val-Xaa6-Xaa7-Xaa8-Xaa9-Xaa10-Xaa11-OH(I)
其中
Xaa1为Pro、Gly、Ala或缺失；
Xaa2为Ala、Leu、Ile、Gly、Cys、Ser或缺失；
Xaa3为Ala、Pro、Gly、Leu、Ile、Cys、Ser或缺失；
Xaa4为Glu、Gln、Asp、Asn、Leu、Ile、Val或缺失；
Xaa5为Pro、Gly、Ala、Val或缺失；
Xaa6为Pro、Gly或Ala；
Xaa7为Leu、Phe、Val、Ala、Tyr、Glu、Lys、Asp、Ile、Met或缺失；
Xaa8为Val、Leu、Gln、Ile、Met或缺失；
Xaa9为Lys、Arg、His、Asp、Val或缺失；
Xaa10为Glu、Gln、Asp、Asn或缺失；以及
Xaa11为Glu、Asp、Asn、Gln或缺失，
条件是：Xaa1、Xaa2、Xaa3、Xaa4、Xaa5、Xaa7、Xaa8、Xaa9、Xaa10和Xaa11中至多有9个是缺失的。
2.权利要求1的化合物或其生理学上相容的盐，其中Xaa5为Pro。
3.权利要求1的化合物或其生理学上相容的盐，其中Xaa6为Pro。
4.权利要求1的化合物或其生理学上相容的盐，其中Xaa7为Leu。
5.权利要求1-5中任一项的化合物或其生理学上相容的盐，其中式(I)化合物具有以下式(II)结构，
H-Xaa1-Xaa2-Xaa3-Xaa4-Pro-Val-Pro-Leu-Xaa8-Xaa9-Xaa10-Xaa11-OH(II)，
其中
Xaa1为Pro、Gly、Ala或缺失；
Xaa2为Ala、Leu、Ile、Gly、Cys、Ser或缺失；
Xaa3为Ala、Pro、Gly、Leu、Ile、Cys、Ser或缺失；
Xaa4为Glu、Gln、Asp、Asn、Leu、Ile、Val或缺失；
Xaa8为Val、Leu、Gln、Ile、Met或缺失；
Xaa9为Lys、Arg、His、Asp、Val或缺失；
Xaa10为Glu、Gln、Asp、Asn或缺失；以及
Xaa11为Glu、Asp、Asn、Gln或缺失。
6.权利要求1-5中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa1为Pro或缺失；优选为Pro。
7.权利要求1-6中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa2为Ala或缺失；优选为Ala。
8.权利要求1-7中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa3为Ala、Gly或缺失；优选为Ala。
9.权利要求1-8中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa4为Glu、Gln、Asp或缺失；优选为Glu或Gln。
10.权利要求1-9中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa8为Val或缺失；优选为Val。
11.权利要求1-10中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa9为Lys、Arg或缺失；优选为Lys或缺失。
12.权利要求1-11中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa10为Glu、Gln或缺失；优选为Gln。
13.权利要求1-12中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa11为Asp或缺失；优选为Asp。
14.权利要求1-13中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa1、Xaa2、Xaa3和Xaa4中有一个是缺失的；或者有两个是缺失的；或者有三个是缺失的；或者都是缺失的。
15.权利要求1-14中任一项的化合物或其生理学上相容的盐，其中式(I)或(II)中的Xaa8、Xaa9、Xaa10和Xaa11中有一个是缺失的；或者有两个是缺失的；或者有三个是缺失的；或者都是缺失的。
16.权利要求1的化合物或其生理学上相容的盐，其中所述化合物选自：
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物1)
Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物2)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys(化合物3)
Pro-Ala-Ala-Glu-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物4)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys-Gln-Asp(化合物5)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Ala-Val-Lys-Gln-Asp(化合物6)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Val-Val-Lys-Gln-Asp(化合物7)
Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu-Val-Lys-Gln-Asp(化合物8)
Pro-Ala-Ala-Glu-Gly-Val-Gly-Leu(化合物9)
Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物10)
Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物11)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys-Gln-Asp(化合物12)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Tyr-Val-Lys-Gln-Asp(化合物13)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Leu-Val-Lys(化合物14)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Val-Val-Lys(化合物15)
Pro-Ala-Ala-Glu-Pro-Val-Ala-Leu-Val-Lys(化合物16)
Pro-Ala-Ala-Glu-Pro-Val-Ala-Val-Val-Lys(化合物17)
Pro-Ala-Ala-Glu-Ala-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物18)
Pro-Ala-Ala-Glu-Pro-Val-Ala-Leu-Val-Lys-Gln-Asp(化合物19)
Pro-Ala-Ala-Glu-Ala-Val-Ala-Leu-Val-Lys-Gln-Asp(化合物20)
Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物21)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Phe-Val-Lys(化合物22)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Tyr-Val-Lys(化合物23)
Pro-Ala-Ala-Glu-Pro-Val-Gly-Phe-Val-Lys(化合物24)
Pro-Ala-Ala-Glu-Pro-Val-Ala-Phe-Val-Lys(化合物25)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu(化合物26)
Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物27)
Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物28)
Pro-Ala-Ala-Glu-Pro-Val-Pro(化合物29)
Ala-Glu-Pro-Val-Pro-Leu(化合物30)
Glu-Pro-Val-Pro-Leu(化合物31)
Pro-Val-Pro-Leu(化合物32)
Ala-Ala-Glu-Pro-Val-Pro-Leu(化合物33)
Pro-Ala-Ala-Glu-Pro-Val(化合物34)
Pro-Ala-Ala-Glu-Pro(化合物35)
Pro-Ala-Ala-Glu(化合物36)
Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物37)
Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物38)
Val-Pro-Leu-Val-Lys-Gln-Asp(化合物39)
Pro-Leu-Val-Lys-Gln-Asp(化合物40)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Ile-Val-Lys(化合物41)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys(化合物42)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Met-Val-Lys(化合物43)
Ala-Glu-Pro-Val-Pro(化合物44)
Ala-Glu-Pro-Val(化合物45)
Pro-Ala-Ala-Asn-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物46)
Pro-Ala-Ala-Leu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物47)
Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物48)
Pro-Ala-Pro-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物49)
Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Lys-Gln-Asn(化合物50)
Pro-Ala-Ala-Glu-Pro-Val-Pro-leu-Val-Val-Gln-Asp(化合物51)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Val-Val-Lys-Gln-Asp(化合物52)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Ile-Val-Lys-Gln-Asp(化合物53)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Met-Val-Lys-Gln-Asp(化合物54)
Pro-Leu-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物55)
Pro-Ile-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物56)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp(化合物57)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asn-Asp(化合物58)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Asp-Asp(化合物59)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu(化合物60)
Pro-Ala-Leu-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物61)
Pro-Ala-Ile-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物62)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Leu-Lys-Gln-Asp(化合物63)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ile-Lys-Gln-Asp(化合物64)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Met-Lys-Gln-Asp(化合物65)
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Arg-Gln-Asp(化合物66)
Pro-Ala-Ala-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物67)
Val-Pro-Leu-Val-Lys-Gln-Asp(化合物68)
Gly-Ala-Ala-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物69)
Gly-Ala-Gly-Val-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物70)
Gly-Ala-Gly-Val-Gly-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物71)
Pro-Ala-Ala-Glu-Pro-Val-Ala-Phe-Val-Lys-Gln-Asp(化合物72)
Val-Pro-Leu-Val(化合物73)。
17.权利要求6的化合物或其生理学上相容的盐，其中所述化合物选自
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物1)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys(化合物3)；
Pro-Ala-Ala-Gln-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物10)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu(化合物26)；
Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物27)；
Ala-Glu-Pro-Val-Pro-Leu(化合物30)；
Glu-Pro-Val-Pro-Leu(化合物31)；
Pro-Val-Pro-Leu(化合物32)；
Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物28)；
Pro-Ala-Ala-Asp-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物11)；
Pro-Ala-Gly-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物48)；
Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Glu-Asp(化合物57)；或
Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp(化合物38)。
18.权利要求1-17中任一项的化合物或其生理学上相容的盐在制备用于修复皮肤创伤或黏膜损伤的药物中的用途。
19.权利要求1-17中任一项的化合物或其生理学上相容的盐在制备用于调控干细胞增殖和分化的药物中的用途。
20.根据权利要求18的用途，其中所述的黏膜损伤是消化系统、呼吸系统等腔道内黏膜损伤。
21.权利要求20的用途，其中所述消化系统黏膜损伤与口腔、食道、胃肠疾病相关，所述口腔疾病包括口腔溃疡、口腔炎、牙龈炎、牙周炎等；所述食道疾病包括食管炎、食管溃疡等；所述胃肠疾病包括慢性胃炎、慢性萎缩性胃炎、急性胃炎、胃十二指肠溃疡、功能性胃肠道疾病、消化不良、癌前病变、消化系统肿瘤、胃肠道出血、胃食管返流疾病、急慢性肠炎、溃疡性结肠炎、克罗恩病和放化疗引起的黏膜损伤；所述皮肤创伤与表皮炎症、机械及手术创面、烧伤及烫伤、溃疡、瘘管、褥疮、放化疗引起的皮肤损伤等疾病相关。
22.权利要求20的用途，其中所述消化系统黏膜损伤是由刺激性物质或药物引起的或应激状态引起的黏膜损伤。
23.权利要求1-17中任一项的化合物或其生理学上相容的盐在制备用于预防、减轻或治疗胃肠疾病或消除炎症水肿的药物中的用途。
24.一种药物、食品、保健品或化妆品、日化品组合物，所述组合物包括权利要求1-17中任一项的化合物或其生理学上相容的盐以及生理学上可接受的载体。
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Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6214795B1 (en) * | 1996-11-12 | 2001-04-10 | Praecis Pharmaceuticals, Inc. | Peptide compounds useful for modulating FGF receptor activity |
| WO2007002469A2 (en) * | 2005-06-24 | 2007-01-04 | Bhatnagar Rajendra S | Therapeutic compositions and methods using transforming growth factor-beta mimics |
| CN107973838A (zh) * | 2017-12-06 | 2018-05-01 | 暨南大学 | 一种促进皮肤损伤修复的小分子多肽及其应用 |
| CN108503690A (zh) * | 2017-02-28 | 2018-09-07 | 暨南大学 | 一种促进创伤后组织修复与再生的修复肽及其应用 |
| CN108715600A (zh) * | 2018-04-12 | 2018-10-30 | 中国科学院南海海洋研究所 | 一种促进肠黏膜上皮细胞增殖和迁移的寡肽及其制备方法和应用 |
| CN110903348A (zh) * | 2019-12-10 | 2020-03-24 | 南京财经大学 | 一种促进伤口愈合的小肽及其应用 |
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Patent Citations (6)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| US6214795B1 (en) * | 1996-11-12 | 2001-04-10 | Praecis Pharmaceuticals, Inc. | Peptide compounds useful for modulating FGF receptor activity |
| WO2007002469A2 (en) * | 2005-06-24 | 2007-01-04 | Bhatnagar Rajendra S | Therapeutic compositions and methods using transforming growth factor-beta mimics |
| CN108503690A (zh) * | 2017-02-28 | 2018-09-07 | 暨南大学 | 一种促进创伤后组织修复与再生的修复肽及其应用 |
| CN107973838A (zh) * | 2017-12-06 | 2018-05-01 | 暨南大学 | 一种促进皮肤损伤修复的小分子多肽及其应用 |
| CN108715600A (zh) * | 2018-04-12 | 2018-10-30 | 中国科学院南海海洋研究所 | 一种促进肠黏膜上皮细胞增殖和迁移的寡肽及其制备方法和应用 |
| CN110903348A (zh) * | 2019-12-10 | 2020-03-24 | 南京财经大学 | 一种促进伤口愈合的小肽及其应用 |
Cited By (2)
| Publication number | Priority date | Publication date | Assignee | Title |
|---|---|---|---|---|
| CN114106100A (zh) * | 2020-08-26 | 2022-03-01 | 四川好医生攀西药业有限责任公司 | 用于修复皮肤创伤或黏膜损伤的多肽及其应用 |
| CN114106100B (zh) * | 2020-08-26 | 2024-05-17 | 四川好医生攀西药业有限责任公司 | 用于修复皮肤创伤或黏膜损伤的多肽及其应用 |
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| IL299498A (en) | 2023-02-01 |
| WO2022002186A1 (zh) | 2022-01-06 |
| CA3184710A1 (en) | 2022-01-06 |
| TW202202515A (zh) | 2022-01-16 |
| CN116133673A (zh) | 2023-05-16 |
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