WO2022042590A1

WO2022042590A1 - Polypeptides for repairing skin wounds or mucosal injuries, and applications thereof

Info

Publication number: WO2022042590A1
Application number: PCT/CN2021/114499
Authority: WO
Inventors: 耿福能
Original assignee: 四川好医生攀西药业有限责任公司
Priority date: 2020-08-26
Filing date: 2021-08-25
Publication date: 2022-03-03
Also published as: TW202207967A; CN114106100B; CN114106100A

Abstract

The present invention provides novel polypeptides for repairing skin wounds or mucosal injuries, and applications thereof. A series of polypeptides of the present invention are not homologous to known polypeptides and have an effect of regulating cell proliferation and differentiation; the polypeptides are used for repairing mucosal injuries or skin wounds, and are used for preventing, relieving, or treating gastrointestinal diseases such as gastritis and gastric ulcer.

Description

用于修复皮肤创伤或黏膜损伤的多肽及其应用Polypeptide for repairing skin wound or mucosal injury and its application

技术领域technical field

本发明涉及用于修复皮肤创伤或黏膜损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，具有修复黏膜损伤或皮肤损伤的效果。The present invention relates to a novel polypeptide for repairing skin wound or mucosal injury and its application. The polypeptide of the present invention has no homology with known polypeptides and has the effect of repairing mucosal injury or skin injury.

背景技术Background technique

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。Skin trauma and/or mucosal damage are common pathological features of many diseases. Skin trauma or skin injury refers to the damage of normal skin (tissue) caused by external injury factors such as surgery, external force, heat, current, chemical substances, low temperature and internal factors in the body such as local blood supply disorders. Skin damage is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue, while at the same time, the normal function of the skin is impaired. Also called a wound or trauma. At present, there are protein/polypeptide drugs including basic fibroblast growth factor, epidermal growth factor, platelet growth factor, granulocyte-macrophage colony-stimulating factor and growth hormone that have obvious effects on wound repair, skin care, anti-wrinkle and anti-aging, but these The long amino acid sequence of protein/polypeptide drugs leads to the disadvantages of high preparation cost and poor stability, so their application is limited to a certain extent.

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，实验中不能达到治疗效果。Epidermal growth factor (EGF) is a polypeptide consisting of 53 amino acid residues, which is widely present in various tissues, organs and body fluids. It can promote the proliferation of epithelial cells and protect the skin. Epidermal growth factor mainly promotes the proliferation and growth of skin tissue cells, so that new cells can replace aging cells, so as to play anti-aging and skin care and health care functions. Epidermal growth factor has been reported to have the effect of repairing wounds. When skin wounds need to be disinfected and debridement, disinfectants containing iodine or hydrogen peroxide will be applied. EGF is unstable under these conditions. Growth factors are related to gastrointestinal healing (J. Surgical Res. 2014; 17:202-210), but when EGF is orally administered orally, it will degrade after entering the body, and the therapeutic effect cannot be achieved in the experiment.

人体黏膜是指呼吸***、消化***、生殖泌尿***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、***、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。Human mucosa refers to the inner layer of cavities or cystic muscular organs such as respiratory system, digestive system, genitourinary system, etc. It is the second largest barrier of human body after skin, including oral cavity, pharynx, trachea, esophagus, stomach and intestines. , vagina, bladder, etc. The wall or cyst wall of these organs has a common stratification law, and has the characteristics of adapting to its function, and its embryonic origin, tissue structure, pathological process, clinical manifestations, prognosis, etc. have the same characteristics. Features.

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。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。临床上急慢性胃炎、消化道溃疡治疗药物主要有胃酸抑制剂、胃黏膜保护剂、抗生素等小分子化合物，治疗的效果有限，保护且促进损伤黏膜的修复是的急慢性胃炎、消化道溃疡治疗重点，胃黏膜保护剂主要通过保护损伤黏膜发挥作用，具有组织修复作用。胃黏膜保护药在临床应用过程中存在治疗效果有限，存在有效性差，疗程长、复发率高等问题，尚不能满足各种原因引起的急慢性胃炎及消化道溃疡的临床治疗需求，因此研发对消化道黏膜具有更好保护及组织修复的药物非常有必要，多肽药物具有生物活性强、安全性高的特点，筛选、发现并开发能够治疗皮肤损伤，且可以通过口服治疗黏膜损伤的多肽药物意义重大。Chronic gastritis is a chronic inflammation of the gastric mucosa, which is a common and frequently-occurring disease in the department of gastroenterology. Atrophic lesions of the glands are called chronic gastritis. The damage of mucosal tissue can clinically lead to gastrointestinal diseases such as chronic gastritis and peptic ulcer. The repair of mucosal epithelium has two different mechanisms: restitution and regeneration (Cur. Med. Chem., 2008, 15, 3133-3144): repair or recovery generally begins within minutes after injury , rapid repair of superficial lesions through cell migration; regeneration is continuous regeneration through the differentiation and proliferation of stem and progenitor cells for days to months. Clinically, the treatment drugs for acute and chronic gastritis and peptic ulcer mainly include gastric acid inhibitors, gastric mucosal protective agents, antibiotics and other small molecular compounds. The therapeutic effect is limited, and it protects and promotes the repair of damaged mucosa. This is the treatment of acute and chronic gastritis and peptic ulcer. It is important to note that gastric mucosal protective agents mainly work by protecting the damaged mucosa and have a tissue repair effect. In the clinical application of gastric mucosal protective drugs, the therapeutic effect is limited, the efficacy is poor, the course of treatment is long, and the recurrence rate is high. It is very necessary to have drugs for better protection and tissue repair of mucosal mucosa. Peptide drugs have the characteristics of strong biological activity and high safety. It is of great significance to screen, discover and develop peptide drugs that can treat skin damage and can treat mucosal damage by oral administration. .

发明内容SUMMARY OF THE INVENTION

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。In order to overcome the deficiencies and defects of the prior art, the purpose of the present invention is to provide a new type of polypeptide.

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：In a first aspect, the present invention provides a compound of formula (I), or a physiologically compatible salt thereof, wherein said compound of formula (I) is as follows:

H-X _aa1-X _aa2-X _aa3-X _aa4-X _aa5-X _aa6-X _aa7-X _aa8-X _aa9-X _aa10-X _aa11-Val-Thr-Val-Ser-X _aa12-X _aa13-X _aa14-X _aa15-X _aa ₁₆-X _aa17-OH HX _aa1 -X _aa2 -X _aa3 -X _aa4 -X _aa5 -X _aa6 -X _aa7 -X _aa8 -X _aa9 -X _aa10 -X _aa11 -Val-Thr-Val-Ser-X _aa12 -X _aa13 -X _aa14 - X _aa15 -X _aa ₁₆ -X _aa17 -OH

其中in

X _aa1为Pro或缺失； X _aa1 is Pro or missing;

X _aa2为Val或缺失； X _aa2 is Val or missing;

X _aa3为Lys、Pro或缺失； X _aa3 is Lys, Pro or missing;

X _aa4为Leu、Val、Ala或缺失； X _aa4 is Leu, Val, Ala or missing;

X _aa5为Lys、Arg或缺失； X _aa5 is Lys, Arg or missing;

X _aa6为Ser、Thr、Ala或缺失； X _aa6 is Ser, Thr, Ala or missing;

X _aa7为Lys、Arg或缺失； X _aa7 is Lys, Arg or missing;

X _aa8为Leu、Val、Ala、Ile或缺失； X _aa8 is Leu, Val, Ala, Ile or missing;

X _aa9为Gly、Pro、Ala或缺失； X _aa9 is Gly, Pro, Ala or missing;

X _aa10为Asp、Glu、Asn、Val或缺失； X _aa10 is Asp, Glu, Asn, Val or missing;

X _aa11为Leu、Val、Ala、Ile、Pro或缺失； X _aa11 is Leu, Val, Ala, Ile, Pro or missing;

X _aa12为Leu、Val、Ala或缺失； X _aa12 is Leu, Val, Ala or missing;

X _aa13为Pro、Ala、Gly、Val或缺失； X _aa13 is Pro, Ala, Gly, Val or missing;

X _aa14为Gly、Ala或缺失； X _aa14 is Gly, Ala or missing;

X _aa15为Gly、Ala或缺失； X _aa15 is Gly, Ala or missing;

X _aa16为Glu、Gln、Asp或缺失； X _aa16 is Glu, Gln, Asp or missing;

X _aa17为Glu、Asp、Gln或缺失。 X _aa17 is Glu, Asp, Gln or missing.

在一实施方案中，X _aa1缺失。 In one embodiment, X _aa1 is deleted.

在一实施方案中，X _aa2缺失。 In one embodiment, X _aa2 is deleted.

在一实施方案中，X _aa1和X _aa2均缺失。 In one embodiment, both X _aa1 and X _aa2 are deleted.

在一实施方案中，X _aa4-X _aa5-X _aa6-X _aa7为Leu-Lys-Ser-Lys。在一实施方案中，X _aa4-X _aa5-X _aa6-X _aa7-X _aa8为Leu-Lys-Ser-Lys-Leu。在一实施方案中，X _aa4-X _aa5-X _aa6-X _aa7-X _aa8为Lys-Ser-Lys-Leu，其中X _aa4缺失。 In one embodiment, X _aa4 -X _aa5 -X _{aa6-X aa7} _is Leu-Lys-Ser-Lys. In one embodiment, X _aa4 -X _aa5 -X _aa6 -X _aa7 -X _aa8 is Leu-Lys-Ser-Lys-Leu. In one embodiment, X _aa4 -X _aa5 -X _aa6 -X _aa7 -X _aa8 is Lys-Ser-Lys-Leu, wherein X _aa4 is deleted.

在一实施方案中，X _aa9-X _aa10为Gly-Asp。在一实施方案中，X _aa9-X _aa10-X _aa11为Gly-Asp-Leu。在一实施方案中，X _aa9-X _aa10-X _aa11为Gly-Asp-Val、Gly-Asp-Ala或Gly-Asp-Ile。 In one embodiment, X _aa9 -X _aa10 are Gly-Asp. In one embodiment, X _aa9 -X _aa10 -X _aa11 is Gly-Asp-Leu. In one embodiment, X _aa9 -X _aa10 -X _aa11 is Gly-Asp-Val, Gly-Asp-Ala, or Gly-Asp-Ile.

在一实施方案中，X _aa12为Leu、Val或Ala，优选为Leu。 In one embodiment, X _aa12 is Leu, Val or Ala, preferably Leu.

在一实施方案中，X _aa13-X _aa14为Pro-Gly。在一实施方案中，X _aa13-X _aa14-X _aa15为Pro-Gly-Gly。在一实施方案中，X _aa13-X _aa14-X _aa15-X _aa16-X _aa17为Pro-Gly-Gly-Glu-Glu。在一实施方案中，X _aa13-X _aa14-X _aa15-X _aa16-X _aa17为Ala-Gly-Gly-Glu-Glu、Gly-Gly-Gly-Glu-Glu、Pro-Gly-Gly-Glu-Asp、Pro-Gly-Gly-Gln-Glu、Pro-Gly-Gly-Glu-Gln、Pro-Gly-Gly-Asp-Asp、Pro-Ala-Ala-Asp-Asp、Val-Gly-Gly-Glu-Glu或Pro-Ala-Ala-Gln-Gln。 In one embodiment, X _aa13 - X _aa14 are Pro-Gly. In one embodiment, X _aa13 -X _aa14 -X _aa15 is Pro-Gly-Gly. In one embodiment, X _aa13- X _aa14 -X _aa15 -X _aa16 -X _aa17 is Pro-Gly-Gly-Glu-Glu. In one embodiment, X _aa13- X _aa14 -X _aa15 -X _aa16 -X _aa17 is Ala-Gly-Gly-Glu-Glu, Gly-Gly-Gly-Glu-Glu, Pro-Gly-Gly-Glu-Asp , Pro-Gly-Gly-Gln-Glu, Pro-Gly-Gly-Glu-Gln, Pro-Gly-Gly-Asp-Asp, Pro-Ala-Ala-Asp-Asp, Val-Gly-Gly-Glu-Glu or Pro-Ala-Ala-Gln-Gln.

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。For convenience, the H on the left and OH on the right are omitted when describing the compounds of the invention in this application.

第二方面，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。In a second aspect, the present invention provides a method of repairing a skin wound, the method comprising contacting the skin wound with a compound of the invention or a physiologically compatible salt thereof. In a preferred embodiment, the skin wound is associated with, but not limited to, epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, bedsores, and skin lesions caused by chemoradiotherapy. In one embodiment, the skin wound refers to the damage to normal skin caused by external injury factors such as surgery, external force, heat, current, chemical substances, low temperature, and internal factors in the body such as local blood supply disorders. . In one embodiment, the skin wound is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue. In another embodiment, the skin wound comprises impairment of the normal function of the skin.

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。The present invention provides a method of promoting the proliferation of HaCAT cells, the method comprising contacting the cells with a compound of the present invention or a physiologically compatible salt thereof.

第三方面，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。In a third aspect, the present invention provides a method of repairing mucosal damage, the method comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof or making the mucosal damage a compound of the present invention or a physiologically compatible salt thereof salt exposure.

在一实施方案中，所述黏膜损伤是消化***、呼吸***等腔道内黏膜损伤。In one embodiment, the mucosal damage is mucosal damage in the lumen of the digestive system, respiratory system and the like.

消化***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***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。Digestive system mucosal damage is related to oral cavity, esophagus, and gastrointestinal diseases, and the oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; the esophageal diseases include esophagitis, esophageal ulcers, etc.; the gastrointestinal diseases Including chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal diseases, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic Enteritis, ulcerative colitis, Crohn's disease, and mucosal damage from chemoradiation, but not limited thereto.

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，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。In a preferred embodiment, the digestive tract mucosa includes gastric mucosa and intestinal mucosa. In a preferred embodiment, the mucosal damage is gastric mucosal damage caused by irritating substances or drugs, stress states. The irritant substances are such as hydrochloric acid, ethanol or alcohol, and the drugs are such as non-steroidal anti-inflammatory drugs aspirin or indomethacin.

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***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。The present invention provides a method of preventing, alleviating or treating a disease of the digestive tract or eliminating inflammatory edema, the method comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof. The gastrointestinal diseases include oral cavity, esophagus, and gastrointestinal diseases, and the oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; the esophageal diseases include esophagitis, esophageal ulcers, etc.; the gastrointestinal diseases include Diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal disease, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute Chronic enteritis, ulcerative colitis, Crohn's disease and mucosal damage from chemoradiation; but not limited thereto. In one embodiment, the prevention, alleviation or treatment of the digestive tract disease is performed by modulating stem cell proliferation and differentiation. In the method, the compounds of the present invention or their physiologically compatible salts play a protective effect on gastrointestinal mucosa such as gastric mucosa or intestinal mucosa, or repair the damage of digestive tract mucosa such as gastric mucosa or intestinal mucosa, thereby preventing and reducing the damage to the digestive tract mucosa. Or the role of the treatment of gastrointestinal diseases.

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。The present invention provides a method of repairing a mucosal or skin wound comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof.

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。In the above method of the present invention, the compound of the present invention or a physiologically compatible salt thereof is administered orally, by injection, subcutaneously, or the like.

第四方面，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。In the fourth aspect, the present invention provides a pharmaceutical, food, health care product or cosmetic, daily necessities composition comprising the compound of the present invention or a physiologically compatible salt thereof and a physiologically acceptable carrier. In one embodiment, the physiologically acceptable carrier includes a pharmaceutically acceptable carrier or a cosmetically acceptable carrier. The pharmaceutical food, health care product or cosmetic, daily necessities composition can be prepared according to conventional techniques of formulation or cosmetics, including mixing the compound of the present invention as an active ingredient with a carrier, and preparing the desired dosage form according to conventional techniques. The composition of the present invention can be formulated into oral administration preparations, mucosal administration preparations, injection preparations, inhalation preparations and external preparations as required.

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仅由至多21个氨基酸残基组成，而且本发明的多肽口服给药后具有显著的消除炎症水肿、促进消化道黏膜损伤修复，减轻急慢性胃炎及消化道溃疡的胃肠疾病病理发展；具有促进皮肤创伤修复、缩短创面愈合时间、调解免疫功能等作用。口服给药也能发挥作用。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，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。The polypeptide of the present invention has no homology with known polypeptides, which is convenient for artificial polypeptide synthesis to obtain a high-purity polypeptide. Compared with the epidermal growth factor polypeptide, the polypeptide of the present invention only consists of at most 21 amino acid residues, and the polypeptide of the present invention is orally administered After administration, it can significantly eliminate inflammation and edema, promote the repair of gastrointestinal mucosal damage, and reduce the pathological development of gastrointestinal diseases such as acute and chronic gastritis and peptic ulcer; it has the functions of promoting skin wound repair, shortening wound healing time, and regulating immune function. Oral administration can also work. In addition, when the polypeptide of the present invention is used for skin wounds on the surface of the body, it can work even after being sterilized by iodine preparations or hydrogen peroxide. effect.

具体实施方式detailed description

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。The term "physiologically compatible salts" refers to salt forms that are physiologically compatible (ie, pharmacologically acceptable) and that are substantially non-toxic to the individual to which the compounds of the present invention will be administered. Physiologically compatible salts of the compounds of the present invention include conventional and stoichiometric acid or base addition salts formed from suitable, non-toxic, organic or inorganic acids or inorganic bases.

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”除了包括皮肤破损，烧伤、烫伤等，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***(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。It will be understood by those skilled in the art that the repair of skin wounds and/or mucosal lesions of the present invention may be administered for cosmetic (ie, non-therapeutic) as well as therapeutic purposes. For this reason, the term "skin damage" in this application includes, in addition to skin breaks, burns, scalds, etc., skin damages repaired for cosmetic purposes such as wrinkles (e.g., wrinkles caused by ultraviolet radiation), skin lines, cracks, bumps, Large pores (eg associated with adnexal structures such as sweat ducts, sebaceous glands, or hair follicles), or uneven or rough, skin loss of elasticity (loss and/or inactivation of functional skin elastin), sagging (including eye and jaw puffiness), Loss of skin firmness, loss of skin firmness, loss of skin's ability to recover from deformation, discoloration (including dark circles), blemishes, sallow complexion, hyperpigmented skin areas such as age spots and freckles, keratin, abnormal differentiation, hyperkeratosis denaturation, elastin degeneration, destruction of collagen, and other tissue changes in the keratinocytes, dermis, epidermis, skin vasculature (eg, telangiectasias or polyforked vessels), and subcutaneous tissue, especially near the skin .

实施例Example

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。The following is a description of the present invention in combination with specific tests, but is not intended to limit the protection scope of the present invention.

实施例1：多肽的化学合成Example 1: Chemical Synthesis of Polypeptides

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。Polypeptide compounds are synthesized by conventional solid-phase synthesis methods, and go through multiple cycles of resin swelling, substitution, deprotection, washing, amino acid dissolution, amino acid activation and condensation, washing, re-deprotection, and finally cleavage and side chain deprotection.

实施例1：多肽的化学合成Example 1: Chemical Synthesis of Polypeptides

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。固相合成的反应方案如下所示：Polypeptide compounds are synthesized by conventional solid-phase synthesis methods, and go through multiple cycles of resin swelling, substitution, deprotection, washing, amino acid dissolution, amino acid activation and condensation, washing, re-deprotection, and finally cleavage and side chain deprotection. The reaction scheme for solid-phase synthesis is shown below:

表1.溶剂、试剂等的中英文缩写Table 1. Chinese and English abbreviations of solvents, reagents, etc.

2-Chlorotrityl Chloride Resin2-Chlorotrityl Chloride Resin	2-氯三苯甲基氯树脂2-Chlorotrityl chloride resin
DMFDMF	N,N-二甲基甲酰胺N,N-Dimethylformamide
DCMDCM	二氯甲烷Dichloromethane
PIPPIP	哌啶piperidine
HOBtHOBt	1-羟基苯并***1-Hydroxybenzotriazole
DIPEADIPEA	N,N-二异丙基乙胺N,N-Diisopropylethylamine
MethanolMethanol	甲醇methanol
Tert-Butyl methyl etherTert-Butyl methyl ether	甲基叔丁基醚Methyl tert-butyl ether
TFATFA	三氟乙酸Trifluoroacetate
TISTIS	三异丙基硅烷Triisopropylsilane
DICDIC	N,N'-二异丙基碳二亚胺N,N'-Diisopropylcarbodiimide
EthanolEthanol	乙醇Ethanol
AaAa	氨基酸amino acid

合成实施例：Synthesis Example:

1)化合物1(Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu)全保护肽树脂的制备1) Preparation of compound 1 (Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu) fully protected peptide resin

(1)树脂溶胀：称取2-Chlorotrityl Chloride Resin 6.94g(SD＝0.65mmol/g)，加入到有筛板的合成管中，用100ml二氯甲烷(DCM)溶胀。(1) Resin swelling: Weigh 6.94 g (SD=0.65 mmol/g) of 2-Chlorotryl Chloride Resin, add it to a synthesis tube with a sieve plate, and swell with 100 ml of dichloromethane (DCM).

(2)制备Fmoc-Glu(OtBu)-树脂：按树脂、Fmoc-Glu(OtBu)-OH·H ₂O、DIPEA，以1:2:5.38的摩尔比分别称取Fmoc-Glu(OtBu)-OH·H ₂O、DIPEA，加入合成管中。室温N ₂鼓泡震荡1～3小时，抽干；然后分别用二甲基甲酰胺(DMF)洗涤5次，100ml/次，抽干树脂。 (2) Preparation of Fmoc-Glu(OtBu)-resin: According to resin, Fmoc-Glu(OtBu)-OH·H ₂ O, DIPEA, Fmoc-Glu(OtBu)- OH·H ₂ O and DIPEA were added to the synthesis tube. Bubble and shake with _N2 at room temperature for 1 to 3 hours, and then drain the resin; then wash with dimethylformamide (DMF) for 5 times, 100 ml/time, and drain the resin.

(3)脱除Fmoc保护基：向反应器中加入100ml的20％哌啶-DMF(v/v)溶液，N ₂鼓泡反应20min，抽干；然后用DMF洗涤5次，100ml/次，3分钟/次，抽干，茚三酮法检测Fmoc脱除结果。 (3) Removal of Fmoc protective group: add 100ml of 20% piperidine-DMF (v/v) solution to the reactor, bubbling with N for 20min, and draining; then wash with DMF ₅ times, 100ml/time, 3 minutes/time, drained, and the results of Fmoc removal were detected by ninhydrin method.

(4)氨基酸预活化：在250ml烧杯中加入13.5mmol的Fmoc保护的氨基酸、13.5mmol HOBt、13.5mmol DIC，用100ml DMF溶解，室温下待用。(4) Amino acid preactivation: add 13.5mmol of Fmoc-protected amino acid, 13.5mmol HOBt, 13.5mmol DIC to a 250ml beaker, dissolve with 100ml DMF, and stand by at room temperature.

(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N ₂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DMF洗涤5次，100ml/次，3min/次，抽干。每一种氨基酸、缩合剂的用量见表2。 (5) Amino acid connection: Pour the activated protected amino acid solution into the reactor, and add an appropriate amount of DCM to clean the utensils. _N2 bubbling reaction at room temperature for 1 to 3 hours, the ninhydrin method detects whether the amino acid connection is complete, if complete, drain. The resin was washed 5 times with DMF, 100ml/time, 3min/time, and drained. The consumption of each amino acid and condensing agent is shown in Table 2.

(6)第一个氨基酸缩合完成后，重复步骤(4)和(5)，按照氨基酸顺序延长肽链至最后一个氨基酸偶联完毕。(6) After the condensation of the first amino acid is completed, steps (4) and (5) are repeated to extend the peptide chain according to the amino acid sequence until the coupling of the last amino acid is completed.

(7)树脂肽用DMF洗涤4次，150ml/次，3min/次；再用DCM洗涤3次，150ml/次，3min/次，抽干。(7) The resin peptide was washed 4 times with DMF, 150ml/time, 3min/time; then washed with DCM 3 times, 150ml/time, 3min/time, and drained.

表2.氨基酸、缩合剂的用量Table 2. Consumption of amino acid and condensing agent

2)切割2) Cutting

(1)在合成管中加入切割剂(TFA:TIS:H ₂O＝95:2.5:2.5，v/v)100ml，N ₂鼓泡反应1.5～3小时。 (1) 100 ml of cutting agent (TFA:TIS:H ₂ O=95:2.5:2.5, v/v) was added to the synthesis tube, and N ₂ was bubbled to react for 1.5-3 hours.

(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四分之一后，加入10倍现有体积的甲基叔丁基醚，沉降得白色固体。将所得混合溶剂过滤，并用50ml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N ₂吹干，使溶剂挥发至粗肽为粉末状。得到粗肽7.39g，粗产率89.0％。 (2) After the cleavage reaction is completed, suction-filter the cleavage agent into a 250ml round-bottom flask. After vacuum concentration to a quarter of the volume of the original cutting agent, 10 times the existing volume of methyl tert-butyl ether was added, and a white solid was precipitated. The obtained mixed solvent was filtered and washed 3 times with 50 ml of methyl tert-butyl ether, respectively, and then the obtained crude peptide product was placed in a sand core funnel in a fume hood and dried under N ₂ to evaporate the solvent until the crude peptide was powdery. 7.39 g of crude peptide was obtained with a crude yield of 89.0%.

3)纯化、换盐和冻干3) Purification, salt exchange and lyophilization

(1)多肽HPLC纯化制备(1) HPLC purification and preparation of polypeptides

A.色谱参数A. Chromatographic parameters

色谱柱：动态轴向压缩柱80*250mm，填料：Daisogel C18(SP-100-8-ODS-P)Chromatographic column: dynamic axial compression column 80*250mm, packing: Daisogel C18 (SP-100-8-ODS-P)

洗脱液A：10mM碳酸氢铵水溶液Eluent A: 10 mM ammonium bicarbonate in water

洗脱液B：乙腈Eluent B: Acetonitrile

流速：180ml/minFlow rate: 180ml/min

紫外检测波长：220nmUV detection wavelength: 220nm

B.操作步骤B. Operation steps

a)用水和/或乙腈溶解粗肽，并经0.45μm滤膜过滤a) Dissolve the crude peptide with water and/or acetonitrile and filter through a 0.45 μm filter

b)进样b) Sample injection

c)乙腈-水流动相梯度洗脱c) Gradient elution with acetonitrile-water mobile phase

d)收集目标肽洗脱液d) Collect the target peptide eluate

e)旋蒸浓缩e) Rotary evaporation concentration

(2)多肽HPLC换盐(醋酸盐)(2) Polypeptide HPLC salt exchange (acetate)

色谱参数Chromatographic parameters

洗脱液A1：0.1M乙酸Eluent A1: 0.1M acetic acid

洗脱液A2：0.025M乙酸—0.1M乙酸铵Eluent A2: 0.025M acetic acid - 0.1M ammonium acetate

洗脱液B：乙腈Eluent B: Acetonitrile

流速：180ml/minFlow rate: 180ml/min

紫外检测波长：220nmUV detection wavelength: 220nm

操作步骤Steps

a)95％A1+5％B平衡色谱柱a) 95%A1+5%B equilibrated column

b)进样b) Sample injection

c)95％A2+5％B平衡色谱柱c) 95%A2+5%B equilibrated column

d)A1和B梯度洗脱d) A1 and B gradient elution

e)收集目的肽洗脱液e) Collect the target peptide eluate

f)旋蒸浓缩f) Rotary evaporation concentration

g)冷冻干燥g) Freeze drying

表3.合成的化合物Table 3. Synthesized compounds

注释：双电荷峰表示目标分子结合2个质子，三电荷峰表示目标分子结合3个质子；N/A代表称量有难度，未计实际重量。Note: The double-charged peak indicates that the target molecule binds 2 protons, and the triple-charged peak indicates that the target molecule binds 3 protons; N/A means that it is difficult to weigh, excluding the actual weight.

化合物1：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 1: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₀N ₂₀O ₂₈；m/z：921.52014([M+2H] ²⁺)，1842.03431([M+H] ⁺). ¹H NMR(600MHz,DMSO-d ₆)δ8.55(s,1H),8.46(s,2H),8.39(s,1H),8.14(s,6H),8.07–8.00(m,2H),7.98(d,J＝7.9Hz,1H),7.74(s,2H),7.60(s,1H),4.57(d,J＝7.9Hz,1H),4.47(d,J＝7.0Hz,1H),4.34–4.19(m,8H),4.18–4.09(m,4H),3.97–3.91(m,2H),3.85–3.79(m,1H),3.73(d,J＝11.8Hz,3H),3.68–3.55(m,7H),3.52(d,J＝5.7Hz,3H),3.43(t,J＝7.0Hz,1H),2.73(s,4H),2.21–2.09(m,4H),2.07–1.94(m,4H),1.92–1.64(m,19H,AcOH),1.63–1.38(m,16H),1.37–1.20(m,5H),1.01(d,J＝6.2Hz,3H),0.90–0.74(m,36H). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₀ N ₂₀ O ₂₈ ; m/z: 921.52014 ([M+2H] ²⁺ ), 1842.03431 ([M+H] ⁺ ). ¹ H NMR (600MHz) , DMSO-d ₆ )δ8.55(s, 1H), 8.46(s, 2H), 8.39(s, 1H), 8.14(s, 6H), 8.07–8.00(m, 2H), 7.98(d, J =7.9Hz,1H),7.74(s,2H),7.60(s,1H),4.57(d,J=7.9Hz,1H),4.47(d,J=7.0Hz,1H),4.34–4.19(m , 8H), 4.18–4.09 (m, 4H), 3.97–3.91 (m, 2H), 3.85–3.79 (m, 1H), 3.73 (d, J=11.8Hz, 3H), 3.68–3.55 (m, 7H) ),3.52(d,J=5.7Hz,3H),3.43(t,J=7.0Hz,1H),2.73(s,4H),2.21–2.09(m,4H),2.07–1.94(m,4H) , 1.92–1.64 (m, 19H, AcOH), 1.63–1.38 (m, 16H), 1.37–1.20 (m, 5H), 1.01 (d, J=6.2Hz, 3H), 0.90–0.74 (m, 36H) .

化合物2：Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 2: Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₆₀H ₁₀₀N ₁₄O ₂₃；m/z：1385.72297([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₆₀ H ₁₀₀ N ₁₄ O ₂₃ ; m/z: 1385.72297 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆)δ8.72(s,1H),8.34(s,1H),8.29(d,J＝7.3Hz,1H),8.17(s,1H),8.04(s,1H),8.02–7.93(m,5H),7.90(d,J＝8.8Hz,1H),7.51(d,J＝8.7Hz,1H),4.56(q,J＝7.6Hz,1H),4.42(q,J＝6.9Hz,1H),4.32–4.12(m,8H),4.08(q,J＝7.0Hz,1H),3.96–3.93(m,1H),3.82–3.71(m,4H),3.68–3.62(m,5H),3.51(d,J＝5.9Hz,3H),2.44–2.39(m,1H),2.23(dt,J＝8.0,4.2Hz,4H),2.06–1.85(m,8H,AcOH),1.84–1.39(m,14H),0.99(d,J＝6.3Hz,3H),0.89–0.78(m,31H). ¹ H NMR (600MHz, DMSO-d ₆ ) δ 8.72(s, 1H), 8.34(s, 1H), 8.29(d, J=7.3Hz, 1H), 8.17(s, 1H), 8.04(s, 1H), 8.02–7.93(m, 5H), 7.90(d, J=8.8Hz, 1H), 7.51(d, J=8.7Hz, 1H), 4.56(q, J=7.6Hz, 1H), 4.42( q, J=6.9Hz, 1H), 4.32–4.12 (m, 8H), 4.08 (q, J=7.0Hz, 1H), 3.96–3.93 (m, 1H), 3.82–3.71 (m, 4H), 3.68 –3.62 (m, 5H), 3.51 (d, J=5.9Hz, 3H), 2.44–2.39 (m, 1H), 2.23 (dt, J=8.0, 4.2Hz, 4H), 2.06–1.85 (m, 8H) , AcOH), 1.84–1.39 (m, 14H), 0.99 (d, J=6.3Hz, 3H), 0.89–0.78 (m, 31H).

化合物3：Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 3: Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

1H NMR(600MHz,DMSO-d6)δ8.52–8.33(m,3H),8.19(d,J＝8.1Hz,1H),8.10–7.87(m,6H),7.53(d,J＝8.8Hz,1H),4.60–4.51(m,2H),4.37–4.14(m,7H),4.11(t,J＝6.4Hz,1H),4.06(q,J＝7.1Hz,1H),3.97–3.90(m,1H),3.84–3.59(m,7H),3.54–3.42(m,6H),2.63–2.51(m,2H),2.22(t,J＝7.8Hz,4H), 2.07–1.66(m,11H,AcOH),1.66–1.47(m,4H),1.42(t,J＝7.0Hz,2H),0.99(d,J＝6.3Hz,3H),0.90–0.72(m,24H).1H NMR(600MHz, DMSO-d6)δ8.52-8.33(m,3H),8.19(d,J=8.1Hz,1H),8.10-7.87(m,6H),7.53(d,J=8.8Hz, 1H), 4.60–4.51 (m, 2H), 4.37–4.14 (m, 7H), 4.11 (t, J=6.4Hz, 1H), 4.06 (q, J=7.1Hz, 1H), 3.97–3.90 (m , 1H), 3.84–3.59 (m, 7H), 3.54–3.42 (m, 6H), 2.63–2.51 (m, 2H), 2.22 (t, J=7.8Hz, 4H), 2.07–1.66 (m, 11H) , AcOH), 1.66–1.47 (m, 4H), 1.42 (t, J=7.0Hz, 2H), 0.99 (d, J=6.3Hz, 3H), 0.90–0.72 (m, 24H).

化合物4：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu(醋酸盐)Compound 4: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu (acetate)

¹H NMR(600MHz,D ₂O)δ4.62–4.60(m,1H),4.40(t,J＝5.6Hz,1H),4.36(t,J＝7.2Hz,1H),4.32–4.24(m,2H),4.18–4.11(m,1H),4.01–3.94(m,2H),3.87–3.77(m,3H),2.97–2.92(m,4H),2.75–2.69(m,1H),2.60–2.53(m,1H),1.95–1.93(m,7H,AcOH),1.84–1.53(m,17H),1.46–1.33(m,4H),0.91–0.85(m,12H),0.82(t,J＝5.9Hz,6H). ¹ H NMR (600MHz, D ₂ O) δ 4.62-4.60 (m, 1H), 4.40 (t, J=5.6Hz, 1H), 4.36 (t, J=7.2Hz, 1H), 4.32-4.24 (m ,2H),4.18–4.11(m,1H),4.01–3.94(m,2H),3.87–3.77(m,3H),2.97–2.92(m,4H),2.75–2.69(m,1H),2.60 –2.53(m,1H),1.95–1.93(m,7H,AcOH),1.84–1.53(m,17H),1.46–1.33(m,4H),0.91–0.85(m,12H),0.82(t, J=5.9Hz, 6H).

化合物5：Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 5: Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,DMSO-d ₆)δ8.45–8.41(m,1H),8.33–8.23(m,2H),8.04(t,J＝8.8Hz,2H),7.99(t,J＝6.0Hz,1H),7.85(d,J＝6.9Hz,1H),7.74(d,J＝8.8Hz,1H),4.58(q,J＝7.8Hz,1H),4.38–4.27(m,3H),4.27–4.21(m,3H),4.08–3.91(m,3H),3.84–3.79(m,1H),3.72–3.60(m,5H),3.56–3.47(m,4H),3.46(d,J＝5.0Hz,1H),2.22(q,J＝7.9Hz,4H),2.07–1.95(m,4H),1.95–1.77(m,8H,AcOH),1.76–1.69(m,1H),1.63–1.55(m,1H),1.45–1.38(m,2H),1.03(d,J＝6.2Hz,3H),0.90(d,J＝6.8Hz,3H),0.86–0.83(m,9H),0.80(d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.45-8.41 (m, 1H), 8.33-8.23 (m, 2H), 8.04 (t, J=8.8 Hz, 2H), 7.99 (t, J=6.0 Hz, 1H), 7.85(d, J＝6.9Hz, 1H), 7.74(d, J＝8.8Hz, 1H), 4.58(q, J＝7.8Hz, 1H), 4.38–4.27(m, 3H), 4.27–4.21 (m, 3H), 4.08–3.91 (m, 3H), 3.84–3.79 (m, 1H), 3.72–3.60 (m, 5H), 3.56–3.47 (m, 4H), 3.46 (d, J = 5.0Hz, 1H), 2.22 (q, J = 7.9Hz, 4H), 2.07–1.95 (m, 4H), 1.95–1.77 (m, 8H, AcOH), 1.76–1.69 (m, 1H), 1.63– 1.55 (m, 1H), 1.45–1.38 (m, 2H), 1.03 (d, J=6.2Hz, 3H), 0.90 (d, J=6.8Hz, 3H), 0.86–0.83 (m, 9H), 0.80 (d,J＝6.8Hz,3H),0.78(d,J＝6.8Hz,3H).

化合物6：Leu-Pro-Gly-Gly-Glu-GluCompound 6: Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₂₅H ₄₀N ₆O ₁₁；m/z：601.28438([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₂₅ H ₄₀ N ₆ O ₁₁ ; m/z: 601.28438 ([M+H] ⁺ ).

化合物7：Pro-Gly-Gly-Glu-GluCompound 7: Pro-Gly-Gly-Glu-Glu

¹H NMR(600MHz,DMSO-d ₆)δ9.04(s,1H),8.50(d,J＝7.6Hz,1H),8.20(s,1H),7.85–7.79(m,1H),4.15(q,J＝7.2Hz,1H),3.93(q,J＝6.8Hz,1H),3.90–3.80(m,3H),3.79–3.57(m,3H),3.16–2.83(m,3H),2.23–2.05(m,6H),1.91–1.77(m,4H). ¹ H NMR (600MHz, DMSO-d ₆ )δ9.04(s,1H),8.50(d,J=7.6Hz,1H),8.20(s,1H),7.85-7.79(m,1H),4.15( q, J=7.2Hz, 1H), 3.93 (q, J=6.8Hz, 1H), 3.90–3.80 (m, 3H), 3.79–3.57 (m, 3H), 3.16–2.83 (m, 3H), 2.23 –2.05(m,6H),1.91–1.77(m,4H).

化合物8：Val-Thr-Val-Ser(醋酸盐)Compound 8: Val-Thr-Val-Ser (acetate)

¹H NMR(600MHz,DMSO-d ₆+D ₂O+TFA)δ4.27(d,J＝5.7Hz,1H),4.25–4.22(m,1H),4.15(d,J＝6.6Hz,1H),3.91(p,J＝6.2Hz,1H),3.71–3.64(m,2H),3.63–3.59(m,1H),2.08–2.00(m,1H),1.96(h,J＝6.8Hz,1H),1.87(s,AcOH),1.04(d,J＝6.4Hz,3H),0.86(dd,J＝6.9,4.5Hz,6H),0.82–0.76(m,6H). ¹ H NMR (600MHz, DMSO-d ₆ +D ₂ O+TFA) δ 4.27 (d, J=5.7 Hz, 1H), 4.25-4.22 (m, 1H), 4.15 (d, J=6.6 Hz, 1H) ), 3.91 (p, J=6.2Hz, 1H), 3.71–3.64 (m, 2H), 3.63–3.59 (m, 1H), 2.08–2.00 (m, 1H), 1.96 (h, J=6.8Hz, 1H), 1.87(s, AcOH), 1.04(d, J=6.4Hz, 3H), 0.86(dd, J=6.9, 4.5Hz, 6H), 0.82–0.76(m, 6H).

化合物9：Gly-Asp-LeuCompound 9: Gly-Asp-Leu

¹H NMR(600MHz,DMSO-d ₆+D ₂O+TFA)δ4.61(dd,J＝8.6,4.6Hz,1H),4.17–4.11(m,1H),3.59–3.49(m,2H),2.71–2.64(m,1H),2.56–2.49(m,1H),1.60–1.42(m,3H),0.82(d,J＝6.5Hz,3H),0.76(d,J＝6.5Hz,3H). ¹ H NMR (600MHz, DMSO-d ₆ +D ₂ O+TFA) δ 4.61 (dd, J=8.6, 4.6 Hz, 1H), 4.17-4.11 (m, 1H), 3.59-3.49 (m, 2H) ,2.71–2.64(m,1H),2.56–2.49(m,1H),1.60–1.42(m,3H),0.82(d,J=6.5Hz,3H),0.76(d,J=6.5Hz,3H) ).

化合物10：Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-LeuCompound 10: Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu

高分辨质谱(TOF-HRMS)，分子式：C ₄₁H ₇₃N ₉O ₁₄；m/z：916.53883([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₄₁ H ₇₃ N ₉ O ₁₄ ; m/z: 916.53883 ([M+H] ⁺ ).

化合物11：Gly-Asp-Leu-Val-Thr-Val-Ser-LeuCompound 11: Gly-Asp-Leu-Val-Thr-Val-Ser-Leu

高分辨质谱(TOF-HRMS)，分子式：C ₃₅H ₆₂N ₈O ₁₃；m/z：803.45303([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₃₅ H ₆₂ N ₈ O ₁₃ ; m/z: 803.45303 ([M+H] ⁺ ).

化合物12：Val-Thr-Val-Ser-Leu-Pro(醋酸盐)Compound 12: Val-Thr-Val-Ser-Leu-Pro (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₂₈H ₅₀N ₆O ₉；m/z：615.37174([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₂₈ H ₅₀ N ₆ O ₉ ; m/z: 615.37174 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆+TFA)δ8.10(s,1H),7.97(d,J＝7.9Hz,1H),7.86(d,J＝8.1Hz,1H),7.71(d,J＝8.7Hz,1H),4.55(q,J＝7.9,7.5Hz,2H),4.32–4.23(m,2H),4.19(dd,J＝8.6,4.3Hz,1H),4.08(s,1H),3.98(td,J＝6.4,4.0Hz,1H),3.87(s,1H),3.65–3.58(m,2H),3.51(d,J＝5.9Hz,1H),3.44(s,2H),3.26(s,1H),3.18(d,J＝4.6Hz,1H),2.12–2.05(m,1H),2.03–1.93(m,3H),1.92–1.75(m,5H,AcOH),1.71–1.61(m,2H),1.52(s,1H),1.47–1.27(m,3H),1.01(d,J＝6.3Hz,3H),0.88–0.82(m,12H),0.80–0.78(m,6H). ¹ H NMR (600MHz, DMSO-d ₆ +TFA) δ 8.10(s, 1H), 7.97(d, J=7.9Hz, 1H), 7.86(d, J=8.1Hz, 1H), 7.71(d, J=8.7Hz, 1H), 4.55 (q, J=7.9, 7.5Hz, 2H), 4.32–4.23 (m, 2H), 4.19 (dd, J=8.6, 4.3Hz, 1H), 4.08 (s, 1H) ), 3.98(td, J＝6.4, 4.0Hz, 1H), 3.87(s, 1H), 3.65–3.58(m, 2H), 3.51(d, J＝5.9Hz, 1H), 3.44(s, 2H) ,3.26(s,1H),3.18(d,J=4.6Hz,1H),2.12-2.05(m,1H),2.03-1.93(m,3H),1.92-1.75(m,5H,AcOH),1.71 –1.61(m, 2H), 1.52(s, 1H), 1.47–1.27(m, 3H), 1.01(d, J=6.3Hz, 3H), 0.88–0.82(m, 12H), 0.80–0.78(m ,6H).

化合物13：Val-Thr-Val-Ser-LeuCompound 13: Val-Thr-Val-Ser-Leu

¹H NMR(600MHz,DMSO-d ₆+D ₂O+TFA)δ4.28(dd,J＝7.3,5.4Hz,2H),4.19(dd,J＝9.7,5.2Hz,1H),4.14(d,J＝6.4Hz,1H),3.91(p,J＝6.2Hz,1H),3.67(d,J＝5.7Hz,1H),3.58–3.54(m,1H),3.53–3.48(m,1H),2.07–2.00(m,1H),1.98–1.92(m,1H),1.58–1.40(m,3H),1.04(d,J＝6.3Hz,3H),0.87(dd,J＝6.9,5.2Hz,6H),0.82–0.74(m,12H). ¹ H NMR (600 MHz, DMSO-d ₆ +D ₂ O+TFA) δ 4.28 (dd, J=7.3, 5.4 Hz, 2H), 4.19 (dd, J=9.7, 5.2 Hz, 1H), 4.14 (d , J=6.4Hz, 1H), 3.91 (p, J=6.2Hz, 1H), 3.67 (d, J=5.7Hz, 1H), 3.58–3.54 (m, 1H), 3.53–3.48 (m, 1H) ,2.07–2.00(m,1H),1.98–1.92(m,1H),1.58–1.40(m,3H),1.04(d,J=6.3Hz,3H),0.87(dd,J=6.9,5.2Hz ,6H),0.82–0.74(m,12H).

化合物14：Leu-Gly-Asp-LeuCompound 14: Leu-Gly-Asp-Leu

高分辨质谱(TOF-HRMS)，分子式：C ₁₈H ₃₂N ₄O ₇；m/z：417.23391([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₁₈ H ₃₂ N ₄ O ₇ ; m/z: 417.23391 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆)δ8.86(s,1H),8.55(d,J＝7.2Hz,1H),7.73(d,J＝7.8Hz,1H),4.37(q,J＝7.1Hz,1H),4.02(q,J＝7.5Hz,1H),3.91–3.80(m,1H),3.64–3.52(m,2H),2.54–2.49(m,1H),2.44–2.38(m,1H),1.66–1.57(m,2H),1.54–1.48(m,1H),1.48–1.37(m,3H),0.90–0.79(m,12H). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.86 (s, 1H), 8.55 (d, J=7.2 Hz, 1H), 7.73 (d, J=7.8 Hz, 1H), 4.37 (q, J= 7.1Hz, 1H), 4.02 (q, J=7.5Hz, 1H), 3.91–3.80 (m, 1H), 3.64–3.52 (m, 2H), 2.54–2.49 (m, 1H), 2.44–2.38 (m ,1H),1.66–1.57(m,2H),1.54–1.48(m,1H),1.48–1.37(m,3H),0.90–0.79(m,12H).

化合物15：Leu-Gly-AspCompound 15: Leu-Gly-Asp

高分辨质谱(TOF-HRMS)，分子式：C ₁₂H ₂₁N ₃O ₆；m/z：304.14925([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₁₂ H ₂₁ N ₃ O ₆ ; m/z: 304.14925 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆)δ8.69(s,1H),7.87(d,J＝6.9Hz,1H),4.22–4.14(m,1H),3.78(d,J＝5.2Hz,2H),3.70(t,J＝7.2Hz,1H),2.46(d,J＝10.6Hz,1H),2.37–2.31(m,1H),1.70–1.63(m,1H),1.59–1.53(m,1H),1.51–1.45(m,1H),0.88(dd,J＝10.4,6.5Hz,6H). ¹ H NMR (600MHz, DMSO-d ₆ )δ8.69(s,1H),7.87(d,J=6.9Hz,1H),4.22-4.14(m,1H),3.78(d,J=5.2Hz, 2H), 3.70 (t, J=7.2Hz, 1H), 2.46 (d, J=10.6Hz, 1H), 2.37–2.31 (m, 1H), 1.70–1.63 (m, 1H), 1.59–1.53 (m ,1H),1.51–1.45(m,1H),0.88(dd,J=10.4,6.5Hz,6H).

化合物16：Leu-Lys-Ser-Lys(醋酸盐)Compound 16: Leu-Lys-Ser-Lys (acetate)

¹H NMR(600MHz,DMSO-d ₆+D ₂O)δ4.35(t,J＝6.7Hz,1H),4.17–4.12(m,1H),3.66–3.60(m,1H),3.56–3.50(m,1H),3.31(d,J＝6.7Hz,1H),2.80–2.66(m,4H),1.84–1.45(m,19H,AcOH),1.45–1.11(m,7H),0.85–0.82(m,3H),0.80(d,J＝6.6Hz,3H). ¹ H NMR (600 MHz, DMSO-d ₆ +D ₂ O) δ 4.35 (t, J=6.7 Hz, 1H), 4.17–4.12 (m, 1H), 3.66–3.60 (m, 1H), 3.56–3.50 (m, 1H), 3.31 (d, J=6.7Hz, 1H), 2.80–2.66 (m, 4H), 1.84–1.45 (m, 19H, AcOH), 1.45–1.11 (m, 7H), 0.85–0.82 (m,3H),0.80(d,J＝6.6Hz,3H).

化合物17：Leu-Lys-Ser-Lys-Leu(醋酸盐)Compound 17: Leu-Lys-Ser-Lys-Leu (acetate)

¹H NMR(600MHz,DMSO-d ₆)δ8.53(d,J＝7.7Hz,1H),8.13(s,1H),7.87(d,J＝7.7Hz,1H),7.72(d,J＝7.8Hz,1H),4.34(s,1H),4.26(q,J＝6.1Hz,1H),4.21(q,J＝6.8Hz,1H),3.89(td,J＝8.4,5.1Hz,1H),3.64–3.49(m,2H),3.18(dd,J＝9.1,5.0Hz,1H),2.75–2.61(m,4H),1.86–1.58(m,12H,AcOH),1.57–1.15(m,14H),0.88–0.79(m,12H). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.53 (d, J=7.7 Hz, 1H), 8.13 (s, 1H), 7.87 (d, J=7.7 Hz, 1H), 7.72 (d, J= 7.8Hz, 1H), 4.34 (s, 1H), 4.26 (q, J=6.1Hz, 1H), 4.21 (q, J=6.8Hz, 1H), 3.89 (td, J=8.4, 5.1Hz, 1H) , 3.64–3.49 (m, 2H), 3.18 (dd, J=9.1, 5.0Hz, 1H), 2.75–2.61 (m, 4H), 1.86–1.58 (m, 12H, AcOH), 1.57–1.15 (m, 14H),0.88–0.79(m,12H).

化合物18：Val-Thr-Val-Ser-Val-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 18: Val-Thr-Val-Ser-Val-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₄₁H ₆₈N ₁₀O ₁₇；m/z：973.48858([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₄₁ H ₆₈ N ₁₀ O ₁₇ ; m/z: 973.48858 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆)δ8.62–8.50(m,2H),8.28(d,J＝8.0Hz,1H),8.11(d,J＝8.1Hz,1H),8.05(q,J＝9.1,7.5Hz,2H),7.77(d,J＝6.8Hz,1H),7.69(d,J＝8.8Hz,1H),4.36–4.29(m,3H),4.24–4.18(m,3H),4.05–3.85(m,4H),3.80–3.67(m,3H),3.59(d,J＝5.5Hz,1H),3.56–3.47(m,6H),2.25–2.16(m,4H),2.06–1.86(m,9H,AcOH),1.86–1.67(m,5H),1.03(d,J＝6.3Hz,3H),0.90(d,J＝6.9Hz,3H),0.86–0.73(m,16H). ¹ H NMR (600 MHz, DMSO-d ₆ ) δ 8.62-8.50 (m, 2H), 8.28 (d, J=8.0 Hz, 1H), 8.11 (d, J=8.1 Hz, 1H), 8.05 (q, J=9.1, 7.5Hz, 2H), 7.77 (d, J=6.8Hz, 1H), 7.69 (d, J=8.8Hz, 1H), 4.36–4.29 (m, 3H), 4.24–4.18 (m, 3H) ), 4.05–3.85 (m, 4H), 3.80–3.67 (m, 3H), 3.59 (d, J=5.5Hz, 1H), 3.56–3.47 (m, 6H), 2.25–2.16 (m, 4H), 2.06–1.86 (m, 9H, AcOH), 1.86–1.67 (m, 5H), 1.03 (d, J=6.3Hz, 3H), 0.90 (d, J=6.9Hz, 3H), 0.86–0.73 (m, 16H).

化合物19：Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 19: Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₃₉H ₆₄N ₁₀O ₁₇；m/z：945.45656([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₃₉ H ₆₄ N ₁₀ O ₁₇ ; m/z: 945.45656 ([M+H] ⁺ ).

¹H NMR(600MHz,DMSO-d ₆)δ8.41–8.35(m,1H),8.32–8.26(m,1H),8.22(d,J＝7.5Hz,1H),8.04(d,J＝8.1Hz,1H),8.00(d,J＝7.5Hz,1H),7.97(t,1H),7.87(d,J＝6.9Hz,1H),7.76(d,J＝8.6Hz,1H),4.58–4.49(m,1H),4.31(s,1H),4.29–4.18(m,4H),4.06–4.00(m,1H),4.00–3.95(m,1H),3.81–3.75(m,1H),3.70–3.62(m,3H),3.60(s,1H),3.53(d,J＝5.8Hz,4H),3.45(d,J＝4.8Hz,1H),2.22(q,J＝7.3Hz,4H),2.07–1.74(m,14H,AcOH),1.74–1.67(m,1H),1.16(d,J＝6.8Hz,3H),1.03(d,J＝6.3Hz,3H),0.90(d,J＝6.9Hz,3H),0.84–0.77(m,9H). ¹ H NMR (600MHz, DMSO-d ₆ ) δ 8.41-8.35 (m, 1H), 8.32-8.26 (m, 1H), 8.22 (d, J=7.5Hz, 1H), 8.04 (d, J=8.1 Hz, 1H), 8.00(d, J＝7.5Hz, 1H), 7.97(t, 1H), 7.87(d, J＝6.9Hz, 1H), 7.76(d, J＝8.6Hz, 1H), 4.58– 4.49 (m, 1H), 4.31 (s, 1H), 4.29–4.18 (m, 4H), 4.06–4.00 (m, 1H), 4.00–3.95 (m, 1H), 3.81–3.75 (m, 1H), 3.70–3.62(m, 3H), 3.60(s, 1H), 3.53(d, J=5.8Hz, 4H), 3.45(d, J=4.8Hz, 1H), 2.22(q, J=7.3Hz, 4H) ), 2.07–1.74 (m, 14H, AcOH), 1.74–1.67 (m, 1H), 1.16 (d, J=6.8Hz, 3H), 1.03 (d, J=6.3Hz, 3H), 0.90 (d, J=6.9Hz, 3H), 0.84–0.77(m, 9H).

化合物20:Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-GluCompound 20: Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₄₀H ₆₈N ₁₀O ₁₇；m/z：961.48753([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₄₀ H ₆₈ N ₁₀ O ₁₇ ; m/z: 961.48753 ([M+H] ⁺ ).

化合物21：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 21: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.45–4.26(m,10H),4.18–4.06(m,6H),4.01–3.91(m,6H),3.86–3.68(m,7H),3.64–3.57(m,1H),2.94(t,J＝7.6Hz,4H),2.70–2.65(m,1H),2.60–2.55(m,1H),2.37–2.21(m,5H),2.11–1.82(m,20H,AcOH),1.82–1.31(m,23H),1.12(d,J＝6.4Hz,3H),0.90–0.85(m,33H),0.82(d,J＝5.4Hz,3H). ¹ H NMR (600MHz, D ₂ O)δ4.45-4.26(m,10H),4.18-4.06(m,6H),4.01-3.91(m,6H),3.86-3.68(m,7H),3.64- 3.57(m,1H),2.94(t,J=7.6Hz,4H),2.70-2.65(m,1H),2.60-2.55(m,1H),2.37-2.21(m,5H),2.11-1.82( m, 20H, AcOH), 1.82–1.31 (m, 23H), 1.12 (d, J=6.4Hz, 3H), 0.90–0.85 (m, 33H), 0.82 (d, J=5.4Hz, 3H).

化合物22：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 22: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.63–4.54(m,4H),4.45–4.25(m,9H),4.16–4.08(m,4H),4.00–3.88(m,6H),3.85–3.70(m,6H),3.60(q,J＝7.4Hz,1H),2.94(t,J＝7.6Hz,4H),2.71–2.64(m,1H),2.63–2.57(m,1H),2.36–2.21(m,5H),2.11–1.86(m,15H,AcOH),1.86–1.46(m,18H),1.44–1.35(m,4H),1.33(d,J＝7.2Hz,3H),1.12(d,J＝6.3Hz,3H),0.90–0.84(m,27H),0.82(d,J＝5.6Hz,3H). ¹ H NMR (600MHz, D ₂ O)δ4.63-4.54(m,4H),4.45-4.25(m,9H),4.16-4.08(m,4H),4.00-3.88(m,6H),3.85- 3.70(m,6H),3.60(q,J=7.4Hz,1H),2.94(t,J=7.6Hz,4H),2.71-2.64(m,1H),2.63-2.57(m,1H),2.36 –2.21(m, 5H), 2.11 – 1.86(m, 15H, AcOH), 1.86 – 1.46(m, 18H), 1.44 – 1.35(m, 4H), 1.33(d, J=7.2Hz, 3H), 1.12 (d, J=6.3Hz, 3H), 0.90–0.84 (m, 27H), 0.82 (d, J=5.6Hz, 3H).

化合物23：Leu-Lys-Ser-Lys-Val-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 23: Leu-Lys-Ser-Lys-Val-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.95–4.72(m,7H),4.60(m,3H),4.44–4.30(m,7H),4.18–4.06(m,5H),4.02(d,J＝7.5Hz,1H),4.00–3.89(m,6H),3.88–3.68(m,6H),3.63–3.56(m,1H),2.93(t,J＝7.8Hz,4H),2.71–2.66(m,1H),2.62–2.56(m,1H),2.39–2.29(m,4H),2.26–2.21(m,1H),2.11–1.84(m,29H,AcOH),1.83–1.74(m,2H),1.74–1.48(m,12H),1.44–1.30(m,4H),1.11(d,J＝6.4Hz,3H),0.90–0.84(m,36H). ¹ H NMR (600MHz, D ₂ O)δ4.95-4.72(m,7H),4.60(m,3H),4.44-4.30(m,7H),4.18-4.06(m,5H),4.02(d, J=7.5Hz, 1H), 4.00–3.89 (m, 6H), 3.88–3.68 (m, 6H), 3.63–3.56 (m, 1H), 2.93 (t, J=7.8Hz, 4H), 2.71–2.66 (m, 1H), 2.62–2.56 (m, 1H), 2.39–2.29 (m, 4H), 2.26–2.21 (m, 1H), 2.11–1.84 (m, 29H, AcOH), 1.83–1.74 (m, 2H), 1.74–1.48 (m, 12H), 1.44–1.30 (m, 4H), 1.11 (d, J=6.4Hz, 3H), 0.90–0.84 (m, 36H).

化合物24：Leu-Lys-Ser-Lys-Ala-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 24: Leu-Lys-Ser-Lys-Ala-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.46–4.22(m,10H),4.17–4.09(m,4H),4.01–3.83(m,8H),3.81–3.70(m,4H),3.63–3.57(m,1H),2.97–2.92(m,4H),2.71–2.66(m,1H),2.65–2.59(m,1H),2.37–2.21(m,5H),2.12–1.85(m,16H,AcOH),1.84–1.48(m,14H),1.45–1.31(m,10H),1.13(d,J＝6.4Hz,3H),0.91–0.85(m,24H). ¹ H NMR (600MHz, D ₂ O)δ4.46-4.22(m,10H),4.17-4.09(m,4H),4.01-3.83(m,8H),3.81-3.70(m,4H),3.63- 3.57 (m, 1H), 2.97–2.92 (m, 4H), 2.71–2.66 (m, 1H), 2.65–2.59 (m, 1H), 2.37–2.21 (m, 5H), 2.12–1.85 (m, 16H) , AcOH), 1.84–1.48 (m, 14H), 1.45–1.31 (m, 10H), 1.13 (d, J=6.4Hz, 3H), 0.91–0.85 (m, 24H).

化合物25：Leu-Lys-Ser-Lys-Ile-Gly-Asp-Ile-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 25: Leu-Lys-Ser-Lys-Ile-Gly-Asp-Ile-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₀N ₂₀O ₂₈；m/z：921.51833([M+2H] ²⁺)，1842.02826([M+H] ⁺). ¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.63–4.53(m,3H),4.37–4.18(m,8H),4.17–4.08(m,4H),4.00(d,J＝7.3Hz,1H),3.97–3.91(m,1H),3.80–3.57(m,8H),3.55–3.42(m,4H),2.84(s,1H),2.76–2.64(m,6H),2.58–2.51(m,1H),2.25(q,J＝9.4,7.6Hz,4H),2.10–2.00(m,1H),1.99–1.59(m,23H,AcOH),1.59–1.44(m,10H),1.42–1.20(m,7H),1.05–0.90(m,5H),0.85–0.68(m,36H). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₀ N ₂₀ O ₂₈ ; m/z: 921.51833 ([M+2H] ²⁺ ), 1842.02826 ([M+H] ⁺ ). ¹ H NMR (600MHz) , D ₂ O+DMSO-d ₆ +TFA)δ4.63-4.53(m,3H),4.37-4.18(m,8H),4.17-4.08(m,4H),4.00(d,J=7.3Hz, 1H), 3.97–3.91 (m, 1H), 3.80–3.57 (m, 8H), 3.55–3.42 (m, 4H), 2.84 (s, 1H), 2.76–2.64 (m, 6H), 2.58–2.51 ( m, 1H), 2.25 (q, J=9.4, 7.6Hz, 4H), 2.10–2.00 (m, 1H), 1.99–1.59 (m, 23H, AcOH), 1.59–1.44 (m, 10H), 1.42– 1.20(m,7H),1.05–0.90(m,5H),0.85–0.68(m,36H).

化合物26：Leu-Arg-Ser-Arg-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-GluCompound 26: Leu-Arg-Ser-Arg-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₃₃H ₆₁N ₉O ₁₁；m/z：633.35164([M+3H] ³⁺)，1898.04261([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₃₃ H ₆₁ N ₉ O ₁₁ ; m/z: 633.35164 ([M+3H] ³⁺ ), 1898.04261 ([M+H] ⁺ ).

化合物27：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-GluCompound 27: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₇₉H ₁₃₈N ₂₀O ₂₈；m/z：606.00885([M+3H] ³⁺)，1816.01835([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₉ H ₁₃₈ N ₂₀ O ₂₈ ; m/z: 606.00885 ([M+3H] ³⁺ ), 1816.01835 ([M+H] ⁺ ).

化合物28：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Gly-Gly-Gly-Glu-GluCompound 28: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Gly-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₇₈H ₁₃₆N ₂₀O ₂₈；m/z：601.33780([M+3H] ³⁺)，1802.01155([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₈ H ₁₃₆ N ₂₀ O ₂₈ ; m/z: 601.33780 ([M+3H] ³⁺ ), 1802.01155 ([M+H] ⁺ ).

化合物29：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Ala-Gly-Gly-Glu-GluCompound 29: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Ala-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₇₆H ₁₃₂N ₂₀O ₂₈；m/z：591.99278([M+3H] ³⁺)，1773.96555([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₆ H ₁₃₂ N ₂₀ O ₂₈ ; m/z: 591.99278 ([M+3H] ³⁺ ), 1773.96555 ([M+H] ⁺ ).

化合物30：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-AspCompound 30: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Asp

高分辨质谱(TOF-HRMS)，分子式：C ₈₀H ₁₃₈N ₂₀O ₂₈；m/z：610.00844([M+3H] ³⁺)，1828.01427([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₀ H ₁₃₈ N ₂₀ O ₂₈ ; m/z: 610.00844 ([M+3H] ³⁺ ), 1828.01427 ([M+H] ⁺ ).

化合物31：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Gln-GluCompound 31: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Gln-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₁N ₂₁O ₂₇；m/z：921.02784([M+2H] ²⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₁ N ₂₁ O ₂₇ ; m/z: 921.02784 ([M+2H] ²⁺ ).

化合物32：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Gln(醋酸盐)Compound 32: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Gln (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₁N ₂₁O ₂₇；m/z：921.02807([M+2H] ²⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₁ N ₂₁ O ₂₇ ; m/z: 921.02807 ([M+2H] ²⁺ ).

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.88–4.73(m,6H),4.55–4.45(m,2H),4.31–4.25(m,3H),4.23–4.01(m,9H),3.99–3.93(m,1H),3.82–3.50(m,12H),3.45(s,1H),2.78–2.67(m,5H),2.66–2.59(m,1H),2.27(t,J＝7.9Hz,2H),2.19–2.11(m,2H),2.11–1.72(m,16H,AcOH),1.71–1.17(m,26H),0.98(d,J＝6.3Hz,3H),0.81–0.73(m,30H),0.71(t,J＝7.0Hz,6H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA)δ4.88-4.73(m,6H),4.55-4.45(m,2H),4.31-4.25(m,3H),4.23-4.01( m, 9H), 3.99–3.93 (m, 1H), 3.82–3.50 (m, 12H), 3.45 (s, 1H), 2.78–2.67 (m, 5H), 2.66–2.59 (m, 1H), 2.27 ( t, J=7.9Hz, 2H), 2.19–2.11 (m, 2H), 2.11–1.72 (m, 16H, AcOH), 1.71–1.17 (m, 26H), 0.98 (d, J=6.3Hz, 3H) ,0.81–0.73(m,30H),0.71(t,J＝7.0Hz,6H).

化合物34：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly(醋酸盐)Compound 34: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.57–4.44(m,3H),4.35–4.21(m,7H),4.19–4.15(m,1H),4.11(q,J＝4.6,3.9Hz,2H),4.07(d,J＝7.5Hz,1H),4.00–3.93(m,1H),3.83–3.46(m,11H),2.80–2.69(m,5H),2.67–2.60(m,1H),2.10–1.75(m,13H,AcOH),1.74–1.20(m,26H),0.99(d,J＝6.3Hz,3H),0.83–0.75(m,30H),0.72(dd,J＝9.1,6.1Hz,6H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.57–4.44 (m, 3H), 4.35–4.21 (m, 7H), 4.19–4.15 (m, 1H), 4.11 (q, J=4.6, 3.9Hz, 2H), 4.07 (d, J=7.5Hz, 1H), 4.00–3.93 (m, 1H), 3.83–3.46 (m, 11H), 2.80–2.69 (m, 5H), 2.67 –2.60(m,1H),2.10-1.75(m,13H,AcOH),1.74-1.20(m,26H),0.99(d,J=6.3Hz,3H),0.83-0.75(m,30H),0.72 (dd,J=9.1,6.1Hz,6H).

化合物35：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly(醋酸盐)Compound 35: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly (acetate)

¹H NMR(600MHz,D ₂O)δ4.62-4.49(m,4H),4.44–4.33(m,4H),4.33–4.24(m,4H),4.15–4.07(m,3H),4.00–3.66(m,12H),3.64–3.56(m,1H),2.94(t,J＝7.7Hz,4H),2.68–2.62(m,1H),2.59–2.51(m,1H),2.28–2.21(m,1H),2.07–1.49(m,32H,AcOH),1.45–1.33(m,4H),1.12(d,J＝6.3Hz,3H),0.90–0.85(m,30H),0.81(t,J＝6.6Hz,6H). ¹ H NMR (600MHz, D ₂ O)δ4.62-4.49(m,4H),4.44-4.33(m,4H),4.33-4.24(m,4H),4.15-4.07(m,3H),4.00- 3.66 (m, 12H), 3.64–3.56 (m, 1H), 2.94 (t, J=7.7Hz, 4H), 2.68–2.62 (m, 1H), 2.59–2.51 (m, 1H), 2.28–2.21 ( m, 1H), 2.07–1.49 (m, 32H, AcOH), 1.45–1.33 (m, 4H), 1.12 (d, J=6.3Hz, 3H), 0.90–0.85 (m, 30H), 0.81 (t, J=6.6Hz, 6H).

化合物36：Leu-Lys-Ser-Lys-Leu-Gly-Glu-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 36: Leu-Lys-Ser-Lys-Leu-Gly-Glu-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.52–4.23(m,11H),4.15–4.08(m,4H),4.00–3.87(m,6H),3.86–3.67(m,6H),3.63–3.56(m,1H),2.96–2.91(m,4H),2.35–2.19(m,7H),2.11–1.46(m,40H,AcOH),1.44–1.32(m,4H),1.11(d,J＝6.4Hz,3H),0.90–0.84(m,30H),0.81(t,J＝6.3Hz,6H). ¹ H NMR (600MHz, D ₂ O)δ4.52-4.23(m,11H),4.15-4.08(m,4H),4.00-3.87(m,6H),3.86-3.67(m,6H),3.63- 3.56 (m, 1H), 2.96–2.91 (m, 4H), 2.35–2.19 (m, 7H), 2.11–1.46 (m, 40H, AcOH), 1.44–1.32 (m, 4H), 1.11 (d, J =6.4Hz,3H),0.90–0.84(m,30H),0.81(t,J=6.3Hz,6H).

化合物37：Leu-Lys-Ser-Lys-Leu-Gly-Asn-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 37: Leu-Lys-Ser-Lys-Leu-Gly-Asn-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+TFA)δ4.48(s,1H),4.43(d,J＝8.4Hz,1H),4.28–4.13(m,8H),4.10(d,J＝6.0Hz,2H),4.00–3.92(m,3H),3.82–3.51(m,12H),3.42(s,1H),2.80–2.71(m,5H),2.60–2.55(m,1H),2.54–2.47(m,1H),2.45(s,3H),2.25(t,J＝7.2Hz,4H),2.10–1.29(m,39H,AcOH),1.21(s,4H),0.94(d,J＝6.4Hz,3H),0.74–0.68(m,30H),0.64(t,J＝6.1Hz,6H). ¹ H NMR (600MHz, D ₂ O+TFA) δ 4.48(s, 1H), 4.43(d, J=8.4Hz, 1H), 4.28-4.13(m, 8H), 4.10(d, J=6.0Hz ,2H),4.00–3.92(m,3H),3.82–3.51(m,12H),3.42(s,1H),2.80–2.71(m,5H),2.60–2.55(m,1H),2.54–2.47 (m, 1H), 2.45 (s, 3H), 2.25 (t, J=7.2Hz, 4H), 2.10–1.29 (m, 39H, AcOH), 1.21 (s, 4H), 0.94 (d, J=6.4 Hz,3H),0.74–0.68(m,30H),0.64(t,J=6.1Hz,6H).

化合物39：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 39: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.37–4.11(m,13H),3.96(dd,J＝6.4,4.5Hz,1H),3.79–3.47(m,13H),2.77–2.63(m,5H),2.29–2.20(m,4H),2.11–1.21(m,42H,AcOH),1.15(d,J＝6.8Hz,3H),0.98(d,J＝6.3Hz,3H),0.86–0.76(m,30H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.37-4.11 (m, 13H), 3.96 (dd, J=6.4, 4.5Hz, 1H), 3.79-3.47 (m, 13H) , 2.77–2.63 (m, 5H), 2.29–2.20 (m, 4H), 2.11–1.21 (m, 42H, AcOH), 1.15 (d, J=6.8Hz, 3H), 0.98 (d, J=6.3Hz) ,3H),0.86–0.76(m,30H).

化合物40：Val-Lys-Thr-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-GluCompound 40: Val-Lys-Thr-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₀N ₂₀O ₂₈；m/z：921.52020([M+2H] ²⁺)，1842.0936([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₀ N ₂₀ O ₂₈ ; m/z: 921.52020 ([M+2H] ²⁺ ), 1842.0936 ([M+H] ⁺ ).

化合物41：Val-Lys-Thr-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-GluCompound 41: Val-Lys-Thr-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₈₀H ₁₃₈N ₂₀O ₂₈；m/z：610.00824([M+3H] ³⁺)，914.51043([M+2H] ²⁺)，1828.01136([M+H] ⁺). High-resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₀ H ₁₃₈ N ₂₀ O ₂₈ ; m/z: 610.00824 ([M+3H] ³⁺ ), 914.51043 ([M+2H] ²⁺ ), 1828.01136 ([M] +H] ⁺ ).

化合物42：Ala-Lys-Ala-Lys-Ala-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-GluCompound 42: Ala-Lys-Ala-Lys-Ala-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₇₅H ₁₂₈N ₂₀O ₂₇；m/z：871.47546([M+2H] ²⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₅ H ₁₂₈ N ₂₀ O ₂₇ ; m/z: 871.47546 ([M+2H] ²⁺ ).

化合物43：Val-Lys-Ala-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-GluCompound 43: Val-Lys-Ala-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu

高分辨质谱(TOF-HRMS)，分子式：C ₇₉H ₁₃₆N ₂₀O ₂₇；m/z：600.00616([M+3H] ³⁺)，899.50814([M+2H] ²⁺)，1798.00999([M+H] ⁺). High-resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₉ H ₁₃₆ N ₂₀ O ₂₇ ; m/z: 600.00616 ([M+3H] ³⁺ ), 899.50814 ([M+2H] ²⁺ ), 1798.00999 ([M] +H] ⁺ ).

化合物44：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Asp-Asp(醋酸盐)Compound 44: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Asp-Asp (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.61–4.45(m,4H),4.36–4.16(m,11H),3.80–3.74(m,3H),3.71–3.65(m,6H),3.64–3.56(m,3H),3.53–3.45(m,4H),2.77–2.61(m,7H),2.59–2.51(m,1H),2.46–2.41(m,1H),2.08–1.76(m,11H),1.73–1.14(m,26H),0.97(d,J＝6.3Hz,3H),0.88–0.76(m,36H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA)δ4.61-4.45(m,4H),4.36-4.16(m,11H),3.80-3.74(m,3H),3.71-3.65( m, 6H), 3.64–3.56 (m, 3H), 3.53–3.45 (m, 4H), 2.77–2.61 (m, 7H), 2.59–2.51 (m, 1H), 2.46–2.41 (m, 1H), 2.08–1.76 (m, 11H), 1.73–1.14 (m, 26H), 0.97 (d, J=6.3Hz, 3H), 0.88–0.76 (m, 36H).

化合物45：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Asp-Asp(醋酸盐)Compound 45: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Asp-Asp (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₀N ₂₀O ₂₈；m/z：614.68030([M+3H] ³⁺)，921.51901([M+2H] ²⁺)，1842.02875([M+H] ⁺). High-resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₀ N ₂₀ O ₂₈ ; m/z: 614.68030 ([M+3H] ³⁺ ), 921.51901 ([M+2H] ²⁺ ), 1842.02875 ([M] +H] ⁺ ).

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.56–4.46(m,4H),4.37–4.10(m,23H),3.77(t,J＝7.3Hz,1H),3.67(s,2H),3.62–3.56(m,2H),3.53–3.44(m,4H),2.77–2.54(m,8H),2.47–2.44(m,1H),2.07–1.74(m,15H,AcOH),1.73–1.14(m,31H),0.97(d,J＝6.3Hz,3H),0.88–0.76(m,36H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.56-4.46 (m, 4H), 4.37-4.10 (m, 23H), 3.77 (t, J=7.3Hz, 1H), 3.67 (s, 2H), 3.62–3.56 (m, 2H), 3.53–3.44 (m, 4H), 2.77–2.54 (m, 8H), 2.47–2.44 (m, 1H), 2.07–1.74 (m, 15H, AcOH), 1.73–1.14 (m, 31H), 0.97 (d, J=6.3Hz, 3H), 0.88–0.76 (m, 36H).

化合物46：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Gln-GlnCompound 46: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Gln-Gln

高分辨质谱(TOF-HRMS)，分子式：C ₈₃H ₁₄₆N ₂₂O ₂₆；m/z：623.36767([M+3H] ³⁺)，1868.08748([M+H] ⁺). High-resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₃ H ₁₄₆ N ₂₂ O ₂₆ ; m/z: 623.36767 ([M+3H] ³⁺ ), 1868.08748 ([M+H] ⁺ ).

化合物47：Leu-Lys-Ser-Lys-Leu-Pro-Val-Pro-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 47: Leu-Lys-Ser-Lys-Leu-Pro-Val-Pro-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.53(t,J＝7.1Hz,1H),4.49–4.44(m,1H),4.41–4.12(m,16H),3.79–3.41(m,18H),2.72(q,J＝7.6Hz,4H),2.28–2.20(m,4H),2.06–1.23(m,50H,AcOH),0.98(d,J＝6.3Hz,3H),0.88–0.76(m,36H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.53(t, J=7.1Hz, 1H), 4.49-4.44(m, 1H), 4.41-4.12(m, 16H), 3.79 -3.41(m, 18H), 2.72(q, J=7.6Hz, 4H), 2.28-2.20(m, 4H), 2.06-1.23(m, 50H, AcOH), 0.98(d, J=6.3Hz, 3H) ),0.88–0.76(m,36H).

化合物48：Leu-Lys-Ser-Lys-Leu-Ala-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 48: Leu-Lys-Ser-Lys-Leu-Ala-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.52(q,J＝7.1Hz,2H),4.35–4.12(m,15H),3.79–3.56(m,9H),3.52–3.44(m,4H),2.76–2.65(m,5H),2.29–2.20(m,4H),2.07–1.23(m,40H,AcOH),1.18(d,J＝7.1Hz,3H),0.97(d,J＝6.3Hz,3H),0.88–0.73(m,36H). ¹ H NMR (600 MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.52 (q, J=7.1 Hz, 2H), 4.35-4.12 (m, 15H), 3.79-3.56 (m, 9H), 3.52 –3.44 (m, 4H), 2.76–2.65 (m, 5H), 2.29–2.20 (m, 4H), 2.07–1.23 (m, 40H, AcOH), 1.18 (d, J=7.1Hz, 3H), 0.97 (d, J=6.3Hz, 3H), 0.88–0.73 (m, 36H).

化合物49：Leu-Lys-Ser-Lys-Leu-Ala-Glu-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 49: Leu-Lys-Ser-Lys-Leu-Ala-Glu-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+DMSO-d ₆+TFA)δ4.54-4.47(m,1H),4.31–4.10(m,14H),3.95(dd,J＝6.4,4.4Hz,1H),3.78–3.56(m,7H),3.54–3.42(m,4H),2.85(s,1H),2.76–2.70(m,4H),2.69(s,1H),2.29–2.12(m,6H),2.07–1.23(m,43H,AcOH),1.18(d,J＝7.1Hz,3H),0.97(d,J＝6.3Hz,3H),0.86–0.74(m,36H). ¹ H NMR (600MHz, D ₂ O+DMSO-d ₆ +TFA) δ 4.54-4.47 (m, 1H), 4.31-4.10 (m, 14H), 3.95 (dd, J=6.4, 4.4Hz, 1H) ,3.78–3.56(m,7H),3.54–3.42(m,4H),2.85(s,1H),2.76–2.70(m,4H),2.69(s,1H),2.29–2.12(m,6H) , 2.07–1.23 (m, 43H, AcOH), 1.18 (d, J=7.1Hz, 3H), 0.97 (d, J=6.3Hz, 3H), 0.86–0.74 (m, 36H).

化合物50：Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 50: Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O+TFA)δ4.49–4.45(m,1H),4.31–4.18(m,5H),4.04(d,J＝8.2Hz,1H),3.99(d,J＝7.3Hz,1H),3.95(dd,J＝6.5,5.4Hz,1H),3.88(t,J＝7.4Hz,1H),3.82–3.72(m,4H),3.67–3.55(m,3H),3.48–3.42(m,1H),2.33–2.26(m,4H),2.14–1.70(m,15H,AcOH),1.58–1.31(m,5H),0.97(d,J＝ 6.4Hz,3H),0.77–0.69(m,24H). ¹ H NMR (600MHz, D ₂ O+TFA)δ4.49-4.45(m,1H),4.31-4.18(m,5H),4.04(d,J=8.2Hz,1H),3.99(d,J= 7.3Hz, 1H), 3.95 (dd, J=6.5, 5.4Hz, 1H), 3.88 (t, J=7.4Hz, 1H), 3.82–3.72 (m, 4H), 3.67–3.55 (m, 3H), 3.48–3.42 (m, 1H), 2.33–2.26 (m, 4H), 2.14–1.70 (m, 15H, AcOH), 1.58–1.31 (m, 5H), 0.97 (d, J=6.4Hz, 3H), 0.77–0.69 (m, 24H).

化合物51：Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Val-Gly-Gly-Glu-Glu(醋酸盐)Compound 51: Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Val-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₈₁H ₁₄₂N ₂₀O ₂₈；m/z：615.35313([M+3H] ³⁺)，922.52805([M+2H] ²⁺)，1844.05005([M+H] ⁺). High-resolution mass spectrometry (TOF-HRMS), molecular formula: C ₈₁ H ₁₄₂ N ₂₀ O ₂₈ ; m/z: 615.35313 ([M+3H] ³⁺ ), 922.52805 ([M+2H] ²⁺ ), 1844.05005 ([M] +H] ⁺ ).

化合物52：Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)高分辨质谱(TOF-HRMS)，分子式：C ₈₇H ₁₅₂N ₂₂O ₂₉；m/z：657.38043([M+3H] ³⁺)，1970.13025([M+H] ⁺). ¹H NMR(600MHz,D ₂O)δ4.64–4.53(m,6H),4.45–4.23(m,11H),4.16–4.08(m,4H),3.99–3.87(m,6H),3.85–3.69(m,6H),3.64–3.56(m,1H),2.97–2.92(m,6H),2.70–2.64(m,1H),2.61–2.54(m,1H),2.35–2.21(m,5H),2.12–1.73(m,23H,AcOH),1.73–1.49(m,20H),1.45–1.33(m,6H),1.12(d,J＝6.4Hz,3H),0.89–0.80(m,36H). Compound 52: Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate) high-resolution mass spectrometry (TOF -HRMS), molecular formula: C ₈₇ H ₁₅₂ N ₂₂ O ₂₉ ; m/z: 657.38043 ([M+3H] ³⁺ ), 1970.13025 ([M+H] ⁺ ). ¹ H NMR (600 MHz, D ₂ O) δ4.64–4.53 (m, 6H), 4.45–4.23 (m, 11H), 4.16–4.08 (m, 4H), 3.99–3.87 (m, 6H), 3.85–3.69 (m, 6H), 3.64–3.56 (m, 1H), 2.97–2.92 (m, 6H), 2.70–2.64 (m, 1H), 2.61–2.54 (m, 1H), 2.35–2.21 (m, 5H), 2.12–1.73 (m, 23H, AcOH), 1.73–1.49 (m, 20H), 1.45–1.33 (m, 6H), 1.12 (d, J=6.4Hz, 3H), 0.89–0.80 (m, 36H).

化合物53：Pro-Val-Pro-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 53: Pro-Val-Pro-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

¹H NMR(600MHz,D ₂O)δ4.62–4.53(m,6H),4.47–4.22(m,15H),4.16–4.08(m,4H),3.97–3.87(m,5H),3.86–3.69(m,7H),3.66–3.56(m,2H),3.42–3.29(m,2H),2.97–2.89(m,4H),2.70–2.64(m,1H),2.62–2.54(m,1H),2.44–2.18(m,7H),2.11–1.72(m,27H,AcOH),1.71–1.47(m,19H),1.43–1.31(m,4H),1.11(d,J＝6.4Hz,3H),0.95(d,J＝6.7Hz,3H),0.90–0.79(m,42H). ¹ H NMR (600MHz, D ₂ O)δ4.62-4.53(m,6H),4.47-4.22(m,15H),4.16-4.08(m,4H),3.97-3.87(m,5H),3.86- 3.69 (m, 7H), 3.66–3.56 (m, 2H), 3.42–3.29 (m, 2H), 2.97–2.89 (m, 4H), 2.70–2.64 (m, 1H), 2.62–2.54 (m, 1H) ), 2.44–2.18 (m, 7H), 2.11–1.72 (m, 27H, AcOH), 1.71–1.47 (m, 19H), 1.43–1.31 (m, 4H), 1.11 (d, J=6.4Hz, 3H) ),0.95(d,J=6.7Hz,3H),0.90–0.79(m,42H).

化合物54：Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(醋酸盐)Compound 54: Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₇₅H ₁₂₉N ₁₉O ₂₇；m/z：864.97732([M+2H] ²⁺)，1728.94810([M+H] ⁺). ¹H NMR(600MHz,D ₂O+CD ₃OD)δ4.61–4.48(m,5H),4.45–4.35(m,2H),4.32–4.22(m,5H),4.21–4.16(m,1H),4.12–4.04(m,4H),3.96(t,J＝6.7Hz,1H),3.92–3.64(m,11H),3.58–3.51(m,1H),2.90(q,J＝7.7Hz,4H),2.68–2.60(m,1H),2.59–2.52(m,1H),2.33–2.14(m,5H),2.06–1.28(m,40H,AcOH),1.07(d,J＝6.4Hz,3H),0.85–0.75(m,31H). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₇₅ H ₁₂₉ N ₁₉ O ₂₇ ; m/z: 864.97732 ([M+2H] ²⁺ ), 1728.94810 ([M+H] ⁺ ). ¹ H NMR (600MHz) ,D ₂ O+CD ₃ OD)δ4.61–4.48(m,5H),4.45–4.35(m,2H),4.32–4.22(m,5H),4.21–4.16(m,1H),4.12–4.04 (m, 4H), 3.96 (t, J=6.7Hz, 1H), 3.92–3.64 (m, 11H), 3.58–3.51 (m, 1H), 2.90 (q, J=7.7Hz, 4H), 2.68– 2.60 (m, 1H), 2.59–2.52 (m, 1H), 2.33–2.14 (m, 5H), 2.06–1.28 (m, 40H, AcOH), 1.07 (d, J=6.4Hz, 3H), 0.85– 0.75(m,31H).

化合物55：Leu-Lys-Ser-Lys-Leu-Gly-Asp(醋酸盐)Compound 55: Leu-Lys-Ser-Lys-Leu-Gly-Asp (acetate)

高分辨质谱(TOF-HRMS)，分子式：C ₃₃H ₆₁N ₉O ₁₁；m/z：380.73248([M+2H] ²⁺)，760.45776([M+H] ⁺). High resolution mass spectrometry (TOF-HRMS), molecular formula: C ₃₃ H ₆₁ N ₉ O ₁₁ ; m/z: 380.73248 ([M+2H] ²⁺ ), 760.45776 ([M+H] ⁺ ).

¹H NMR(600MHz,D ₂O)δ4.44–4.25(m,5H),4.01–3.93(m,2H),3.88–3.75(m,3H),2.94(q,J＝7.3Hz,4H),2.73–2.65(m,1H),2.62–2.53(m,1H),1.94(s,8H,AcOH),1.84–1.50(m,14H),1.46–1.31(m,4H),0.92–0.85(m,9H),0.82(d,J＝5.4Hz,3H). ¹ H NMR (600MHz, D ₂ O) δ 4.44-4.25 (m, 5H), 4.01-3.93 (m, 2H), 3.88-3.75 (m, 3H), 2.94 (q, J=7.3Hz, 4H) , 2.73–2.65 (m, 1H), 2.62–2.53 (m, 1H), 1.94 (s, 8H, AcOH), 1.84–1.50 (m, 14H), 1.46–1.31 (m, 4H), 0.92–0.85 ( m,9H),0.82(d,J＝5.4Hz,3H).

实施例2多肽化合物1及其相关多肽对HaCAT细胞增殖的促进作用Example 2 Promoting effect of polypeptide compound 1 and its related polypeptides on HaCAT cell proliferation

实验方法:将人永生化角质形成细胞(HaCaT细胞)浓度调整为1.0×10 ⁵～5.0×10 ⁵/mL进行传代培养，于37℃，5％CO ₂条件下培养24～36小时后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2.5×10 ⁴/mL接种于96孔细胞培养板中，每孔100μL，于37℃，5％CO ₂条件下培养过夜。再加入50μL用无血清培养基配制的不同浓度多肽化合物溶液，使待测多肽化合物终浓度为0.2ug/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。 Experimental method: The concentration of human immortalized keratinocytes (HaCaT cells) was adjusted to 1.0 × 10 ⁵ ～ 5.0 × 10 ⁵ /mL for subculture, and cultured at 37°C under 5% CO ₂ for 24 to 36 hours. Biological activity assay. Cells were digested with trypsin and collected, and inoculated into a 96-well cell culture plate with serum-free medium at a concentration of 2.5×10 ⁴ /mL, 100 μL per well, and cultured overnight at 37°C under 5% CO ₂ . Then add 50 μL of different concentrations of polypeptide compound solutions prepared in serum-free medium, so that the final concentration of the polypeptide compound to be tested is 0.2ug/mL; at the same time, set the EGF control group, that is, add 50 μL of recombinant human epidermal growth factor prepared in serum-free medium. (EGF) solution with a final concentration of 100ng/mL; model control group, that is, adding an equal volume of serum-free medium. Incubate at 37°C, 5% CO2 for 72 hours.

The kit was used to detect the proliferation of HaCaT cell line.

结果：试验结果统计分析见表4。多肽化合物1及其相关多肽促进HaCaT细胞增殖的效果具有强弱差异性。其中多肽H308无促增殖作用，而其它多肽都具有显著促增殖作用，说明多肽化合物1及其相关多肽在皮肤相关疾病方面具有潜在的应用价值。Results: The statistical analysis of the test results is shown in Table 4. The effect of polypeptide compound 1 and its related polypeptides on promoting the proliferation of HaCaT cells was different. Among them, the polypeptide H308 has no pro-proliferation effect, while other polypeptides have significant pro-proliferation effects, indicating that the polypeptide compound 1 and its related polypeptides have potential application value in skin-related diseases.

表4多肽对HaCaT细胞的促增殖作用Table 4 Proliferative effects of polypeptides on HaCaT cells

注：Note:

－表示无促增殖作用；- Indicates no proliferative effect;

以空白对照组的增殖率为100％计算，+代表增殖率为120～150％；++代表增殖率为150～200％；+++代表增殖率为200～250％；++++代表增殖率为250～300％Calculated based on the proliferation rate of the blank control group as 100%, + represents the proliferation rate of 120-150%; ++ represents the proliferation rate of 150-200%; +++ represents the proliferation rate of 200-250%; ++++ represents the proliferation rate The proliferation rate is 250 to 300%

实验例3多肽化合物1在急性机械损伤动物模型上的创面修复作用Experimental Example 3 The effect of polypeptide compound 1 on wound repair in an animal model of acute mechanical injury

将SPF级SD大鼠(体重180～230g)分别饲养于干净消毒笼内，每天定时给予水、饲料和更换垫料，保持饲养温度22℃，湿度55％～65％，饲养一周使其适应环境。大鼠用3％戊巴比妥钠腹腔注射麻醉成功后，剪去创口边缘1cm处毛发，先用碘伏消毒创口区，再用75％的酒精局部消毒创口区，于耳连线中间向背部下4cm近颈侧以脊柱为中线位制作1.5cm×1.5cm(即直径是1.5cm)圆形全层皮肤创口，深至肌层。用橡胶圈固定其周围皮肤，形成急性机械性损伤动物模型。造模后大鼠伤口暴露，单笼饲养。设置模型对照组(生理盐水)、EGF对照组(商品名：金因肽)、化合物1治疗组(高低剂量，浓度分别为2、0.4mg/mL)，每组6只。换药时均先用碘伏清创，再以无菌生理盐水冲洗创面并拭干。每日定时局部给药1次，于创面滴加35μL，持续给药14+天。SPF grade SD rats (body weight 180-230 g) were kept in clean and sterilized cages, given water, feed and bedding at regular intervals every day, keeping the raising temperature at 22°C and humidity at 55%-65%, and rearing for a week to make them adapt to the environment . After the rats were successfully anesthetized by intraperitoneal injection of 3% sodium pentobarbital, the hair at the edge of the wound was cut off 1 cm, and the wound area was first disinfected with iodophor, and then 75% alcohol was used to locally disinfect the wound area. A 1.5cm×1.5cm (that is, a diameter of 1.5cm) circular full-thickness skin incision was made with the spine as the midline on the 4cm proximal side of the neck, deep to the muscle layer. The surrounding skin was fixed with a rubber ring to form an animal model of acute mechanical injury. After modeling, the wounds of the rats were exposed, and they were kept in a single cage. The model control group (physiological saline), the EGF control group (trade name: Jinin peptide), and the compound 1 treatment group (high and low doses, 2 and 0.4 mg/mL, respectively) were set, with 6 animals in each group. When changing dressings, debridement with iodophor was used first, and then the wound surface was rinsed with sterile saline and wiped dry. Local administration was administered once a day, and 35 μL was dripped onto the wound surface for 14+ days.

每天进行1次体重监测以及创面观察(包括创面有无红肿、渗出液及有无感染，创口收缩、表面结痂、新生表皮的情况)。得到结果如下：Body weight monitoring and wound surface observation (including whether there is redness, swelling, exudate, infection, wound shrinkage, surface crusting, and new epidermis on the wound surface) were performed once a day. The result is as follows:

(1)本研究过程对大鼠体重进行定期监测，结果显示大鼠的体重处于正常生长的状态，各组别的大鼠体重无显著差异性。(1) During this study, the body weight of the rats was regularly monitored, and the results showed that the body weight of the rats was in a state of normal growth, and there was no significant difference in the body weight of the rats in each group.

(2)在建模后的第0、10、14天，摄取每组大鼠的创面图像，采用图像分析软件(Image J)计算创面面积，根据公式，进而得出创面愈合率。最后用统计分析软件分析各组愈合率有无统计学意义。创面愈合率结果如表5所示。(2) On the 0th, 10th, and 14th days after modeling, the wound images of each group of rats were taken, and the wound area was calculated by image analysis software (Image J), and the wound healing rate was obtained according to the formula. Finally, statistical analysis software was used to analyze whether the healing rate of each group was statistically significant. The results of wound healing rate are shown in Table 5.

表5创面愈合率(％)Table 5 Wound healing rate (%)

组别group	给药第0天Dosing Day 0	给药第10天Dosing day 10	给药第14天Dosing day 14
模型对照组model control group	0.00±0.000.00±0.00	13.51±7.2013.51±7.20	61.96±7.5561.96±7.55
EGF对照组EGF control group	0.00±0.000.00±0.00	26.52±9.4626.52±9.46	72.88±2.6372.88±2.63
化合物1低剂量组Compound 1 low dose group	0.00±0.000.00±0.00	35.99±2.4735.99±2.47	73.79±6.5173.79±6.51
化合物1高剂量组Compound 1 high dose group	0.00±0.000.00±0.00	35.60±6.5435.60±6.54	84.20±1.0084.20±1.00

注：*表示与模型对照组相对，P<0.05Note: * means relative to the model control group, P<0.05

表5结果显示与模型对照组相比，多肽化合物1的高剂量组具有显著促创面愈合的效果(P<0.05)。The results in Table 5 show that compared with the model control group, the high-dose group of polypeptide compound 1 has a significant effect of promoting wound healing (P<0.05).

实施例4新多肽化合物1对小鼠皮肤创伤的修复作用Example 4 The repairing effect of the new polypeptide compound 1 on skin wounds in mice

试验方法：选取60只8～10周雄性昆明小鼠(购自北京斯贝福生物技术有限公司)分笼饲养，自由取食，试验前一天停止进食。用0.2ml质量分数1％戊巴比妥钠腹腔注射麻醉小鼠，背部剪毛，脊柱表皮皮肤上下对称开0.5cm*0.5cm正方形伤口，剪去全层皮肤，勿伤及肌肉层，伤口止血备用。次日，用***麻醉小鼠，伤口处滴加不同溶液浓度的化合物1(0.15mg/ml或0.30mg/ml)、生理盐水和康复新液各0.1ml，每日换药一次，在4、7、11天观察创面愈合情况。按照公示计算创面愈合率：创面愈合率(％)＝(原始创面面积-未愈合创面面积)/原始创面面积。结果见表6。Test method: 60 8-10 week old male Kunming mice (purchased from Beijing Speifu Biotechnology Co., Ltd.) were selected and raised in separate cages and fed freely, and stopped eating one day before the test. The mice were anesthetized by intraperitoneal injection of 0.2 ml of 1% pentobarbital sodium, the back was sheared, and a 0.5cm*0.5cm square wound was opened symmetrically up and down the epidermis of the spine. . The next day, the mice were anesthetized with ether, and compound 1 (0.15mg/ml or 0.30mg/ml) of different solution concentrations, 0.1ml of normal saline and 0.1ml of Kangfuxin solution were added dropwise to the wound, and the dressings were changed once a day. 7, 11 days to observe the wound healing. Calculate the wound healing rate according to the announcement: wound healing rate (%)=(original wound area-unhealed wound area)/original wound area. The results are shown in Table 6.

表6小鼠创伤愈合率统计结果Table 6 Statistical results of wound healing rate in mice

注：与模型组相比，*P<0.05有显著性差异Note: Compared with the model group, *P<0.05 has a significant difference

试验结果表明，新多肽化合物1能够明显促进小鼠皮肤创伤的愈合，与对照组比较具有显著性差异，且优于康复新液。The test results show that the new polypeptide compound 1 can significantly promote the healing of skin wounds in mice, which has a significant difference compared with the control group, and is better than Kangfuxin Liquid.

实施例5：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Example 5: Anti-ulcer effect of some polypeptide samples obtained in Example 1 on ethanol-induced gastric ulcer model in mice

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)2020-0341. Experimental animal: SPF grade C57BL/6 mice, Chengdu Yaokang Biotechnology Co., Ltd., animal license number: SCXK (Chuan) 2020-034

2、方法：2. Method:

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、替普瑞酮组10只、各多肽化合物给药组10只，除空白组及模型组灌胃给予纯化水以外，替普瑞酮组按照160mg/kg灌胃，多肽给药组均按照0.2mg/kg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，并拍摄胃全景照片。After the experimental animals were adaptively fed, all animals began to fast for 24 hours after the drug was administered one day before the experiment. Before modeling, the experimental mice were randomly divided into 5 groups: 5 mice in the blank group, 10 mice in the model group, 10 mice in the teprenone group, and 10 mice in each polypeptide compound administration group. The prednone group was given 160 mg/kg by intragastric administration, and the polypeptide administration group was given different test samples by intragastric administration at 0.2 mg/kg. Absolute ethanol was used for modeling, and the animals were sacrificed by de-neck method after 1 h, the gastric cardia was ligated and the pylorus was clipped, and the whole stomach was extracted. 1 mL of 1% formaldehyde solution was injected into the stomach, the cardia was ligated, and the stomach was taken out and put into 1% formaldehyde solution. After soaking for 30 minutes, the gastric tissue was taken out, cut along the greater curvature of the stomach, and the gastric contents were rinsed with normal saline. After flattening, the gastric mucosal damage of the mice was observed and measured, the ulcer index and the ulcer inhibition rate were calculated, and panoramic photos of the stomach were taken.

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。Ulcer index calculation method: If the length of the cord-like injury is greater than 1mm, the length is measured, and each millimeter is counted as 1 point; if the width is greater than 1mm, the score will be doubled according to the number of millimeters of the width; if the length is less than 1mm, 0.5 points will be scored. Addition gives the animal's ulcer index.

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％；Ulcer inhibition rate %=(Ulcer index in model group-Ulcer index in drug administration group)/Ulcer index in model group×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)。Relative ulcer inhibition rate=(Ulcer inhibition rate of test compound)/(Ulcer inhibition rate of compound 1).

3、结果：表7示出了本发明化合物的相对溃疡抑制率：3. Results: Table 7 shows the relative ulcer inhibition rates of the compounds of the present invention:

表7本发明化合物的相对溃疡抑制率Table 7 Relative ulcer inhibition rate of the compounds of the present invention

*注释：*Note:

系列化合物的抗溃疡作用经多批试验完成，为便于比较活性以相对溃疡抑制率表示。The anti-ulcer effect of the series of compounds has been completed by several batches of tests, and the relative activity is expressed as the relative ulcer inhibition rate for the convenience of comparison.

溃疡指数高于模型组的为阴性，表示为“-”；溃疡指数低于模型组的为阳性，表示为“+”。The ulcer index higher than the model group is negative, indicated as "-"; the ulcer index lower than the model group is positive, indicated as "+".

每批试验都以化合物1作为对照组，设化合物1的相对溃疡抑制率为1，表示为“+++”；Compound 1 was used as the control group for each batch of experiments, and the relative ulcer inhibition rate of compound 1 was set to 1, denoted as "+++";

相对溃疡抑制率>1.20，表示为“++++”；Relative ulcer inhibition rate>1.20, expressed as "++++";

相对溃疡抑制率为0.9-1.20，表示为“+++”；The relative ulcer inhibition rate was 0.9-1.20, expressed as "+++";

相对溃疡抑制率为0.6–0.9，表示为“++”；The relative ulcer inhibition rate was 0.6–0.9, denoted as "++";

相对溃疡抑制率为0.3–0.6，表示为“+”；The relative ulcer inhibition rate was 0.3–0.6, denoted as "+";

相对溃疡抑制率<0.3，表示为“/”(极低活性)。Relative ulcer inhibition rate < 0.3, expressed as "/" (very low activity).

实施例6新多肽化合物1对大鼠应激性胃溃疡的治疗作用Example 6 Therapeutic effect of new polypeptide compound 1 on stress gastric ulcer in rats

试验方法：选取75只体重180～210g雄性SD大鼠(购自北京斯贝福生物技术有限公司)，分笼适应性饲养1周后，随机分空白组、模型组、硫糖铝组(1g/kg，阳性药组)、化合物1低剂量组(1.5mg/kg)和高剂量组(3.0mg/kg)。给药组灌胃给药。造模前一天禁食不禁水，除对照组外，采用束缚水浸法造模，将各组大鼠固定于鼠板，头向上垂直浸泡在温度为20℃的恒温水槽中8小时，水面与大鼠剑突齐平。应激造模结束后，将大鼠颈椎脱臼处死，剖腹，结扎幽门。向胃内灌注2ml体积分数为10％甲醛溶液，结扎贲门，取出胃体至于甲醛溶液中固定15分钟。沿胃大弯剪开，生理盐水冲洗后展开，观察胃黏膜损失并计算胃溃疡指数。按照Guth标准计算溃疡指数(UI)：点状出血计为1分，线状出血长度<1mm为2分，2～4mm为4分，>4mm为5分，宽度>1mm时分值*2。结果见表8。Test method: 75 male SD rats weighing 180-210 g (purchased from Beijing Speifu Biotechnology Co., Ltd.) were selected, and after 1 week of adaptive feeding in separate cages, they were randomly divided into blank group, model group, and sucralfate group (1 g /kg, positive drug group), compound 1 low dose group (1.5 mg/kg) and high dose group (3.0 mg/kg). The administration group was given intragastric administration. One day before the modeling, the rats were fasted and watered. Except for the control group, the model was established by the bound water immersion method. The rats in each group were fixed on the rat board and immersed in a constant temperature water tank with a temperature of 20 °C for 8 hours. The rat xiphoid process is flush. After stress modeling, the rats were sacrificed by cervical dislocation, laparotomy, and pylorus ligation. 2 ml of 10% formaldehyde solution was perfused into the stomach, the cardia was ligated, and the gastric body was taken out and fixed in formaldehyde solution for 15 minutes. It was cut along the greater curvature of the stomach, washed with normal saline, and unfolded to observe the loss of gastric mucosa and calculate the gastric ulcer index. The ulcer index (UI) was calculated according to the Guth standard: 1 point for spot bleeding, 2 points for linear bleeding length <1 mm, 4 points for 2-4 mm, 5 points for > 4 mm, and 2 points for width > 1 mm. The results are shown in Table 8.

表8大鼠胃溃疡指数统计结果Table 8 Statistical results of gastric ulcer index in rats

注：与模型组相比，*P<0.01有显著性差异Note: Compared with the model group, *P<0.01 has a significant difference

试验结果表明，新多肽化合物1对大鼠应激性胃溃疡具有明显的保护作用，与模型组比较具有显著性差异，其保护效果优于阳性药硫糖铝。The test results show that the new polypeptide compound 1 has obvious protective effect on stress gastric ulcer in rats, and there is a significant difference compared with the model group, and its protective effect is better than that of the positive drug sucralfate.

实施例7部分多肽样品的胃、肠稳定性试验和消毒剂处理后稳定性Example 7 Gastric and intestinal stability test of some polypeptide samples and stability after disinfectant treatment

方法：取待测样品(化合物1、化合物2、化合物3、化合物5、化合物18、化合物19及对照品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。Method: Take 1 mg of each sample to be tested (compound 1, compound 2, compound 3, compound 5, compound 18, compound 19 and reference substance EGF)), add 1 ml of water to dissolve. Take 100ul of the sample solution, add 900ul of water, mix well, and use it as the reference solution. Take 100ul of each sample solution, add artificial gastric juice (W), artificial intestinal juice (X), povidone-iodine solution (I), hydrogen peroxide solution (O) 900ul, 37 ° C constant temperature water bath for 1 hour, let cool, filter , as the test solution, the peak areas of the samples before and after the treatment were detected by high performance liquid chromatography, and the test results were calculated by comparing the peak areas of the samples. Take the stock solution without any treatment after dilution with water as the control, and compare and count the changes of the peak area (content) at the corresponding position of the other test solutions.

表9多肽样品的胃、肠,体外消毒剂处理后稳定性试验Stomach and intestine of table 9 polypeptide samples, stability test after in vitro disinfectant treatment

编号serial number	W保留％W reserved %	X保留％X Reserved %	I保留％I reserved %	O保留％O Reserved %
EGFEGF	00	00	00	00
化合物1Compound 1	00	00	106106	104104
化合物2Compound 2	00	5656	9999	9999
化合物3Compound 3	00	6363	101101	9999

化合物5Compound 5	9999	100100	9898	100100
化合物18Compound 18	9999	100100	9999	100100
化合物19Compound 19	101101	100100	9999	9898

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Note: W stands for artificial gastric juice, X stands for artificial intestinal fluid, I stands for povidone-iodine solution, and O stands for hydrogen peroxide solution

结果：如表9所示，供试品化合物1、2、3、5、18、19的样品在聚维酮碘溶液(I)和过氧化氢溶液(O)都100％保留，说明可以和消毒剂共同使用，消毒处理后很稳定；化合物5、18、19对人工胃液(W)、人工肠液(X)也稳定，化合物2、3对人工肠液(X)也有一定的稳定性；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。Results: As shown in Table 9, the samples of the test compounds 1, 2, 3, 5, 18, and 19 were 100% retained in the povidone-iodine solution (I) and the hydrogen peroxide solution (O), indicating that they can be combined with Disinfectants are used together and are very stable after disinfection; compounds 5, 18, and 19 are also stable to artificial gastric juice (W) and artificial intestinal juice (X), and compounds 2 and 3 are also stable to artificial intestinal juice (X). There is no retention in gastric juice and intestinal juice, indicating that it is not stable in gastric juice and intestinal juice, and povidone-iodine solution and hydrogen peroxide solution will be destroyed after applying EGF for external use.

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。Although the present invention discloses the above-mentioned embodiments, the embodiments of the present invention are not limited to the above-mentioned embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the present invention shall be equivalent substitutions including within the protection scope of the present invention.

Claims

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：A compound of formula (I) or a physiologically compatible salt thereof, wherein said compound of formula (I) is as follows:

H-X _aa1-X _aa2-X _aa3-X _aa4-X _aa5-X _aa6-X _aa7-X _aa8-X _aa9-X _aa10-X _aa11-Val-Thr-Val-Ser-X _aa12-X _aa13-X _aa14-X _aa15-X _aa16-X _aa17-OH HX _aa1 -X _aa2 -X _aa3 -X _aa4 -X _aa5 -X _aa6 -X _aa7 -X _aa8 -X _aa9 -X _aa10 -X _aa11 -Val-Thr-Val-Ser-X _aa12 -X _aa13 -X _aa14 - X _aa15 -X _aa16 -X _aa17 -OH

其中in

X _aa1为Pro或缺失； X _aa1 is Pro or missing;

X _aa2为Val或缺失； X _aa2 is Val or missing;

X _aa3为Lys、Pro或缺失； X _aa3 is Lys, Pro or missing;

X _aa4为Leu、Val、Ala或缺失； X _aa4 is Leu, Val, Ala or missing;

X _aa5为Lys、Arg或缺失； X _aa5 is Lys, Arg or missing;

X _aa6为Ser、Thr、Ala或缺失； X _aa6 is Ser, Thr, Ala or missing;

X _aa7为Lys、Arg或缺失； X _aa7 is Lys, Arg or missing;

X _aa8为Leu、Val、Ala、Ile或缺失； X _aa8 is Leu, Val, Ala, Ile or missing;

X _aa9为Gly、Pro、Ala或缺失； X _aa9 is Gly, Pro, Ala or missing;

X _aa10为Asp、Glu、Asn、Val或缺失； X _aa10 is Asp, Glu, Asn, Val or missing;

X _aa11为Leu、Val、Ala、Ile、Pro或缺失； X _aa11 is Leu, Val, Ala, Ile, Pro or missing;

X _aa12为Leu、Val、Ala或缺失； X _aa12 is Leu, Val, Ala or missing;

X _aa13为Pro、Ala、Gly、Val或缺失； X _aa13 is Pro, Ala, Gly, Val or missing;

X _aa14为Gly、Ala或缺失； X _aa14 is Gly, Ala or missing;

X _aa15为Gly、Ala或缺失； X _aa15 is Gly, Ala or missing;

X _aa16为Glu、Gln、Asp或缺失； X _aa16 is Glu, Gln, Asp or missing;

X _aa17为Glu、Asp、Gln或缺失。 X _aa17 is Glu, Asp, Gln or missing.
权利要求1的化合物或其生理学上相容的盐，其中X _aa1缺失。 8. The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa1 is deleted.
权利要求1的化合物或其生理学上相容的盐，其中X _aa2缺失。 8. The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa2 is deleted.
权利要求1的化合物或其生理学上相容的盐，其中X _aa1和X _aa2均缺失。 8. The compound of claim 1, or a physiologically compatible salt thereof, wherein both X _aa1 and X _aa2 are deleted.
权利要求1的化合物或其生理学上相容的盐，其中X _aa4-X _aa5-X _aa6-X _aa7为Leu-Lys-Ser-Lys。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa4 -X _aa5 -X _{aa6-X aa7} _is Leu-Lys-Ser-Lys.
权利要求1的化合物或其生理学上相容的盐，其中X _aa4-X _aa5-X _aa6-X _aa7-X _aa8为Leu-Lys-Ser-Lys-Leu或Lys-Ser-Lys-Leu，其中X _aa4缺失。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa4 - _Xaa5 - _Xaa6 - _Xaa7 - _Xaa8 is Leu-Lys-Ser-Lys-Leu or Lys-Ser-Lys-Leu, wherein X _aa4 is missing.
权利要求1的化合物或其生理学上相容的盐，其中X _aa9-X _aa10为Gly-Asp。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa9 -X _aa10 is Gly-Asp.
权利要求1的化合物或其生理学上相容的盐，其中X _aa9-X _aa10-X _aa11为Gly-Asp-Leu。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa9 -X _aa10 -X _aa11 is Gly-Asp-Leu.
权利要求1的化合物或其生理学上相容的盐，其中X _aa9-X _aa10-X _aa11为Gly-Asp-Val、 Gly-Asp-Ala或Gly-Asp-Ile。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa9 -X _aa10 -X _aa11 is Gly-Asp-Val, Gly-Asp-Ala or Gly-Asp-Ile.
权利要求1的化合物或其生理学上相容的盐，其中X _aa12为Leu、Val或Ala，优选为Leu。 The compound of claim 1 or a physiologically compatible salt thereof, wherein X _aa12 is Leu, Val or Ala, preferably Leu.
权利要求1的化合物或其生理学上相容的盐，其中X _aa13-X _aa14为Pro-Gly。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa13 -X _aa14 is Pro-Gly.
权利要求1的化合物或其生理学上相容的盐，其中X _aa13-X _aa14-X _aa15为Pro-Gly-Gly。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa13 -X _aa14 -X _aa15 is Pro-Gly-Gly.
权利要求1的化合物或其生理学上相容的盐，其中X _aa13-X _aa14-X _aa15-X _aa16-X _aa17为Pro-Gly-Gly-Glu-Glu。 The compound of claim 1, or a physiologically compatible salt thereof, wherein X _aa13 - _Xaa14 - _Xaa15 - _Xaa16 - _Xaa17 is Pro-Gly-Gly-Glu-Glu.
权利要求1的化合物或其生理学上相容的盐，其中X _aa13-X _aa14-X _aa15-X _aa16-X _aa17为Ala-Gly-Gly-Glu-Glu、Gly-Gly-Gly-Glu-Glu、Pro-Gly-Gly-Glu-Asp、Pro-Gly-Gly-Gln-Glu、Pro-Gly-Gly-Glu-Gln、Pro-Gly-Gly-Asp-Asp、Pro-Ala-Ala-Asp-Asp、Val-Gly-Gly-Glu-Glu或Pro-Ala-Ala-Gln-Gln。 The compound of claim 1 or a physiologically compatible salt thereof, wherein X _aa13 - _Xaa14 - _Xaa15 - _Xaa16 - _Xaa17 is Ala-Gly-Gly-Glu-Glu, Gly-Gly-Gly-Glu-Glu, Pro-Gly-Gly-Glu-Asp, Pro-Gly-Gly-Gln-Glu, Pro-Gly-Gly-Glu-Gln, Pro-Gly-Gly-Asp-Asp, Pro-Ala-Ala-Asp-Asp, Val-Gly-Gly-Glu-Glu or Pro-Ala-Ala-Gln-Gln.
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：The compound of claim 1, or a physiologically compatible salt thereof, wherein the compound is selected from the group consisting of:

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物1)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 1)

Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物2)Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 2)

Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物3)Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 3)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu(化合物4)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu (Compound 4)

Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物5)Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 5)

Leu-Pro-Gly-Gly-Glu-Glu(化合物6)Leu-Pro-Gly-Gly-Glu-Glu (Compound 6)

Pro-Gly-Gly-Glu-Glu(化合物7)Pro-Gly-Gly-Glu-Glu (Compound 7)

Val-Thr-Val-Ser(化合物8)Val-Thr-Val-Ser (Compound 8)

Gly-Asp-Leu(化合物9)Gly-Asp-Leu (Compound 9)

Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu(化合物10)Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu (Compound 10)

Gly-Asp-Leu-Val-Thr-Val-Ser-Leu(化合物11)Gly-Asp-Leu-Val-Thr-Val-Ser-Leu (Compound 11)

Val-Thr-Val-Ser-Leu-Pro(化合物12)Val-Thr-Val-Ser-Leu-Pro (Compound 12)

Val-Thr-Val-Ser-Leu(化合物13)Val-Thr-Val-Ser-Leu (Compound 13)

Leu-Gly-Asp-Leu(化合物14)Leu-Gly-Asp-Leu (Compound 14)

Leu-Gly-Asp(化合物15)Leu-Gly-Asp (Compound 15)

Leu-Lys-Ser-Lys(化合物16)Leu-Lys-Ser-Lys (Compound 16)

Leu-Lys-Ser-Lys-Leu(化合物17)Leu-Lys-Ser-Lys-Leu (Compound 17)

Val-Thr-Val-Ser-Val-Pro-Gly-Gly-Glu-Glu(化合物18)Val-Thr-Val-Ser-Val-Pro-Gly-Gly-Glu-Glu (Compound 18)

Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(化合物19)Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu (Compound 19)

Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu(化合物20)Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu (Compound 20)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物21)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 21)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物22)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 22)

Leu-Lys-Ser-Lys-Val-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物23)Leu-Lys-Ser-Lys-Val-Gly-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 23)

Leu-Lys-Ser-Lys-Ala-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物24)Leu-Lys-Ser-Lys-Ala-Gly-Asp-Ala-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 24)

Leu-Lys-Ser-Lys-Ile-Gly-Asp-Ile-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物25)Leu-Lys-Ser-Lys-Ile-Gly-Asp-Ile-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 25)

Leu-Arg-Ser-Arg-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物26)Leu-Arg-Ser-Arg-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 26)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu(化合物27)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Ala-Gly-Gly-Glu-Glu (Compound 27)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Gly-Gly-Gly-Glu-Glu(化合物28)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Gly-Gly-Gly-Glu-Glu (Compound 28)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Ala-Gly-Gly-Glu-Glu(化合物29)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Ala-Gly-Gly-Glu-Glu (Compound 29)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Asp(化合物30)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Asp (Compound 30)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Gln-Glu(化合物31)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Gln-Glu (Compound 31)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Gln(化合物32)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Gln (Compound 32)

Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly(化合物33)Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly (Compound 33)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly(化合物34)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly (Compound 34)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly(化合物35)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly (Compound 35)

Leu-Lys-Ser-Lys-Leu-Gly-Glu-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物36)Leu-Lys-Ser-Lys-Leu-Gly-Glu-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 36)

Leu-Lys-Ser-Lys-Leu-Gly-Asn-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物37)Leu-Lys-Ser-Lys-Leu-Gly-Asn-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 37)

Leu-Lys-Ser-Lys-Leu-Pro-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物38)Leu-Lys-Ser-Lys-Leu-Pro-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 38)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu(化合物39)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Ala-Pro-Gly-Gly-Glu-Glu (Compound 39)

Val-Lys-Thr-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物40)Val-Lys-Thr-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 40)

Val-Lys-Thr-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物41)Val-Lys-Thr-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 41)

Ala-Lys-Ala-Lys-Ala-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物42)Ala-Lys-Ala-Lys-Ala-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 42)

Val-Lys-Ala-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物43)Val-Lys-Ala-Lys-Val-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 43)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Asp-Asp(化合物44)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Asp-Asp (Compound 44)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Asp-Asp(化合物45)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Asp-Asp (Compound 45)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Gln-Gln(化合物46)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Ala-Ala-Gln-Gln (Compound 46)

Leu-Lys-Ser-Lys-Leu-Pro-Val-Pro-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物47)Leu-Lys-Ser-Lys-Leu-Pro-Val-Pro-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 47)

Leu-Lys-Ser-Lys-Leu-Ala-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物48)Leu-Lys-Ser-Lys-Leu-Ala-Asp-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 48)

Leu-Lys-Ser-Lys-Leu-Ala-Glu-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物49)Leu-Lys-Ser-Lys-Leu-Ala-Glu-Val-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 49)

Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物50)Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 50)

Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Val-Gly-Gly-Glu-Glu(化合物51)Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Val-Gly-Gly-Glu-Glu (Compound 51)

Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物52)Lys-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 52)

Pro-Val-Pro-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物53)Pro-Val-Pro-Leu-Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 53)

Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu(化合物54)Lys-Ser-Lys-Leu-Gly-Asp-Leu-Val-Thr-Val-Ser-Leu-Pro-Gly-Gly-Glu-Glu (Compound 54)

Leu-Lys-Ser-Lys-Leu-Gly-Asp(化合物55)。Leu-Lys-Ser-Lys-Leu-Gly-Asp (compound 55).
权利要求1-15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。15. Use of a compound of any one of claims 1 to 15, or a physiologically compatible salt thereof, in the manufacture of a medicament for repairing skin wounds or mucosal damage.
根据权利要求16的用途，其中所述的黏膜损伤是消化***、呼吸***的腔道内黏膜损伤。The use according to claim 16, wherein the mucosal damage is mucosal damage in the lumen of the digestive system and the respiratory system.
权利要求16的用途，其中所述消化***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；所述食道疾病包括食管炎、食管溃疡；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***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的疾病相关。The purposes of claim 16, wherein the mucosal damage of the digestive system is related to oral cavity, esophagus, gastrointestinal diseases, the oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis; The esophageal diseases include esophagitis, esophagitis Ulcers; the gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcers, functional gastrointestinal diseases, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastric Esophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease and mucosal damage caused by radiotherapy and chemotherapy; the skin wounds and epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, bedsores, Disease associated with chemotherapy-induced skin damage.
权利要求18的用途，其中所述消化***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。The use of claim 18, wherein the mucosal damage of the digestive system is mucosal damage caused by an irritant substance or drug or by a stress state.
权利要求1-15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。Use of a compound according to any one of claims 1 to 15 or a physiologically compatible salt thereof in the manufacture of a medicament for preventing, alleviating or treating gastrointestinal diseases or eliminating inflammation and edema.
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1-15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。A pharmaceutical, food, health care product or cosmetic, daily chemical composition, said composition comprising the compound of any one of claims 1-15 or a physiologically compatible salt thereof and a physiologically acceptable carrier.