Polypeptides and their use in repairing mucosal or skin lesions

Abstract

This invention relates to polypeptides and their applications in repairing mucosal or skin damage. The polypeptides of this invention are not homologous to known polypeptides and can exist stably both in vivo and in vitro, and have the effect of regulating stem cell proliferation and differentiation to repair mucosal or skin damage; as well as the use of the novel polypeptides in repairing mucosal or skin damage by regulating stem cell proliferation and differentiation, and their use in preventing, alleviating or treating gastrointestinal diseases.

Description

Technical Field

[0001] This invention relates to polypeptides and their applications in repairing mucosal or skin damage. The polypeptides of this invention are not homologous to known polypeptides and can exist stably both in vivo and in vitro. They have the effect of regulating stem cell proliferation and differentiation, repairing mucosal or skin damage, and the use of the novel polypeptides in repairing mucosal or skin damage by regulating stem cell proliferation and differentiation, as well as their use in preventing, alleviating or treating gastrointestinal diseases. Background Technology

[0002] Skin injury and / or mucosal injury are common pathological features of many diseases. Skin injury refers to damage to normal skin (tissue) caused by external traumatic factors such as surgery, external force, heat, electric current, chemicals, and low temperature, as well as internal factors such as local blood supply disorders. Skin injury is often accompanied by the disruption of skin integrity and the loss of a certain amount of normal tissue, while the normal function of the skin is impaired. It is also called a wound or trauma. Currently, protein / peptide drugs, including basic fibroblast growth factor, epidermal growth factor, platelet-derived growth factor, granulocyte-macrophage colony-stimulating factor, and growth hormone, have significant effects on wound repair, skin care, anti-wrinkle, and anti-aging. However, the long amino acid sequences of these protein / peptide drugs lead to high preparation costs and poor stability, thus limiting their application.

[0003] Human mucosa refers to the inner layer of cavities or sac-like muscular organs such as the respiratory system, digestive system, and reproductive and urinary system. It is the second largest barrier in the human body after the skin. It includes the oral cavity, pharynx, trachea, esophagus, stomach, intestines, vagina, bladder, etc. The walls or sac walls of these organs have common layering patterns and characteristics adapted to their functions. Their embryonic origin, tissue structure, pathological process, clinical manifestations, and prognosis all have common characteristics.

[0004] Chronic gastritis is a chronic inflammation of the gastric mucosa, a common and frequently occurring disease in gastroenterology. Clinically, chronic gastritis refers to chronic inflammation of the gastric mucosa (pathologically manifested as mononuclear cell and lymphocyte infiltration) and / or glandular atrophy caused by different reasons. Chronic atrophic gastritis (CAG), characterized by atrophy of the gastric mucosal epithelium and glands, has an insidious onset, long course, nonspecific symptoms, and is difficult to cure. It accounts for 11% to 31% of chronic gastritis cases, and is more common in middle-aged and elderly people. The onset is related to age but not to gender. It has a slow onset and a protracted course, making it difficult to cure and challenging to treat. Chronic atrophic gastritis is an important stage in the development of gastric cancer and is considered a precancerous lesion. In 1978, the World Health Organization (WHO) listed CAG as a precancerous condition. It is often accompanied by pseudopyloric gland metaplasia and intestinal metaplasia, or atypical hyperplasia, among other precancerous lesions. Especially in cases accompanied by diffuse intestinal metaplasia or dysplasia, the likelihood of cancerous transformation is higher. Most professionals in the field agree that the progression follows a pattern of chronic superficial gastritis, atrophic gastritis, intestinal metaplasia, dysplasia, and intestinal-type gastric cancer. Therefore, early and accurate diagnosis and treatment are of great significance for patients with chronic atrophic gastritis. Currently, modern medical treatment for this disease mainly focuses on symptom relief and surgical intervention; there are no effective solutions for glandular atrophy and intestinal metaplasia. CAG is a crucial stage in the transformation of chronic gastritis into gastric cancer, and actively treating CAG has profound significance in preventing its cancerous transformation and reducing the incidence of gastric cancer. Seeking effective treatments for atrophic gastritis is one of the important measures for better gastric cancer prevention.

[0005] Damage to mucosal tissues can clinically lead to gastrointestinal diseases such as chronic gastritis and peptic ulcers. Mucosal epithelial repair involves two distinct mechanisms: restitution and regeneration (Cur. Med. Chem., 2008, 15, 3133-3144). Restitution or recovery generally begins within minutes of injury, rapidly repairing superficial lesions through cell migration; regeneration, on the other hand, involves continuous regeneration through the differentiation and proliferation of stem cells and progenitor cells, lasting from several days to several months.

[0006] Therefore, there is a need for peptides that are stable both in vivo and in vitro and can treat skin and / or mucosal injuries, especially gastrointestinal mucosal injuries. Summary of the Invention

[0007] In order to overcome the shortcomings and defects of the prior art, the purpose of this invention is to provide a new type of polypeptide.

[0008] In a first aspect, the present invention provides compounds of formula (I) or physiologically compatible salts thereof, wherein the compounds of formula (I) are as follows:

[0009] H-Xaa1-Xaa2-Xaa3-Xaa4-Xaa5-Xaa6-Xaa7-Xaa8-Ala-Ala-Glu-Pro-Val-Pro-Leu -Xaa9-Xaa 10 -Xaa 11 -Xaa 12 -Xaa 13 -Xaa 14 -Xaa 15 -Xaa 16 -Xaa 17 -Xaa 18 -Xaa 19 -Xaa 20 -Xaa 21 -Xaa 22 -Xaa 23 -Xaa 24 -Xaa 25 -OH (I)

[0010] in

[0011] Xaa1 is either Ala or missing;

[0012] Xaa2 is either Ala or missing;

[0013] Xaa3 is Ala, Arg, Glu, or absent;

[0014] Xaa4 is Pro, Lys, Ala, or missing;

[0015] Xaa5 is Glu, Val, Asp, Gln, Lys, Ala, Pro or missing;

[0016] Xaa6 is Pro, Gln, Lys, Val, Ala, or missing;

[0017] Xaa7 is Ala, Leu, Gly, Lys, Gln, Glu, Val, Asp, Pro, Tyr or missing;

[0018] Xaa8 is Pro, Leu, Lys, Glu, Gly, Ile, Leu, Val, Gly, Ala or missing;

[0019] Xaa9-Xaa 10 -Xaa 11 For Val-Lys-Gln, Ala-Gly-Leu, Ala-Ala-Val, Val-Pro-Ala;

[0020] Xaa 12 For Asp, Ala, Gln, Lys, Glu, Ala or missing;

[0021] Xaa 13 For Ala, Leu, Gly, Lys, Gln, Asp, Cys, Glu or missing;

[0022] Xaa 14 Ala, Leu, Val, Pro, Gly, Glu or missing;

[0023] Xaa 15 -Xaa 16 For Gly-Leu, Pro-Leu, Val-Pro, Pro-Leu, Ala-Glu, Ala-Ala, Val-Pro, Cys-Gly or missing;

[0024] Xaa 17 For Asp, Leu, Pro, Glu, or missing;

[0025] Xaa 18 -Xaa 19 -Xaa 20 -Xaa 21 Val-Lys-Gln-Asp, Pro-Val-Pro-Leu, Val-Pro-Leu-Val, or missing;

[0026] Xaa 22 -Xaa 23 -Xaa 24 For Lys-Gln-Asp, Val-Lys-Gln, or missing;

[0027] and Xaa 25 For ASP or missing;

[0028] The compound is at least 10 peptides.

[0029] In one embodiment, the compound is selected from:

[0030] Compound 1: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0031] Compound 2: Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0032] Compound 3: Gly-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0033] Compound 4: Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0034] Compound 5: Gln-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0035] Compound 6: Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0036] Compound 7: Glu-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0037] Compound 8: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0038] Compound 9: Val-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0039] Compound 10: Asp-Gln-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0040] Compound 11: Gln-Lys-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0041] Compound 12: Lys-Val-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0042] Compound 13: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala

[0043] Compound 14: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu

[0044] Compound 15: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly

[0045] Compound 16: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Lys

[0046] Compound 17: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gln

[0047] Compound 18: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Asp

[0048] Compound 19: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Ala

[0049] Compound 20: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Gln

[0050] Compound 21: Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0051] Compound 22: Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0052] Compound 23: Glu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0053] Compound 24: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Lys

[0054] Compound 25: Ala-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0055] Compound 26: Ala-Ile-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0056] Compound 27: Ala-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0057] Compound 28: Ala-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0058] Compound 29: Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0059] Compound 30: Leu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0060] Compound 31: Lys-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0061] Compound 32: Glu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0062] Compound 33: Lys-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0063] Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0064] Compound 35: Val-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0065] Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0066] Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0067] Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0068] Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0069] Compound 40: Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0070] Compound 41:

[0071] Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0072] Compound 42:

[0073] Ala-Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0074] Compound 43: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Gly-Leu-Asp,

[0075] Compound 44: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Ala-Val-Asp,

[0076] Compound 45: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu

[0077] Compound 46: Asp-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0078] Compound 47: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala

[0079] Compound 48: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala-Leu

[0080] Compound 49: Ala-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0081] Compound 50: Leu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0082] Compound 51: Lys-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0083] Compound 52: Glu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0084] Compound 53: Lys-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0085] Compound 54: Glu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0086] Compound 55: Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0087] Compound 56: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu

[0088] Compound 57: Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu

[0089] Compound 58: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu

[0090] Compound 59: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala-Gly-Leu-Asp,

[0091] Compound 60: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu,

[0092] Compound 61: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Pro-Val-Pro-Leu,

[0093] Compound 62:

[0094] Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu,

[0095] Compound 63:

[0096] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0097] Compound 64:

[0098] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0099] Compound 65: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Leu,

[0100] Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Ala,

[0101] Compound 67: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu,

[0102] Compound 68: Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu

[0103] Compound 69: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln

[0104] Compound 70: Arg-Lys-Asp-Val-Tyr-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0105] Compound 71: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Cys-Gly

[0106] Compound 72: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu- Val-Lys-Gln-Asp,

[0107] Compound 73: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Glu-Cys-Gly

[0108] Compound 74: Ala-Ala-Ala-Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0109] Compound 75: Ala-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0110] Compound 76: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp.

[0111] For convenience, the H on the left and the OH on the right are omitted when describing the compounds of the present invention in this application.

[0112] In one implementation scheme, Xaa9-Xaa 10 -Xaa 11 It is Val-Lys-Gln.

[0113] In one implementation scheme, Xaa12 For Asp.

[0114] In one implementation scheme, Xaa 12 For Glu.

[0115] In one implementation, Xaa8 is Pro, Val, or Leu.

[0116] In one embodiment, the compound is selected from:

[0117] Compound 1: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0118] Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0119] Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0120] Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0121] Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp or

[0122] Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp.

[0123] In a second aspect, the present invention provides a method for repairing mucosal damage, the method comprising administering the compound of the present invention or a physiologically compatible salt thereof to a subject or contacting the mucosal damage with the compound of the present invention or a physiologically compatible salt thereof.

[0124] In one implementation scheme, repair is achieved by regulating stem cell proliferation and differentiation.

[0125] In one implementation scheme, mucosal injury refers to mucosal injury within cavities such as the digestive system and respiratory system.

[0126] Mucosal damage to the digestive system is associated with oral, esophageal, and gastrointestinal diseases. Oral diseases include oral ulcers, stomatitis, gingivitis, and periodontitis; esophageal diseases include esophagitis and esophageal ulcers; and gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcers, functional gastrointestinal disorders, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease, and mucosal damage caused by radiotherapy and chemotherapy, but is not limited to these.

[0127] In a preferred embodiment, the digestive tract mucosa includes the gastric mucosa and the intestinal mucosa.

[0128] In a preferred embodiment, chronic gastritis includes chronic atrophic gastritis.

[0129] In a preferred embodiment, the mucosal injury is gastric mucosal injury caused by irritants or drugs, or stress. Irritants include hydrochloric acid, ethanol, or alcohol; drugs include nonsteroidal anti-inflammatory drugs such as aspirin or indomethacin; carcinogens; or acid suppressants.

[0130] The present invention provides a method for preventing, alleviating or treating digestive tract diseases or eliminating inflammatory edema, the method comprising administering to a subject a compound of the present invention or a physiologically compatible salt thereof.

[0131] Digestive tract diseases include those related to the oral cavity, esophagus, and gastrointestinal tract. Oral diseases include oral ulcers, stomatitis, gingivitis, periodontitis, etc.; esophageal diseases include esophagitis, esophageal ulcers, etc.; gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcers, functional gastrointestinal disorders, dyspepsia, precancerous lesions, digestive system tumors, gastrointestinal bleeding, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease, and mucosal damage caused by radiotherapy and chemotherapy; but are not limited to these.

[0132] In one embodiment, the prevention, mitigation, or treatment of gastrointestinal diseases is achieved by regulating stem cell proliferation and differentiation. The method utilizes the compounds of the present invention or their physiologically compatible salts to protect or repair damage to the gastrointestinal mucosa, such as the gastric or intestinal mucosa, thereby preventing, mitigating, or treating gastrointestinal diseases.

[0133] This invention provides a method for repairing mucosal or skin wounds, the method comprising administering to a subject a compound of the invention or a physiologically compatible salt thereof. In one embodiment, the repair of the mucosal or skin wound includes regulating stem cell proliferation and differentiation.

[0134] In the methods of the present invention described above, the compounds of the present invention or their physiologically compatible salts are administered by oral, injection, subcutaneous, or other means.

[0135] Thirdly, the present invention provides a method for repairing skin damage, the method comprising contacting the skin damage with a compound of the present invention or a physiologically compatible salt thereof.

[0136] In a preferred embodiment, skin damage is associated with, but not limited to, epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulas, pressure sores, and skin damage caused by radiotherapy and chemotherapy.

[0137] In one implementation, skin damage refers to damage to normal skin caused by external injury factors such as surgery, external force, heat, electric current, chemical substances, low temperature, and internal factors such as local blood supply obstruction.

[0138] In one implementation scheme, skin damage is often accompanied by disruption of skin integrity and loss of a certain amount of normal tissue.

[0139] In another embodiment, skin damage includes impairment of normal skin function.

[0140] In one implementation, the recovery of skin damage is achieved by regulating the proliferation and differentiation of stem cells.

[0141] The present invention provides a method for promoting the proliferation of HaCAT cells, the method comprising contacting the cells with the compound of the present invention or a physiologically compatible salt thereof.

[0142] Fourthly, the present invention provides a method for regenerating damaged blood vessels, the method comprising contacting the damaged blood vessels with a compound of the present invention or a physiologically compatible salt thereof.

[0143] In a preferred embodiment, the damaged blood vessels include those resulting from damage to the digestive tract mucosa and skin.

[0144] Fifthly, the present invention provides a pharmaceutical, food, health product, cosmetic, or daily necessities composition, the composition comprising at least one compound of the present invention or a physiologically compatible salt thereof and a physiologically acceptable carrier.

[0145] In one embodiment, a physiologically acceptable carrier includes a pharmaceutically acceptable carrier or a cosmetically acceptable carrier. Pharmaceutical, food, health product, or cosmetic / daily product compositions can be prepared using conventional pharmaceutical or cosmetic techniques, including mixing the compound of the present invention as an active ingredient with a carrier and formulating it into the desired dosage form using conventional techniques. The compositions of the present invention can be formulated into oral, mucosal, injectable, inhaled, and topical formulations as needed.

[0146] The polypeptides of this invention are not homologous to known polypeptides, facilitating the synthesis of high-purity polypeptides through artificial synthesis. Compared to epidermal growth factor polypeptides, the polypeptides of this invention consist of at most 25 amino acid residues and are stable in vivo. Furthermore, the polypeptides of this invention can promote stem cell proliferation and differentiation, particularly the proliferation and differentiation of gastric organoids, participating in and regulating the proliferation and differentiation of gastric epithelial stem cells. This allows for the repair of damage to gastrointestinal stem cells and epidermal stem cells, significantly alleviating the pathological development of gastrointestinal diseases such as chronic gastritis and peptic ulcers, eliminating inflammatory edema, promoting the repair of gastrointestinal mucosal and skin damage, shortening wound healing time, and regulating immune function. In addition, the polypeptides of this invention remain effective even after disinfection with iodine preparations or hydrogen peroxide when applied to skin wounds, and are stable in artificial gastric or intestinal fluids. In contrast, epidermal growth factor, when applied to skin, will have its structure destroyed after disinfection with iodine preparations or hydrogen peroxide, rendering it ineffective. Attached Figure Description

[0147] Figure 1 A schematic diagram of the solid-phase synthesis steps of peptides is shown;

[0148] Figure 2 The effect of compound 34 on the viability of mouse gastric organoids was shown;

[0149] Figure 3 The effect of compound 36 on the viability of mouse gastric organoids was shown;

[0150] Figure 4 The effect of compound 38 on the viability of mouse gastric organoids was shown;

[0151] Figure 5 The effect of compound 39 on the viability of gastric organoids in mice was shown. Detailed Implementation

[0152] The term "physiologically compatible salt" refers to a salt form that is physiologically compatible (i.e., pharmacologically acceptable) and substantially non-toxic to the individual to whom the compounds of the present invention will be administered. Physiologically compatible salts of the compounds of the present invention include conventional and stoichiometric acid addition salts or base addition salts formed from suitable, non-toxic organic or inorganic acids or inorganic bases.

[0153] The term "subject" refers to an animal, preferably a mammal, and most preferably a human. Specifically, the term "subject" refers to a mammal or human with skin lesions and / or mucosal lesions. Those skilled in the art will understand that the repair of skin lesions and / or mucosal lesions of the present invention can be applied for cosmetic (i.e., non-therapeutic) and therapeutic purposes. Therefore, the term "skin damage" in this application also includes skin damage repaired for cosmetic purposes, such as wrinkles (e.g., wrinkles caused by ultraviolet radiation), skin lines, cracks, lumps, large pores (e.g., associated with appendage structures such as sweat ducts, sebaceous glands, or hair follicles), or unevenness or roughness, loss of skin elasticity (loss and / or inactivation of functional elastin), sagging (including puffiness around the eyes and jaw), loss of skin firmness, loss of skin tightness, loss of the ability to recover after skin deformation, discoloration (including dark circles), freckles, grayish-yellow skin tone, hyperpigmented skin areas such as age spots and freckles, keratin, abnormal differentiation, hyperkeratosis, degeneration of elastic tissue, destruction of collagen, and other tissue changes in the stratum corneum, dermis, epidermis, vascular system of the skin (e.g., telangiectasia or bifurcated vessels), and subcutaneous tissue, especially other tissue changes in the subcutaneous tissue close to the skin.

[0154] The following description of the present invention is based on specific experiments and is not intended to limit the scope of protection of the present invention.

[0155]

[0156] Example 1: Chemical Synthesis of Peptides

[0157] The synthesis of polypeptide compounds adopts conventional solid-phase synthesis methods, which involves multiple cycles of resin swelling, amino acid substitution, deprotection, washing, amino acid activation, condensation, washing, and deprotection, and finally cleavage and side chain deprotection.

[0158] See the schematic diagram of the solid-phase synthesis steps of peptides. Figure 1 . Figure 1 In this context, Cl-2-Cl-Resin represents 2-chlorotriphenylmethyl chloro resin (2-Chlorotrityl Chloride Resin); Fmoc-Aa(n) et al. represent amino acids with a 9-fluorenylmethoxycarbonyl group; and TIPS represents triisopropylsilane.

[0159] The following uses compound 14 (Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu) as an example, and demonstrates the synthesis and purification method of compound 14 using a CS BIO CS 136M automated peptide synthesizer.

[0160] The method includes steps 1, preparation of fully protected peptide resin; 2, cleavage and deprotection; 3, purification (salt replacement) and lyophilization.

[0161] Step 1: Preparation of fully protected peptide resin

[0162] (1) Preparation of Fmoc-Leu-Resin resin: 2.67 g of 2-Chlorotrityl Chloride Resin (SD = 0.75 mmol / g) was weighed and added to the synthesis tube of an automated peptide synthesizer CS 136M. The first amino acid substitution reaction and the removal of the protecting group Fmoc were carried out using the program set in the peptide synthesizer. The specific reaction process is as follows: The resin was swollen with DCM for 20 minutes and then drained. Fmoc-Leu-OH (3 eq, 6 mmol) was dissolved in DMF (40 mL), and then DIPEA (7 eq, 14 mmol) was added. The DMF mixed solution of Fmoc-Leu-OH / DIPEA was added to the reaction flask containing the resin and reacted for 1 hour, and then drained. Add 40 mL of 20% MeOH / DMF and react for 30 minutes to seal the end. After draining, wash 3 times with DMF, then remove the protecting group Fmoc with 20% PIP / DMF (v / v), and wash 5 times with DMF solution.

[0163] (2) Preparation of fully protected peptide resin: The circulating water bath temperature was adjusted to 35℃. Using the coupling program set in the peptide synthesizer, amino acids were coupled one by one according to the peptide sequence, starting from the (n-1)th amino acid. The specific reaction process is as follows: Fmoc-Asp(OtBu)-OH (3 eq, 6 mmol) and HOBt (3 eq, 6 mmol) were dissolved in DMF (40 mL) in an activation flask, and then DIC (4 eq, 8 mmol) was added to activate the amino acids. The DMF mixture of Fmoc-Asp(OtBu)-OH / HOBt / DIC was added to the amino acid resin in the reaction flask for coupling. After reacting for 1 hour, the solvent was removed, and the solid resin was washed 3 times with DMF solution. Then, the protecting group Fmoc was removed with 20% PIP / DMF (v / v) and washed 5 times with DMF solution. The above steps were repeated until the entire amino acid sequence was coupled.

[0164] Step 2, Cutting

[0165] (1) Transfer the resin from the peptide synthesizer to a manual synthesis tube with a sieve plate and wash it 5 times with DCM. Add 200 mL of cleavage agent (TFA: TIS: H2O = 95: 2.5: 2.5, v / v) to the synthesis tube and bubble the reaction under nitrogen (N2) for 1.5 to 3 hours.

[0166] (2) After the cleavage reaction was completed, the cleavage agent was filtered into a 250 mL round-bottom flask. After vacuum concentration to one-quarter of the original cleavage agent volume, 10 times the existing volume of methyl tert-butyl ether was added, and a white solid was obtained by precipitation. The resulting mixed solvent was filtered and washed three times with 20 mL of methyl tert-butyl ether. The obtained crude peptide product was placed in a vacuum drying oven to remove excess solvent until the crude peptide was in powder form. 1.70 g of crude peptide was obtained, with a crude yield of 61.7%.

[0167] Step 3: Purification, salt replacement, and freeze drying

[0168] Chromatographic parameters

[0169] Chromatographic column: YMC-Actus Triart C18 30*250 mm (LD S-5 um, 12 nm)

[0170] Eluent A1: 0.1M acetic acid

[0171] Eluent A2: 0.025M acetic acid – 0.1M ammonium acetate

[0172] Elution Buffer B: Acetonitrile

[0173] Flow rate: 25 mL / min

[0174] UV detection wavelength: 220 nm

[0175] Operating steps

[0176] a) 95% A1 + 5% B equilibrium chromatographic column

[0177] b) Injection: Dissolve 0.464 g of sample in 8 mL of purified water and filter through a 0.45 μm filter.

[0178] c) 95% A2 + 5% B equilibrium chromatographic column

[0179] d) Gradient elution using A1 and B, with the gradients as follows:

[0180]

[0181] e) Collect the eluent of the target peptide

[0182] f) Rotary evaporation concentration: water bath temperature 40℃

[0183] g) Freeze-drying

[0184] 0.464g of crude product was purified to obtain 0.371g of pure product, with a purity of 100% and a yield of 79.95%.

[0185] Other compounds were synthesized in a similar manner to those synthesized for compound 14. Results are shown in Table 2 and other parts of the specification.

[0186]

[0187]

[0188]

[0189]

[0190]

[0191] Note: Double charge peaks indicate that the target molecule has bound 2 protons, and triple charge peaks indicate that the target molecule has bound 3 protons; N / A indicates that the crude product was not weighed and the purification yield was not calculated.

[0192] Compound 1: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0193] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 60 H 99 N 15 O 19 m / z: 667.86710 ([M+2H]) 2+ ), 1334.72627 ([M+H]) + ).

[0194] Compound 2: Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0195] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 105 N 15 O 19 m / z: 688.89313 ([M+2H]) 2+ ).

[0196] 1H NMR (600 MHz, D2O) δ 4.59 – 4.53 (m, 1H), 4.45 – 4.36 (m, 3H), 4.35 – 4.29 (m, 3H), 4.29 – 4.18 (m, 5H), 4.04 (d, J = 8.2 Hz, 1H), 3.84 – 3.59(m, 4H), 3.57 – 3.50 (m, 1H), 2.94 (t, J = 7.4 Hz, 2H), 2.74 – 2.61 (m, 2H), 2.45 – 1.47 (m, 31H), 1.42 – 1.35 (m, 2H), 1.35 – 1.28 (m, 6H), 0.97 – 0.81 (m, 24H).

[0197] Compound 3: Gly-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0198] 1 H NMR (600 MHz, D2O) δ 4.56 – 4.52 (m, 1H), 4.41 – 4.31 (m, 3H), 4.31– 4.13 (m, 7H), 3.99 (d, J = 8.2 Hz, 1H), 3.88 (s, 2H), 3.85 – 3.73 (m, 1H), 3.73 – 3.66 (m, 1H), 3.62 – 3.54 (m, 2H), 3.54 – 3.42 (m, 2H), 2.89 (t, J =7.4 Hz, 2H), 2.76 – 2.62 (m, 2H), 2.39 – 2.13 (m, 7H), 2.08 – 1.42 (m, 29H,AcOH), 1.39 – 1.30 (m, 2H), 1.30 – 1.24 (m, 6H), 0.92 – 0.76 (m, 18H).

[0199] Compound 4: Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0200] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 106 N 16 O 19 m / z: 696.40099 ([M+2H])2+ 1391.78631 ([M+H]) + ).

[0201] 1 H NMR (600 MHz, D2O) δ 4.53 – 4.48 (m, 1H), 4.43 (t, J = 7.8 Hz, 1H), 4.40 – 4.23 (m, 9H), 4.23 – 4.17 (m, 1H), 4.04 (d, J = 8.2 Hz, 1H), 3.84 – 3.59 (m, 4H), 3.58 – 3.51 (m, 1H), 2.99 – 2.92 (m, 4H), 2.63 – 2.57 (m, 1H), 2.55 – 2.48 (m, 1H), 2.34 – 1.36 (m, 36H), 1.35 (d, J = 7.2 Hz, 3H), 1.32 –1.27 (m, 3H), 0.98 – 0.81 (m, 18H).

[0202] Compound 5: Gln-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0203] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 102 N 16 O 20 m / z: 696.38223 ([M+2H]) 2+ ).

[0204] 1H NMR (600 MHz, D2O) δ 4.49 (dd, J = 9.4, 4.8 Hz, 1H), 4.38 (dd, J =8.2, 6.7 Hz, 1H), 4.36 – 4.26 (m, 6H), 4.25 – 4.14 (m, 4H), 3.99 (d, J = 8.2Hz, 1H), 3.81 – 3.47 (m, 5H), 2.90 (t, J = 7.3 Hz, 2H), 2.64 – 2.58 (m, 1H), 2.57 – 2.50 (m, 1H), 2.45 – 2.38 (m, 2H), 2.29 – 2.13 (m, 7H), 2.12 – 1.69(m, 18H, AcOH), 1.68 – 1.43 (m, 6H), 1.38 – 1.31 (m, 2H), 1.31 – 1.24 (m,6H), 0.91 – 0.77 (m, 18H).

[0205] Compound 6: Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0206] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 62 H 101 N 15 O 21 m / z: 696.87068 ([M+2H]) 2+ ), 1392.73264 ([M+H] + ).

[0207] 1 H NMR (600 MHz, D2O) δ 4.56 (dd, J = 9.5, 4.8 Hz, 1H), 4.43 – 4.14(m, 10H), 3.99 (d, J = 8.2 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.73 – 3.45 (m, 4H),2.89 (t, J = 7.5 Hz, 2H), 2.76 – 2.65 (m, 2H), 2.44 – 2.21 (m, 7H), 2.20 –1.43 (m, 31H, AcOH), 1.39 – 1.30 (m, 2H), 1.30 – 1.24 (m, 6H), 0.92 – 0.76 (m, 18H).

[0208] Compound 7: Glu-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0209] 1 H NMR (600 MHz, D2O) δ 4.62 – 4.56 (m, 2H), 4.50 – 4.46 (m, 1H), 4.45 – 4.41 (m, 1H), 4.41 – 4.36 (m, 1H), 4.35 – 4.29 (m, 5H), 4.28 – 4.13 (m,4H), 4.03 (d, J = 8.2 Hz, 1H), 3.85 – 3.78 (m, 2H), 3.77 – 3.71 (m, 1H), 3.70– 3.54 (m, 4H), 2.94 (t, J = 7.5 Hz, 2H), 2.80 – 2.68 (m, 2H), 2.45 (t, J =7.2 Hz, 2H), 2.43 – 2.35 (m, 2H), 2.31 (t, J = 7.6 Hz, 2H), 2.28 – 1.73 (m,31H, AcOH), 1.72 – 1.47 (m, 6H), 1.43 – 1.34 (m, 2H), 1.34 – 1.27 (m, 6H), 0.97 – 0.80 (m, 24H).

[0210] Compound 8: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0211] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 121 N 17 O 21 m / z: 786.95519 ([M+2H]) 2+ ).

[0212] 1H NMR (600 MHz, D2O) δ 4.56 – 4.48 (m, 2H), 4.42 – 4.31 (m, 3H), 4.31 – 4.25 (m, 4H), 4.24 – 4.14 (m, 4H), 4.08 (d, J = 5.5 Hz, 1H), 3.99 (d, J =8.3 Hz, 1H), 3.79 – 3.35 (m, 7H), 2.90 (t, J = 7.4 Hz, 2H), 2.72 – 2.58 (m,2H), 2.38 – 2.23 (m, 4H), 2.23 – 2.12 (m, 4H), 2.08 – 1.43 (m, 33H, AcOH),1.38 – 1.29 (m, 2H), 1.29 – 1.24 (m, 6H), 1.01 (d, J = 7.0 Hz, 3H), 0.92 –0.78 (m, 27H).

[0213] Compound 9: Val-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0214] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 72 H 119 N 17 O 21 m / z: 779.94770 ([M+2H]) 2+ ).

[0215] 11H NMR (600 MHz, D2O) δ 4.60 – 4.54 (m, 2H), 4.49 – 4.44 (m, 1H), 4.43– 4.36 (m, 2H), 4.36 – 4.29 (m, 4H), 4.29 – 4.19 (m, 4H), 4.12 (d, J = 5.5Hz, 1H), 4.03 (d, J = 8.2 Hz, 1H), 3.84 – 3.79 (m, 1H), 3.77 – 3.67 (m, 2H),3.66 – 3.51 (m, 4H), 2.94 (t, J = 7.4 Hz, 2H), 2.76 – 2.64 (m, 2H), 2.40 –2.17 (m, 8H), 2.12 – 1.73 (m, 26H, AcOH), 1.72 – 1.48 (m, 5H), 1.43 – 1.34(m, 2H), 1.34 – 1.27 (m, 6H), 1.05 (d, J = 7.0 Hz, 3H), 0.96 – 0.82 (m, 27H).

[0216] Compound 10: Asp-Gln-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0217] 1 1H NMR (600 MHz, D2O) δ 4.61 – 4.50 (m, 3H), 4.42 – 4.29 (m, 7H), 4.28– 4.17 (m, 5H), 4.03 (d, J = 8.2 Hz, 1H), 3.83 – 3.71 (m, 2H), 3.66 – 3.54(m, 2H), 2.94 (q, J = 7.0 Hz, 4H), 2.80 – 2.62 (m, 4H), 2.40 – 2.16 (m, 9H),2.11 – 1.72 (m, 25H, AcOH), 1.70 – 1.47 (m, 9H), 1.46 – 1.33 (m, 4H), 1.33 –1.26 (m, 6H), 0.96 – 0.80 (m, 18H).

[0218] Compound 11: Gln-Lys-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0219] 1 H NMR (600 MHz, D2O) δ 4.55 (dd, J = 9.5, 4.5 Hz, 2H), 4.40 – 4.19(m, 11H), 4.06 – 4.00 (m, 2H), 3.83 – 3.79 (m, 1H), 3.74 (q, J = 7.4 Hz, 1H), 3.66 – 3.60 (m, 2H), 2.93 (q, J = 8.6, 8.1 Hz, 4H), 2.71 – 2.58 (m, 2H), 2.39 – 2.16 (m, 8H), 2.12 – 1.48 (m, 35H, AcOH), 1.44 – 1.33 (m, 4H), 1.33 – 1.27(m, 6H), 0.97 – 0.81(m, 24H).

[0220] Compound 12: Lys-Val-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0221] 1 H NMR (600 MHz, D2O) δ 4.62 – 4.54 (m, 3H), 4.47 – 4.17 (m, 10H), 4.11 – 3.97 (m, 3H), 3.84 – 3.70 (m, 2H), 3.67 – 3.58 (m, 2H), 2.93 (td, J =7.6, 4.8 Hz, 4H), 2.74 – 2.62 (m, 2H), 2.39 – 2.28 (m, 4H), 2.26 – 2.18 (m,2H), 2.11 – 1.47 (m, 40H, AcOH), 1.42 – 1.33 (m, 4H), 1.33 – 1.26 (m, 6H), 0.97 – 0.81 (m, 30H).

[0222] Compound 13: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala (acetate)

[0223] 1 H NMR (600 MHz, D2O) δ 4.54 (dt, J = 8.5, 4.6 Hz, 2H), 4.38 – 4.31(m, 1H), 4.31 – 4.13 (m, 8H), 4.06 (q, J = 7.2 Hz, 1H), 3.99 (d, J = 8.1 Hz,1H), 3.77 (q, J = 6.9, 5.6 Hz, 1H), 3.73 – 3.65 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.75 – 2.69 (m, 1H), 2.64 –2.56 (m, 1H), 2.40 – 2.24 (m, 5H), 2.22 – 2.12 (m, 2H), 2.06 – 1.83 (m, 17H,AcOH), 1.82 – 1.43 (m, 10H), 1.39 – 1.30 (m, 2H), 1.30 – 1.23 (m, 9H), 0.92 –0.77 (m, 18H).

[0224] Compound 14: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate)

[0225] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 105 N 15 O 19 m / z: 688.89126 ([M+2H]) 2+ ), 1376.77455 ([M+H) + ).

[0226] 1H NMR (600 MHz, D2O) δ 4.61 – 4.52 (m, 2H), 4.34 (dd, J = 8.4, 5.8Hz, 1H), 4.31 – 4.27 (m, 3H), 4.26 – 4.16 (m, 5H), 4.15 – 4.10 (m, 1H), 3.99(d, J = 8.1 Hz, 1H), 3.77 (q, J = 7.0, 5.8 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63– 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.77 – 2.70(m, 1H), 2.63 – 2.56 (m, 1H), 2.40 – 2.22 (m, 5H), 2.21 – 2.12 (m, 2H), 2.03– 1.68 (m, 23H, AcOH), 1.67 – 1.42 (m, 9H), 1.42 – 1.30 (m, 2H), 1.30 – 1.23 (m, 6H), 0.93 – 0.74 (m, 24H).

[0227] Compound 15: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly (acetate)

[0228] 1H NMR (600 MHz, D2O) δ 4.61 (dd, J = 8.1, 5.3 Hz, 1H), 4.55 (dd, J =9.5, 4.7 Hz, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.29 (dd, J = 8.3, 5.9 Hz,3H), 4.26 – 4.17 (m, 5H), 3.99 (d, J = 8.1 Hz, 1H), 3.82 – 3.73 (m, 1H), 3.72– 3.67 (m, 3H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.5Hz, 2H), 2.77 – 2.70 (m, 1H), 2.66 – 2.60 (m, 1H), 2.40 – 2.29 (m, 3H), 2.26(t, J = 7.6 Hz, 2H), 2.22 – 2.12 (m, 2H), 2.06 – 1.83 (m, 21H, AcOH), 1.82 –1.67 (m, 4H), 1.67 – 1.42 (m, 6H), 1.39 – 1.30 (m, 2H), 1.30 – 1.24 (m, 6H), 0.94 – 0.73 (m, 18H).

[0229] Compound 16: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Lys (acetate)

[0230] 1H NMR (600 MHz, D2O) δ 4.56 – 4.50 (m, 2H), 4.34 (dd, J = 8.4, 5.8Hz, 1H), 4.31 – 4.16 (m, 8H), 4.07 (dd, J = 7.9, 5.1 Hz, 1H), 3.99 (d, J =8.2 Hz, 1H), 3.77 (q, J = 6.6, 6.0 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54(m, 2H), 3.37 – 3.24 (m, 2H), 2.92 – 2.86 (m, 4H), 2.70 – 2.63 (m, 1H), 2.60– 2.53 (m, 1H), 2.40 – 2.24 (m, 5H), 2.23 – 2.12 (m, 2H), 2.06 – 1.84 (m,21H, AcOH), 1.82 – 1.67 (m, 5H), 1.66 – 1.50 (m, 8H), 1.50 – 1.42 (m, 1H), 1.37 – 1.22 (m, 10H), 0.93 – 0.77 (m, 18H).

[0231] Compound 17: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gln (acetate)

[0232] 1H NMR (600 MHz, D2O) δ 4.58 – 4.52 (m, 2H), 4.34 (dd, J = 8.3, 5.8Hz, 1H), 4.31 – 4.14 (m, 8H), 4.10 (dd, J = 8.6, 4.9 Hz, 1H), 3.99 (d, J =8.1 Hz, 1H), 3.82 – 3.74 (m, 1H), 3.73 – 3.65 (m, 1H), 3.64 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.77 – 2.70 (m, 1H), 2.66 –2.59 (m, 1H), 2.40 – 2.23 (m, 5H), 2.23 – 2.13 (m, 4H), 2.05 – 1.81 (m, 20H,AcOH), 1.80 – 1.67 (m, 4H), 1.66 – 1.42 (m, 6H), 1.38 – 1.24 (m, 8H), 0.92 –0.77 (m, 18H).

[0233] Compound 18: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Asp (acetate)

[0234] 1H NMR (600 MHz, D2O) δ 4.60 (dd, J = 8.1, 5.2 Hz, 1H), 4.58 – 4.54(m, 1H), 4.42 (t, J = 5.9 Hz, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.31 –4.13 (m, 8H), 3.99 (d, J = 8.1 Hz, 1H), 3.80 – 3.73 (m, 1H), 3.73 – 3.66 (m,1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.90 (t, J = 7.5 Hz, 2H), 2.80– 2.73 (m, 1H), 2.73 – 2.66 (m, 2H), 2.66 – 2.59 (m, 1H), 2.41 – 2.29 (m,3H), 2.26 (t, J = 7.6 Hz, 2H), 2.20 – 2.13 (m, 2H), 2.05 – 1.83 (m, 20H,AcOH), 1.82 – 1.67 (m, 4H), 1.67 – 1.42 (m, 6H), 1.37 – 1.24 (m, 8H), 0.92 –0.76 (m, 18H).

[0235] Compound 19: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Ala (acetate)

[0236] 11H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.5, 4.7 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31 – 4.27 (m, 3H), 4.27 – 4.18 (m, 5H), 4.07 – 4.01 (m, 1H), 3.99 (d, J = 8.2 Hz, 1H), 3.80 – 3.74 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.40 – 2.24 (m, 5H), 2.22 – 2.12 (m, 2H), 2.06 – 1.83 (m, 19H, AcOH), 1.82 – 1.42 (m, 9H), 1.36 – 1.22 (m, 11H), 0.92 – 0.77 (m, 18H).

[0237] Compound 20: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Gln (acetate)

[0238] 1 1H NMR (600 MHz, D2O) δ 4.52 (dd, J = 9.5, 4.7 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31 – 4.26 (m, 3H), 4.25 – 4.14 (m, 5H), 4.07 (dd, J = 8.4, 4.9 Hz, 1H), 3.99 (d, J = 8.2 Hz, 1H), 3.81 – 3.74 (m, 1H), 3.74 – 3.67 (m, 1H), 3.64 – 3.54 (m, 2H), 3.37 - 3.24 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.40 – 2.23 (m, 5H), 2.23 – 2.12 (m, 4H), 2.07 – 1.43 (m, 28H, AcOH), 1.38 – 1.24 (m, 8H), 0.93 – 0.77 (m, 18H).

[0239] Compound 21: Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0240] 1 H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.38 (dd, J =7.0, 5.1 Hz, 1H), 4.34 (dd, J = 8.3, 5.9 Hz, 1H), 4.31 – 4.14 (m, 7H), 3.99(d, J = 8.2 Hz, 1H), 3.90 (t, J = 7.1 Hz, 1H), 3.80 – 3.66 (m, 2H), 3.63 –3.54 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.74 – 2.62 (m, 2H), 2.39 – 2.23 (m,4H), 2.22 – 2.12 (m, 2H), 2.08 – 1.43 (m, 28H, AcOH), 1.37 – 1.23 (m, 8H), 0.93 – 0.76 (m, 24H).

[0241] Compound 22: Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0242] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 58 H 99 N 15 O 18 m / z: 647.87059 ([M+2H]) 2+ ), 1294.73375 ([M+H] + ).

[0243] 1H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.7, 4.6 Hz, 1H), 4.38 – 4.31(m, 2H), 4.31 – 4.10 (m, 7H), 3.99 (d, J = 8.3 Hz, 1H), 3.90 (t, J = 6.6 Hz,1H), 3.80 – 3.73 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.94 –2.87 (m, 4H), 2.70 – 2.58 (m, 2H), 2.31 – 2.22 (m, 4H), 2.22 – 2.12 (m, 2H), 2.08 – 2.01 (m, 1H), 2.00 – 1.68 (m, 22H, AcOH), 1.66 – 1.24 (m, 18H), 0.91 –0.76 (m, 18H).

[0244] Compound 23: Glu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0245] 1 H NMR (600 MHz, D2O) δ 4.56 (dd, J = 9.5, 4.8 Hz, 1H), 4.40 (dd, J =6.8, 5.2 Hz, 1H), 4.37 – 4.09 (m, 8H), 4.03 – 3.92 (m, 2H), 3.76 (q, J = 6.7,5.6 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.89 (t, J = 7.4 Hz,2H), 2.76 – 2.65 (m, 2H), 2.42 – 2.31 (m, 4H), 2.27 (t, J = 7.6 Hz, 2H), 2.21– 2.12 (m, 2H), 2.09 – 1.82 (m, 16H, AcOH), 1.82 – 1.42 (m, 10H), 1.38 – 1.24(m, 8H), 0.92 – 0.76 (m, 18H).

[0246] Compound 24: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Lys (acetate)

[0247] 1 H NMR (600 MHz, D2O) δ 4.53 – 4.48 (m, 1H), 4.33 (dd, J = 8.4, 5.8Hz, 1H), 4.31 – 4.27 (m, 3H), 4.27 – 4.16 (m, 5H), 4.03 (dd, J = 7.9, 5.4 Hz,1H), 3.98 (d, J = 8.2 Hz, 1H), 3.83 – 3.74 (m, 1H), 3.74 – 3.67 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.6 Hz, 4H), 2.40 – 2.31(m, 1H), 2.31 – 2.22 (m, 4H), 2.21 – 2.12 (m, 2H), 2.07 – 1.84 (m, 22H,AcOH), 1.82 – 1.68 (m, 5H), 1.66 – 1.43 (m, 9H), 1.37 – 1.24 (m, 10H), 0.93 –0.76 (m, 18H).

[0248] Compound 25: Ala-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0249] 11H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.5, 4.8 Hz, 1H), 4.37 (dd, J = 7.1, 5.1 Hz, 1H), 4.34 (dd, J = 8.3, 5.9 Hz, 1H), 4.32 – 4.24 (m, 3H), 4.24 – 4.16 (m, 4H), 4.04 (q, J = 7.1 Hz, 1H), 3.99 (d, J = 8.2 Hz, 1H), 3.90 (s, 2H), 3.76 (q, J = 6.9, 5.5 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 – 2.58 (m, 2H), 2.37 – 2.24 (m, 4H), 2.22 – 2.12 (m, 2H), 2.08 – 1.43 (m, 26H, AcOH), 1.39 – 1.23 (m, 8H), 0.91 – 0.76 (m, 18H).

[0250] Compound 26: Ala-Ile-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0251] 1 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.40 – 4.31 (m, 2H), 4.31 – 4.24 (m, 3H), 4.24 – 4.13 (m, 4H), 4.08 (d, J = 7.8 Hz, 1H), 4.05 – 3.97 (m, 2H), 3.80 – 3.74 (m, 1H), 3.74 – 3.67 (m, 1H), 3.64 – 3.53 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 – 2.59 (m, 2H), 2.39 – 2.22 (m, 4H), 2.22 – 2.12 (m, 2H), 2.08 – 1.23 (m, 36H, AcOH), 1.14 – 1.04 (m, 1H), 0.92 – 0.75 (m, 24H).

[0252] Compound 27: Ala-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0253] 1 H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.41 – 4.36(m, 1H), 4.36 – 4.31 (m, 1H), 4.31 – 4.15 (m, 8H), 4.02 – 3.95 (m, 2H), 3.76(q, J = 7.0, 5.5 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.89 (t,J = 7.4 Hz, 2H), 2.74 – 2.63 (m, 2H), 2.40 – 2.23 (m, 4H), 2.22 – 2.12 (m,2H), 2.08 – 1.43 (m, 30H, AcOH), 1.42 (d, J = 7.1 Hz, 3H), 1.38 – 1.23 (m,8H), 0.92 – 0.77 (m, 24H).

[0254] Compound 28: Ala-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0255] 11H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.4, 4.8 Hz, 1H), 4.39 – 4.32(m, 2H), 4.31 – 4.25 (m, 3H), 4.24 – 4.17 (m, 4H), 4.07 – 3.97 (m, 3H), 3.76(q, J = 7.0, 5.4 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.90 (t,J = 7.4 Hz, 2H), 2.72 – 2.59 (m, 2H), 2.38 – 2.23 (m, 4H), 2.22 – 2.12 (m,2H), 2.08 – 1.43 (m, 24H, AcOH), 1.41 (d, J = 7.1 Hz, 3H), 1.38 – 1.23 (m,8H), 0.91 – 0.77 (m, 24H).

[0256] Compound 29: Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0257] 1 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.38 (dd, J =7.0, 5.1 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31 – 4.24 (m, 3H), 4.24 –4.17 (m, 4H), 4.03 – 3.92 (m, 2H), 3.90 (d, J = 2.3 Hz, 2H), 3.76 (q, J =6.9, 5.7 Hz, 1H), 3.72 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.89 (t, J = 7.4Hz, 2H), 2.74 – 2.63 (m, 2H), 2.39 – 2.23 (m, 4H), 2.22 – 2.12 (m, 2H), 2.07– 1.43 (m, 29H, AcOH), 1.37 – 1.23 (m, 8H), 0.92 – 0.76 (m, 24H).

[0258] Compound 30: Leu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0259] 1 H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.40 – 4.31(m, 2H), 4.31 – 4.14 (m, 8H), 3.99 (d, J = 8.2 Hz, 1H), 3.90 (t, J = 7.1 Hz,1H), 3.77 (q, J = 6.8, 5.7 Hz, 1H), 3.73 – 3.67 (m, 1H), 3.63 – 3.54 (m, 2H),2.89 (t, J = 7.4 Hz, 2H), 2.73 – 2.61 (m, 2H), 2.39 – 2.23 (m, 4H), 2.21 –2.12 (m, 2H), 2.07 – 1.43 (m, 27H, AcOH), 1.40 – 1.23 (m, 11H), 0.92 – 0.76 (m, 24H).

[0260] Compound 31: Lys-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0261] 1H NMR (600 MHz, D2O) δ 4.49 (dd, J = 9.4, 4.8 Hz, 1H), 4.36 – 4.25 (m, 5H), 4.24 – 4.15 (m, 4H), 4.05 (d, J = 7.5 Hz, 1H), 4.03 – 3.94 (m, 2H),3.80 – 3.67 (m, 2H), 3.63 – 3.54 (m, 2H), 2.90 (t, J = 7.8 Hz, 4H), 2.66 –2.60 (m, 1H), 2.59 – 2.53 (m, 1H), 2.30 – 2.21 (m, 4H), 2.20 – 2.12 (m, 2H), 2.08 – 1.68 (m, 20H, AcOH), 1.68 – 1.42 (m, 8H), 1.40 – 1.29 (m, 4H), 1.29 –1.24 (m, 6H), 0.92 – 0.77 (m, 24H).

[0262] Compound 32: Glu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0263] 1H NMR (600 MHz, D2O) δ 4.66 – 4.59 (m, 1H), 4.55 (dd, J = 9.5, 4.8Hz, 1H), 4.39 (dd, J = 6.9, 5.1 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31– 4.13 (m, 8H), 3.99 (d, J = 8.2 Hz, 1H), 3.95 (t, J = 6.5 Hz, 1H), 3.84 –3.73 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.89 (t, J = 7.4 Hz,2H), 2.74 – 2.63 (m, 2H), 2.41 – 2.29 (m, 4H), 2.27 (t, J = 7.6 Hz, 2H), 2.22 – 2.12 (m, 2H), 2.10 – 1.42 (m, 23H, AcOH), 1.40 – 1.30 (m, 2H), 1.30 – 1.24(m, 9H), 0.90 – 0.77 (m, 18H).

[0264] Compound 33: Lys-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0265] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 104 N 16 O 19 m / z: 683.39009 ([M+2H]) 2+ ), 1365.77275 ([M+H) + ).

[0266] 1H NMR (600 MHz, DMSO-d6) δ 8.44 (s, 1H), 8.34 – 8.22 (m, 2H), 8.12 –7.85 (m, 5H), 7.64 – 7.56 (m, 2H), 7.21 (s, 1H), 6.72 (s, 1H), 4.43 – 4.04(m, 13H), 3.67 – 3.47 (m, 4H), 3.23 (s, 1H), 2.79 – 2.70 (m, 4H), 2.46 – 2.35(m, 2H), 2.13 – 2.05 (m, 4H), 2.03 – 1.26 (m, 35H, AcOH), 1.24 – 1.12 (m,9H), 0.90 – 0.76 (m, 18H).

[0267] Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0268] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 104 N 16 O 20 m / z: 703.38943 ([M+2H]) 2+ ).

[0269] 1 H NMR (600 MHz, D2O) δ 4.56 – 4.49 (m, 2H), 4.39 – 4.24 (m, 6H), 4.24 – 4.13 (m, 4H), 4.03 – 3.95 (m, 2H), 3.80 – 3.74 (m, 1H), 3.74 – 3.67 (m,2H), 3.62 – 3.52 (m, 3H), 2.90 (t, J = 7.4 Hz, 2H), 2.71 – 2.58 (m, 2H), 2.37– 2.13 (m, 7H), 2.08 – 1.68 (m, 18H, AcOH), 1.68 – 1.43 (m, 6H), 1.41 (d, J =7.1 Hz, 3H), 1.38 – 1.29 (m, 2H), 1.29 – 1.21 (m, 9H), 0.93 – 0.77 (m, 18H).

[0270] Compound 35: Val-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0271] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 68 H 115 N 17 O 20 m / z: 745.93036 ([M+2H]) 2+ ), 1490.85402 ([M+H] + ).

[0272] 1 H NMR (600 MHz, D2O) δ 4.59 – 4.54 (m, 1H), 4.49 (dd, J = 9.4, 4.9Hz, 1H), 4.36 – 4.24 (m, 6H), 4.24 – 4.19 (m, 3H), 4.19 – 4.11 (m, 1H), 3.99(d, J = 8.2 Hz, 1H), 3.81 – 3.73 (m, 2H), 3.73 – 3.67 (m, 2H), 3.63 – 3.52(m, 3H), 2.93 – 2.84 (m, 4H), 2.67 – 2.61 (m, 1H), 2.61 – 2.54 (m, 1H), 2.32– 1.43 (m, 38H, AcOH), 1.42 – 1.34 (m, 2H), 1.33 – 1.30 (m, 1H), 1.28 (d, J =7.2 Hz, 3H), 1.25 (d, J = 7.2 Hz, 3H), 0.94 – 0.77 (m, 24H).

[0273] Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0274] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 65 H 106 N 16 O 22 m / z: 732.38868 ([M+2H]) 2+ ), 1463.76896 ([M+H) + ).

[0275] 1H NMR (600 MHz, D2O) δ 4.61 – 4.52 (m, 2H), 4.39 (t, J = 6.0 Hz, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.31 – 4.24 (m, 4H), 4.24 – 4.14 (m, 4H), 4.04 – 3.96 (m, 2H), 3.80 – 3.74 (m, 1H), 3.74 – 3.66 (m, 2H), 3.64 – 3.54(m, 3H), 2.89 (t, J = 7.4 Hz, 2H), 2.75 – 2.63 (m, 2H), 2.41 – 2.29 (m, 4H),2.27 (t, J = 7.6 Hz, 2H), 2.24 – 2.13 (m, 3H), 2.08 – 1.68 (m, 21H, AcOH),1.68 – 1.42 (m, 6H), 1.41 (d, J = 7.2 Hz, 3H), 1.38 – 1.29 (m, 2H), 1.29 –1.22 (m, 6H), 0.92 – 0.76 (m, 18H).

[0276] Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0277] 1H NMR (600 MHz, D2O) δ 4.57 – 4.51 (m, 1H), 4.40 – 4.31 (m, 3H), 4.31– 4.14 (m, 8H), 4.08 (d, J = 5.4 Hz, 1H), 3.99 (dd, J = 8.2, 4.2 Hz, 2H),3.80 – 3.73 (m, 1H), 3.73 – 3.63 (m, 2H), 3.62 – 3.48 (m, 3H), 2.89 (t, J =7.4 Hz, 2H), 2.73 – 2.62 (m, 2H), 2.40 – 2.29 (m, 2H), 2.29 – 2.12 (m, 6H), 2.08 – 1.82 (m, 19H, AcOH), 1.81 – 1.68 (m, 5H), 1.67 – 1.42 (m, 9H), 1.38 –1.28 (m, 2H), 1.26 (dd, J = 7.2, 1.7 Hz, 6H), 1.00 (d, J = 6.9 Hz, 3H), 0.92– 0.76 (m, 33H).

[0278] Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0279] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 121 N 17 O 21 m / z: 786.95783 ([M+2H]) 2+ ).

[0280] 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.41 – 4.15 (m, 12H), 4.01 – 3.96 (m, 1H), 3.85 – 3.75 (m, 2H), 3.73 – 3.65 (m, 1H), 3.65– 3.37 (m, 3H), 3.36 – 3.25 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.74 – 2.62(m, 2H), 2.40 – 2.24 (m, 5H), 2.24 – 2.09 (m, 3H), 2.08 – 1.83 (m, 23H,AcOH), 1.82 – 1.68 (m, 5H), 1.68 – 1.42 (m, 9H), 1.39 – 1.28 (m, 2H), 1.28 –1.23 (m, 6H), 0.93 – 0.77 (m, 30H).

[0281] Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0282] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 78 H 128 N 18 O 22 m / z: 835.48070 ([M+2H]) 2+ ).

[0283] 1H NMR (600 MHz, D2O) δ 4.55 (dd, J = 9.4, 4.8 Hz, 1H), 4.49 (dd, J =9.6, 5.0 Hz, 1H), 4.40 – 4.12 (m, 12H), 3.99 (d, J = 8.2 Hz, 1H), 3.80 – 3.73(m, 3H), 3.72 – 3.67 (m, 1H), 3.62 – 3.51 (m, 3H), 3.37 – 3.25 (m, 2H), 2.89(t, J = 7.4 Hz, 2H), 2.74 – 2.62 (m, 2H), 2.41 – 2.29 (m, 3H), 2.27 (t, J =7.6 Hz, 2H), 2.22 – 2.13 (m, 3H), 2.07 – 1.67 (m, 31H, AcOH), 1.67 – 1.44 (m,8H), 1.38 – 1.29 (m, 2H), 1.29 – 1.23 (m, 6H), 0.93 – 0.77 (m, 30H).

[0284] Compound 40: Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0285] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 83 H 135 N 19 O 25 m / z: 899.99976 ([M+2H]) 2+ ), 1798.99118 ([M+H]) + ).

[0286] 11H NMR (600 MHz, D2O) δ 4.56 (dd, J = 9.3, 4.8 Hz, 1H), 4.49 (dd, J = 9.7, 4.8 Hz, 1H), 4.46 – 4.38 (m, 2H), 4.38 – 4.10 (m, 11H), 3.99 (d, J = 8.2 Hz, 1H), 3.80 – 3.45 (m, 9H), 2.89 (t, J = 7.4 Hz, 2H), 2.76 – 2.65 (m, 2H), 2.45 – 2.30 (m, 4H), 2.27 (t, J = 7.6 Hz, 2H), 2.24 – 1.84 (m, 30H, AcOH), 1.83 – 1.44 (m, 15H), 1.38 – 1.29 (m, 2H), 1.27 (t, J = 7.2 Hz, 6H), 0.92 – 0.76 (m, 30H).

[0287] Compound 41: Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0288] 1H NMR (600 MHz, D2O) δ 4.64 – 4.53 (m, 2H), 4.49 (dd, J = 9.7, 4.8Hz, 1H), 4.40 (dd, J = 6.9, 5.2 Hz, 1H), 4.37 – 4.32 (m, 2H), 4.32 – 4.25 (m,5H), 4.25 – 4.10 (m, 4H), 4.04 – 3.95 (m, 2H), 3.80 – 3.66 (m, 4H), 3.64 –3.44 (m, 5H), 2.89 (t, J = 7.4 Hz, 2H), 2.76 – 2.64 (m, 2H), 2.43 – 2.29 (m,4H), 2.27 (t, J = 7.6 Hz, 2H), 2.22 – 2.10 (m, 4H), 2.07 – 1.68 (m, 32H,AcOH), 1.67 – 1.43 (m, 9H), 1.43 – 1.39 (m, 3H), 1.37 – 1.29 (m, 2H), 1.29 –1.23 (m, 6H), 0.93 – 0.76 (m, 30H).

[0289] Compound 42:

[0290] Ala-Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0291] 1H NMR (600 MHz, D2O) δ 4.56 (dd, J = 9.7, 4.7 Hz, 2H), 4.49 (dd, J =9.7, 4.8 Hz, 1H), 4.43 – 4.38 (m, 1H), 4.37 – 4.10 (m, 12H), 4.03 – 3.95 (m,2H), 3.79 – 3.66 (m, 4H), 3.64 – 3.45 (m, 5H), 2.89 (t, J = 7.4 Hz, 2H), 2.76 – 2.65 (m, 2H), 2.43 – 2.29 (m, 4H), 2.27 (t, J = 7.6 Hz, 2H), 2.22 – 2.11(m, 4H), 2.06 – 1.83 (m, 28H, AcOH), 1.83 – 1.68 (m, 8H), 1.68 – 1.45 (m,9H), 1.43 (d, J = 7.1 Hz, 3H), 1.39 – 1.29 (m, 2H), 1.29 – 1.23 (m, 9H), 0.93 – 0.76 (m, 30H).

[0292] Compound 43: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Gly-Leu-Asp (acetate)

[0293] 1H NMR (600 MHz, D2O) δ 4.58 (dd, J = 9.5, 4.7 Hz, 1H), 4.48 – 4.43(m, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.32 – 4.27 (m, 4H), 4.27 – 4.12 (m,4H), 3.86 – 3.82 (m, 2H), 3.80 – 3.73 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 –3.54 (m, 2H), 3.38 – 3.24 (m, 2H), 2.81 – 2.74 (m, 1H), 2.74 – 2.67 (m, 1H),2.43 – 2.31 (m, 3H), 2.21 – 2.12 (m, 2H), 2.03 – 1.84 (m, 12H, AcOH), 1.83 –1.74 (m, 3H), 1.62 – 1.44 (m, 6H), 1.33 – 1.24 (m, 9H), 0.92 – 0.75 (m, 18H).

[0294] Compound 44: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Ala-Val-Asp (acetate)

[0295] 1H NMR (600 MHz, D2O) δ 4.56 (dd, J = 9.6, 4.7 Hz, 1H), 4.43 (t, J =6.1 Hz, 1H), 4.34 (dd, J = 8.5, 5.9 Hz, 1H), 4.31 – 4.27 (m, 3H), 4.26 – 4.11(m, 5H), 4.04 (d, J = 7.2 Hz, 1H), 3.79 – 3.73 (m, 1H), 3.72 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.78 – 2.66 (m, 2H), 2.40 – 0.93 – 0.77 (m, 18H).

[0296] Compound 45: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate)

[0297] 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.8 Hz, 1H), 4.39 – 4.31(m, 2H), 4.31 – 4.18 (m, 7H), 4.18 – 4.14 (m, 1H), 4.11 (dd, J = 8.6, 4.9 Hz,1H), 3.99 (d, J = 8.2 Hz, 1H), 3.80 – 3.74 (m, 1H), 3.73 – 3.66 (m, 1H), 3.65 – 3.54 (m, 3H), 3.53 – 3.46 (m, 1H), 2.88 (t, J = 7.6 Hz, 2H), 2.39 – 2.13(m, 9H), 2.06 – 1.44 (m, 30H, AcOH), 1.42 (d, J = 7.0 Hz, 3H), 1.35 – 1.31(m, 1H), 1.29 (d, J = 7.2 Hz, 3H), 1.25 (d, J = 7.1 Hz, 3H), 0.92 – 0.77 (m,18H).

[0298] Compound 46: Asp-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0299] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 99 N 15 O 21 m / z: 689.86298 ([M+H]) + ), 1378.71780 ([M+H] + ).

[0300] 1H NMR (600 MHz, D2O) δ 4.47 (dd, J = 9.4, 4.7 Hz, 1H), 4.36 – 4.31(m, 2H), 4.29 – 4.21 (m, 2H), 4.21 – 4.03 (m, 7H), 3.91 – 3.86 (m, 1H), 3.71– 3.64 (m, 1H), 3.63 – 3.52 (m, 2H), 3.52 – 3.42 (m, 3H), 2.79 (t, J = 7.5Hz, 2H), 2.73 – 2.67 (m, 1H), 2.65 – 2.61 (m, 2H), 2.51 – 2.43 (m, 1H), 2.35– 2.22 (m, 2H), 2.20 – 2.15 (m, 2H), 2.15 – 2.10 (m, 1H), 2.10 – 2.02 (m,2H), 1.97 – 1.70 (m, 20H, AcOH), 1.70 – 1.33 (m, 10H), 1.30 – 1.19 (m, 2H), 1.19 – 1.13 (m, 6H), 0.81 – 0.66 (m, 18H).

[0301] Compound 47: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala (acetate)

[0302] 1H NMR (600 MHz, D2O) δ 4.58 – 4.52 (m, 2H), 4.34 (dd, J = 8.4, 5.8Hz, 1H), 4.31 – 4.27 (m, 3H), 4.27 – 4.15 (m, 6H), 4.08 (q, J = 7.3 Hz, 1H), 4.02 – 3.97 (m, 1H), 3.77 (q, J = 6.9, 5.9 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.75 – 2.68(m, 1H), 2.63 – 2.56 (m, 1H), 2.39 – 2.13 (m, 6H), 2.03 – 1.82 (m, 18H,AcOH), 1.82 – 1.68 (m, 4H), 1.67 – 1.50 (m, 8H), 1.50 – 1.42 (m, 1H), 1.38 –1.31 (m, 1H), 1.30 (d, J = 7.3 Hz, 3H), 1.28 – 1.23 (m, 6H), 0.92 – 0.75 (m, 24H).

[0303] Compound 48: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala-Leu (acetate)

[0304] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 66 H 110 N 16 O 20 m / z: 724.41274 ([M+2H]) 2+ ).

[0305] 1H NMR (600 MHz, D2O) δ 4.56 – 4.49 (m, 2H), 4.34 (dd, J = 8.3, 5.8Hz, 1H), 4.32 – 4.27 (m, 3H), 4.27 – 4.16 (m, 6H), 4.15 – 4.10 (m, 1H), 4.01– 3.97 (m, 1H), 3.81 – 3.74 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m,2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.73 – 2.66 (m, 1H), 2.64– 2.57 (m, 1H), 2.40 – 2.29 (m, 3H), 2.26 (t, J = 7.6 Hz, 2H), 2.22 – 2.12(m, 2H), 2.04 – 1.83 (m, 19H, AcOH), 1.82 – 1.68 (m, 4H), 1.67 – 1.43 (m,9H), 1.41 – 1.31 (m, 2H), 1.31 – 1.24 (m, 9H), 0.91 – 0.75 (m, 24H).

[0306] Compound 49: Ala-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0307] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 104 N 16 O 19 m / z: 683.38997 ([M+2H]) 2+ ), 1365.77292 ([M+H) + ).

[0308] 1H NMR (600 MHz, DMSO-d6) δ 8.52 – 8.41 (m, 1H), 8.34 (s, 1H), 8.28 –8.15 (m, 2H), 8.14 – 8.06 (m, 1H), 8.06 – 7.93 (m, 2H), 7.83 – 7.74 (m, 1H),7.69 – 7.56 (m, 2H), 7.30 – 7.18 (m, 1H), 6.76 (s, 1H), 4.59 – 4.50 (m, 1H),4.42 – 4.36 (m, 1H), 4.36 – 4.08 (m, 10H), 3.79 – 3.48 (m, 4H), 3.43 (d, J =6.8 Hz, 1H), 2.81 – 2.67 (m, 4H), 2.48 – 2.34 (m, 2H), 2.16 – 2.04 (m, 4H), 2.04 – 1.40 (m, 29H, AcOH), 1.39 – 1.25 (m, 4H), 1.22 (d, J = 7.1 Hz, 3H), 1.17 (d, J = 6.7 Hz, 6H), 0.92 – 0.70 (m, 18H).

[0309] Compound 50: Leu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0310] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 110 N 16 O 19 m / z: 704.41729 ([M+2H]) 2+ ), 1407.82000 ([M+H] + ).

[0311] 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 9.5, 4.7 Hz, 1H), 4.33 (dd, J =7.9, 5.2 Hz, 2H), 4.31 – 4.14 (m, 8H), 3.99 (d, J = 8.3 Hz, 1H), 3.92 (t, J =7.3 Hz, 1H), 3.82 – 3.73 (m, 1H), 3.73 – 3.67 (m, 1H), 3.64 – 3.54 (m, 2H), 2.90 (t, J = 7.5 Hz, 4H), 2.68 – 2.55 (m, 2H), 2.32 – 2.22 (m, 4H), 2.22 –2.12 (m, 2H), 2.08 – 2.00 (m, 1H), 2.00 – 1.82 (m, 13H, AcOH), 1.81 – 1.42(m, 17H), 1.40 – 1.29 (m, 4H), 1.29 – 1.24 (m, 6H), 0.91 – 0.77 (m, 24H).

[0312] Compound 51: Lys-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0313] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 111 N 17 O 19 m / z: 711.92148 ([M+2H]) 2+ ), 1422.82606 ([M+H] + ).

[0314] 1H NMR (600 MHz, D2O) δ 4.48 (dd, J = 9.6, 4.6 Hz, 1H), 4.36 – 4.25(m, 5H), 4.25 – 4.14 (m, 5H), 3.99 (d, J = 8.2 Hz, 1H), 3.92 (t, J = 6.6 Hz,1H), 3.77 (q, J = 7.6 Hz, 1H), 3.73 – 3.66 (m, 1H), 3.64 – 3.54 (m, 2H), 2.93– 2.87 (m, 6H), 2.65 – 2.52 (m, 2H), 2.29 – 2.21 (m, 4H), 2.21 – 2.13 1.41 – 1.30 (m, 6H), 1.29 (d, J =7.2 Hz, 3H), 1.26 (d, J = 7.2 Hz, 3H), 0.91 – 0.77 (m, 18H).

[0315] Compound 52: Glu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0316] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 106 N 16 O 21 m / z: 712.39490 ([M+2H]) 2+ ), 1423.77335 ([M+H]) + ).

[0317] 1H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.5, 4.7 Hz, 1H), 4.39 – 4.14(m, 10H), 4.03 – 3.93 (m, 2H), 3.83 – 3.74 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63– 3.54 (m, 2H), 2.92 – 2.86 (m, 4H), 2.72 – 2.60 (m, 2H), 2.36 – 2.24 (m,6H), 2.21 – 2.12 (m, 2H), 2.08 – 1.79 (m, 19H, AcOH), 1.79 – 1.43 (m, 14H), 1.39 – 1.29 (m, 4H), 1.29 – 1.24 (m, 6H), 0.90 – 0.77 (m, 18H).

[0318] Compound 53: Lys-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0319] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 60 H 102 N 16 O 19 m / z: 676.38574 ([M+2H]) 2+ ), 1351.75361 ([M+H] + ).

[0320] 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 9.5, 4.7 Hz, 1H), 4.36 – 4.24(m, 5H), 4.24 – 4.13 (m, 4H), 4.00 – 3.94 (m, 2H), 3.93 – 3.89 (m, 2H), 3.80– 3.74 (m, 1H), 3.73 – 3.66 (m, 1H), 3.63 – 3.54 (m, 2H), 2.93 – 2.87 (m,4H), 2.68 – 2.55 (m, 2H), 2.29 – 2.23 (m, 4H), 2.20 – 2.13 (m, 2H), 2.07 –1.69 (m, 21H, AcOH), 1.67 – 1.42 (m, 8H), 1.42 – 1.29 (m, 4H), 1.29 – 1.24(m, 6H), 0.90 – 0.77 (m, 18H).

[0321] Compound 54: Glu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0322] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 59 H 97 N 15 O 21 m / z: 676.85849 ([M+2H]) 2+ ), 1352.70235 ([M+H]) + ).

[0323] 1H NMR (600 MHz, D2O) δ 4.55 (dd, J = 9.5, 4.7 Hz, 1H), 4.42 – 4.37(m, 1H), 4.36 – 4.13 (m, 8H), 4.03 – 3.96 (m, 2H), 3.96 – 3.85 (m, 2H), 3.82– 3.73 (m, 1H), 3.73 – 3.66 (m, 1H), 3.62 – 3.54 (m, 2H), 2.89 (t, J = 7.4 Hz, 2H), 2.76 – 2.64 (m, 2H), 2.41 – 2.29 (m, 4H), 2.27 (t, J = 7.6 Hz, 2H), 2.21– 2.12 (m, 2H), 2.10 – 1.83 (m, 15H, AcOH), 1.83 – 1.68 (m, 4H), 1.67 – 1.43(m, 6H), 1.39 – 1.28 (m, 2H), 1.28 – 1.24 (m, 6H), 0.90 – 0.77 (m, 18H).

[0324] Compound 55: Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0325] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 117 N 17 O 21 m / z: 766.94110 ([M+2H]) 2+ ), 1532.86012 ([M+H] + ).

[0326] 1H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.4, 4.9 Hz, 1H), 4.42 – 4.36 (m, 2H), 4.34 (dd, J = 8.3, 5.9 Hz, 1H), 4.31 – 4.24 (m, 3H), 4.24 – 4.15 (m,5H), 4.08 (d, J = 5.5 Hz, 1H), 3.99 (d, J = 8.1 Hz, 1H), 3.83 – 3.80 (m, 2H), 3.80 – 3.74 (m, 1H), 3.73 – 3.63 (m, 2H), 3.63 – 3.54 (m, 2H), 3.54 – 3.47(m, 1H), 2.89 (t, J = 7.4 Hz, 2H), 2.74 – 2.62 (m, 2H), 2.40 – 2.12 (m, 8H), 2.08 – 1.83 (m, 19H, AcOH), 1.82 – 1.68 (m, 5H), 1.67 – 1.42 (m, 9H), 1.38 – 1.28 (m, 2H), 1.28 – 1.23 (m, 6H), 1.00 (d, J = 6.9 Hz, 3H), 0.91 – 0.77 (m, 27H).

[0327] Compound 56: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate)

[0328] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 79 H 132 N 18 O 22 m / z: 843.49445 ([M+2H]) 2+ ), 1685.97986 ([M+H]) + ).

[0329] 1H NMR (600 MHz, D2O) δ 4.61 – 4.57 (m, 1H), 4.57 – 4.53 (m, 1H), 4.52– 4.48 (m, 1H), 4.40 (t, J = 7.4 Hz, 1H), 4.37 – 4.32 (m, 1H), 4.31 – 4.23(m, 4H), 4.23 – 4.10 (m, 5H), 4.08 (d, J = 5.4 Hz, 1H), 4.00 (d, J = 8.1 Hz,1H), 3.81 – 3.73 (m, 2H), 3.73 – 3.63 (m, 2H), 3.63 – 3.37 (m, 4H), 2.90 (t,J = 7.5 Hz, 2H), 2.76 – 2.67 (m, 1H), 2.63 – 2.53 (m, 1H), 2.40 – 2.28 (m,2H), 2.28 – 2.10 (m, 7H), 2.02 – 1.85 (m, 18H, AcOH), 1.83 – 1.70 (m, 6H), 1.67 – 1.46 (m, 12H), 1.40 – 1.30 (m, 2H), 1.27 (t, J = 7.4 Hz, 6H), 1.01 (d,J = 6.9 Hz, 3H), 0.90 – 0.75 (m, 33H).

[0330] Compound 57: Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate)

[0331] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 55 H 92 N 14 O 18 m / z: 619.34296 ([M+2H]) 2+ ), 1237.67627 ([M+H]) + ).

[0332] 1H NMR (600 MHz, D2O) δ 4.57 – 4.49 (m, 1H), 4.37 – 4.31 (m, 1H), 4.29(d, J = 7.6 Hz, 2H), 4.25 – 4.18 (m, 5H), 4.15 – 4.08 (m, 1H), 3.99 (d, J =8.1 Hz, 1H), 3.81 – 3.73 (m, 3H), 3.72 – 3.66 (m, 1H), 3.64 – 3.54 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.35 – 2.29 (m, 2H), 2.29 – 2.22 (m, 4H), 2.20 –2.12 (m, 2H), 2.05 – 1.86 (m, 15H, AcOH), 1.84 – 1.74 (m, 4H), 1.73 – 1.68(m, 1H), 1.67 – 1.61 (m, 1H), 1.60 – 1.50 (m, 4H), 1.50 – 1.42 (m, 1H), 1.36 – 1.29 (m, 2H), 1.29 – 1.24 (m, 6H), 0.89 – 0.85 (m, 5H), 0.84 – 0.77 (m, 13H).

[0333] Compound 58: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate)

[0334] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 66 H 110 N 16 O 20 m / z: 724.41187 ([M+2H]) 2+ ), 1447.81372 ([M+H]) + ).

[0335] 1H NMR (600 MHz, D2O) δ 4.60 – 4.56 (m, 1H), 4.56 – 4.52 (m, 1H), 4.39 – 4.32 (m, 2H), 4.31 – 4.27 (m, 2H), 4.27 – 4.23 (m, 2H), 4.23 – 4.15 (m,4H), 4.12 (t, J = 6.7 Hz, 1H), 4.00 (d, J = 8.1 Hz, 1H), 3.81 – 3.75 (m, 1H), 3.70 (t, J = 8.3 Hz, 1H), 3.65 – 3.54 (m, 3H), 3.53 – 3.47 (m, 1H), 2.93 –2.86 (m, 2H), 2.73 (d, J = 5.1 Hz, 1H), 2.71 (d, J = 5.0 Hz, 1H), 2.61 – 2.54(m, 1H), 2.38 – 2.28 (m, 2H), 2.28 – 2.23 (m, 3H), 2.22 – 2.13 (m, 2H), 2.03 – 1.85 (m, 16H, AcOH)), 1.84 – 1.68 (m, 5H), 1.67 – 1.61 (m, 1H), 1.60 – 1.54(m, 3H), 1.54 – 1.45 (m, 5H), 1.42 (d, J = 7.0 Hz, 3H), 1.39 – 1.30 (m, 2H), 1.29 (d, J = 7.2 Hz, 3H), 1.26 (d, J = 7.1 Hz, 3H), 0.90 – 0.86 (m, 5H), 0.84– 0.78 (m, 16H), 0.77 (d, J = 5.3 Hz, 3H).

[0336] Compound 59: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala-Gly-Leu-Asp (acetate)

[0337] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 78 H 129 N 19 O 25 m / z: 866.97784 ([M+2H]) 2+ ), 1732.94507 ([M+H]) + ).

[0338] 1 H NMR (600 MHz, D2O) δ 4.58 – 4.53 (m, 2H), 4.44 – 4.41 (m, 1H), 4.36 – 4.33 (m, 1H), 4.32 – 4.27 (m, 4H), 4.26 – 4.17 (m, 7H), 4.00 (d, J = 8.0Hz, 1H), 3.85 – 3.82 (m, 2H), 3.80 – 3.75 (m, 1H), 3.73 – 3.67 (m, 1H), 3.64– 3.54 (m, 2H), 3.36 – 3.25 (m, 2H), 2.94 – 2.85 (m, 2H), 2.78 – 2.71 (m,2H), 2.71 – 2.65 (m, 1H), 2.65 – 2.58 (m, 1H), 2.40 – 2.29 (m, 3H), 2.27 –2.22 (m, 2H), 2.21 – 2.13 (m, 2H), 2.02 – 1.85 (m, 18H, AcOH)), 1.81 – 1.75(m, 3H), 1.74 – 1.68 (m, 1H), 1.68 – 1.62 (m, 1H), 1.62 – 1.43 (m, 12H), 1.39– 1.31 (m, 2H), 1.30 (d, J = 7.0 Hz, 6H), 1.27 (d, J = 7.2 Hz, 3H), 0.90 –0.86 (m, 5H), 0.85 – 0.80 (m, 16H), 0.79 (d, J = 6.3 Hz, 3H), 0.78 – 0.75 (m,6H).

[0339] Compound 60: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu (acetate)

[0340] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 79 H 132 N 18 O 22 m / z: 843.49530 ([M+2H]) 2+ ), 1685.98096 ([M+H] + ).

[0341] 1 H NMR (600 MHz, D2O) δ 4.58 – 4.50 (m, 2H), 4.37 – 4.28 (m, 5H), 4.28 – 4.16 (m, 6H), 4.15 – 4.08 (m, 1H), 4.00 (d, J = 8.0 Hz, 1H), 3.82 – 3.73(m, 2H), 3.72 – 3.67 (m, 1H), 3.64 – 3.56 (m, 3H), 3.37 – 3.32 (m, 1H), 3.31 – 3.26 (m, 1H), 2.93 – 2.86 (m, 2H), 2.70 – 2.63 (m, 1H), 2.59 – 2.52 (m,1H), 2.40 – 2.30 (m, 3H), 2.29 – 2.22 (m, 2H), 2.22 – 2.14 (m, 3H), 2.03 –1.82 (m, 19H, AcOH), 1.82 – 1.69 (m, 4H), 1.68 (s, 1H), 1.62 – 1.44 (m, 11H), 1.40 – 1.31 (m, 2H), 1.31 (d, J = 7.3 Hz, 3H), 1.27 (d, J = 7.2 Hz, 3H), 0.94– 0.85 (m, 9H), 0.85 – 0.81 (m, 18H), 0.79 (d, J = 6.5 Hz, 6H), 0.76 (d, J =5.7 Hz, 3H).

[0342] Compound 61:Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Pro-Val-Pro-Leu

[0343] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 84 H 139 N 19 O 23 m / z: 892.02161 ([M+2H]) 2+ ).

[0344] 1H NMR (600 MHz, D2O) δ 4.48 – 4.39 (m, 3H), 4.28 – 4.16 (m, 7H), 4.15– 4.06 (m, 5H), 4.01 (dd, J = 9.7, 5.2 Hz, 1H), 3.89 (d, J = 8.1 Hz, 1H),3.72 – 3.64 (m, 2H), 3.64 – 3.56 (m, 2H), 3.54 – 3.35 (m, 4H), 3.26 – 3.14(m, 2H), 2.79 (t, J = 7.6 Hz, 2H), 2.61 – 2.53 (m, 1H), 2.48 – 2.40 (m, 1H),2.30 – 2.19 (m, 3H), 2.18 – 2.12 (m, 2H), 2.10 – 2.03 (m, 3H), 1.92 – 1.71(m, 24H, AcOH), 1.71 – 1.31 (m, 17H), 1.30 – 1.21 (m, 2H), 1.20 (d, J = 7.3Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H), 0.85 – 0.67 (m, 36H).

[0345] Compound 62:

[0346] Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu (acetate)

[0347] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 92 H 155 N 21 O 25 m / z: 978.08408 ([M+2H]) 2+ ), 1955.14559 ([M+H] + ).

[0348] 1H NMR (600 MHz, D2O) δ 4.57 – 4.51 (m, 2H), 4.39 (t, J = 7.5 Hz, 1H), 4.37 – 4.27 (m, 5H), 4.27 – 4.15 (m, 7H), 4.11 (dd, J = 9.1, 5.6 Hz, 1H), 4.08 (d, J = 5.4 Hz, 1H), 3.99 (d, J = 8.0 Hz, 1H), 3.84 – 3.80 (m, 2H), 3.79– 3.64 (m, 3H), 3.63 – 3.35 (m, 4H), 2.89 (t, J = 7.5 Hz, 2H), 2.72 – 2.65(m, 1H), 2.39 – 2.27 (m, 2H), 2.39 – 2.27 (m, 2H), 2.27 – 2.06 (m, 7H), 2.03– 1.68 (m, 27H, AcOH), 1.68 – 1.42 (m, 15H), 1.39 – 1.28 (m, 2H), 1.28 – 1.24 (m, 6H), 1.00 (d, J = 7.0 Hz, 3H), 0.91 – 0.77 (m, 42H), 0.75 (d, J = 5.8 Hz, 3H).

[0349] Compound 63:

[0350] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0351] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 111 H 182 N 28 O 35 m / z: 823.79035 ([M+3H]) 3+ ), 1235.17867 ([M+2H]) 2+ ).

[0352] 1H NMR (600 MHz, D2O) δ 4.59 – 4.51 (m, 3H), 4.39 (dd, J = 6.8, 5.2Hz, 1H), 4.37 – 4.32 (m, 2H), 4.31 – 4.18 (m, 14H), 4.02 – 3.97 (m, 2H), 3.83(s, 2H), 3.80 – 3.67 (m, 3H), 3.62 – 3.55 (m, 3H), 3.37 – 3.24 (m, 2H), 2.92– 2.86 (m, 4H), 2.74 – 2.60 (m, 4H), 2.41 – 2.22 (m, 9H), 2.20 – 2.13 (m,3H), 2.08 – 1.82 (m, 35H), 1.82 – 1.67 (m, 8H), 1.67 – 1.42 (m, 12H), 1.40 –1.30 (m, 4H), 1.30 – 1.23 (m, 12H), 0.92 – 0.76 (m, 36H).

[0353] Compound 64:

[0354] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0355] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 117 H 193 N 29 O 36 m / z: 861.48234 ([M+3H]) 3+ ), 1291.71630 ([M+2H] 2+ ).

[0356] 1H NMR (600 MHz, D2O) δ 4.59 – 4.52 (m, 3H), 4.39 (dd, J = 6.9, 5.1Hz, 1H), 4.37 – 4.32 (m, 2H), 4.32 – 4.27 (m, 5H), 4.26 – 4.24 (m, 1H), 4.24– 4.18 (m, 9H), 4.00 – 3.97 (m, 2H), 3.83 – 3.80 (m, 2H), 3.80 – 3.74 (m,2H), 3.73 – 3.66 (m, 2H), 3.62 – 3.55 (m, 3H), 3.36 – 3.25 (m, 2H), 2.92 –2.86 (m, 4H), 2.75 – 2.64 (m, 3H), 2.61 – 2.55 (m, 1H), 2.41 – 2.31 (m, 4H), 2.30 – 2.12 (m, 8H), 2.07 – 1.83 (m, 36H, AcOH), 1.82 – 1.68 (m, 8H), 1.67 –1.42 (m, 15H), 1.41 – 1.30 (m, 4H), 1.30 – 1.24 (m, 12H), 0.92 – 0.74 (m,42H).

[0357] Compound 65: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Leu

[0358] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 64 H 107 N 15 O 19 m / z: 695.90275 ([M+2H]) 2+ ), 1390.78841 ([M+H] + ).

[0359] Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Ala (acetate)

[0360] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 61 H 101 N 15 O 19 m / z: 674.87902 ([M+2H]) 2+ ).

[0361] 1 H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.7 Hz, 1H), 4.34 (dd, J =8.4, 5.8 Hz, 1H), 4.31 – 4.27 (m, 3H), 4.27 – 4.17 (m, 6H), 4.06 (q, J = 7.2Hz, 1H), 3.98 (d, J = 8.1 Hz, 1H), 3.80 – 3.74 (m, 1H), 3.73 – 3.65 (m, 1H), 3.63 – 3.54 (m, 2H), 3.37 – 3.24 (m, 2H), 2.89 (t, J = 7.6 Hz, 2H), 2.40 –2.22 (m, 7H), 2.22 – 2.12 (m, 2H), 2.05 – 1.81 (m, 19H, AcOH), 1.81 – 1.66(m, 4H), 1.66 – 1.42 (m, 6H), 1.41 – 1.30 (m, 2H), 1.30 – 1.23 (m, 9H), 0.91– 0.77 (m, 18H).

[0362] Compound 67: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate)

[0363] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 53 H 89 N 13 O 17 m / z: 590.83474 ([M+2H]) 2+ ), 1180.65606 ([M+H] + ).

[0364] 1H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.4, 4.6 Hz, 1H), 4.37 – 4.31(m, 1H), 4.31 – 4.15 (m, 6H), 4.13 – 4.06 (m, 1H), 4.02 – 3.94 (m, 2H), 3.83– 3.66 (m, 2H), 3.64 – 3.53 (m, 2H), 2.88 (t, J = 7.5 Hz, 2H), 2.38 – 2.30(m, 2H), 2.29 – 2.22 (m, 4H), 2.21 – 2.12 (m, 2H), 2.06 – 1.45 (m, 26H,AcOH), 1.43 (d, J = 7.2 Hz, 3H), 1.35 – 1.28 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H), 0.92 – 0.75 (m, 18H).

[0365] Compound 68: Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate)

[0366] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 69 H 116 N 16 O 20 m / z: 745.43743 ([M+2H]) 2+ ), 1489.85546 ([M+H]) + ).

[0367] 1H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.5, 4.8 Hz, 1H), 4.41 – 4.31(m, 2H), 4.31 – 4.26 (m, 2H), 4.26 – 4.14 (m, 6H), 4.13 – 4.06 (m, 2H), 4.03– 3.96 (m, 1H), 3.80 – 3.49 (m, 5H), 2.88 (t, J = 7.5 Hz, 2H), 2.40 – 2.29(m, 2H), 2.29 – 2.12 (m, 8H), 2.05 – 1.68 (m, 24H, AcOH), 1.67 – 1.43 (m,9H), 1.38 – 1.28 (m, 2H), 1.28 – 1.24 (m, 6H), 1.00 (d, J = 6.9 Hz, 3H), 0.91– 0.77 (m, 27H).

[0368] Compound 69: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln (acetate)

[0369] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 48 H 82 N 12 O 14 m / z: 526.31294 ([M+2H]) 2+ ), 1051.61322 ([M+H]) + .

[0370] 11H NMR (600 MHz, D2O) δ 4.52 (dd, J = 9.6, 4.7 Hz, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.31 – 4.19 (m, 5H), 4.08 (dd, J = 8.8, 4.8 Hz, 1H), 4.01 – 3.95 (m, 2H), 3.80 – 3.67 (m, 2H), 3.65 – 3.54 (m, 2H), 2.89 (t, J = 7.5 Hz, 2H), 2.34 – 2.26 (m, 2H), 2.26 – 2.12 (m, 4H), 2.04 – 1.69 (m, 18H, AcOH), 1.68 – 1.45 (m, 6H), 1.43 (d, J = 7.2 Hz, 3H), 1.39 – 1.28 (m, 2H), 1.27 (d, J = 7.2 Hz, 3H), 0.93 – 0.76 (m, 18H).

[0371] Compound 70: Arg-Lys-Asp-Val-Tyr-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0372] 1H NMR (600 MHz, D2O) δ 7.02 (d, J = 8.5 Hz, 2H), 6.72 (d, J = 8.4 Hz, 2H), 4.54 – 4.44 (m, 3H), 4.36 – 4.24 (m, 6H), 4.23 – 4.14 (m, 4H), 4.01 – 3.97 (m, 1H), 3.97 – 3.91 (m, 2H), 3.81 – 3.64 (m, 4H), 3.60 – 3.52 (m, 2H), 3.15 – 3.06 (m, 2H), 3.02 – 2.96 (m, 1H), 2.91 – 2.79 (m, 5H), 2.68 – 2.46(m, 4H), 2.32 – 2.21 (m, 4H), 2.20 – 2.10 (m, 2H), 2.07 – 1.99 (m, 1H), 1.99– 1.67 (m, 25H), 1.66 – 1.42 (m, 11H), 1.37 – 1.28 (m, 3H), 1.28 – 1.23 (m,6H), 0.91 – 0.74 (m, 18H), 0.68 (dd, J = 6.7, 2.7 Hz, 6H).

[0373] Compound 71: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Cys-Gly (acetate)

[0374] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 104 N 16 O 20 S; m / z: 719.37693 ([M+2H] 2+ ), 1437.73683 ([M+H) + ).

[0375] 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.7 Hz, 1H), 4.46 (dd, J =7.2, 5.2 Hz, 1H), 4.34 (dd, J = 8.3, 5.9 Hz, 1H), 4.31 – 4.26 (m, 4H), 4.26 – 4.14 (m, 5H), 3.98 (d, J = 8.0 Hz, 1H), 3.81 – 3.74 (m, 1H), 3.71 (s, 2H), 3.71 – 3.67 (m, 1H), 3.63 – 3.54 (m, 2H), 3.36 – 3.25 (m, 2H), 2.91 – 2.79(m, 4H), 2.40 – 2.23 (m, 7H), 2.22 – 2.12 (m, 2H), 2.08 – 1.85 (m, 19H,AcOH), 1.81 – 1.61 (m, 5H), 1.61 – 1.43 (m, 5H), 1.39 – 1.30 (m, 2H), 1.30 (d, J = 7.3 Hz, 3H), 1.26 (d, J = 7.2 Hz, 3H), 0.93 – 0.76 (m, 18H).

[0376] Compound 72:

[0377] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0378] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 99 H 161 N 23 O 29 m / z: 713.40155 ([M+3H]) 3+ ), 1069.59802 ([M+2H] 2+ ).

[0379] 1H NMR (600 MHz, D2O) δ 4.59 – 4.54 (m, 2H), 4.42 – 4.38 (m, 1H), 4.37– 4.33 (m, 3H), 4.30 (t, J = 7.4 Hz, 5H), 4.28 – 4.25 (m, 2H), 4.25 – 4.20(m, 6H), 4.20 – 4.11 (m, 2H), 4.00 (d, J = 8.2 Hz, 1H), 3.81 – 3.74 (m, 3H), 3.73 – 3.67 (m, 2H), 3.64 – 3.55 (m, 5H), 3.37 – 3.24 (m, 2H), 2.90 (t, J =7.4 Hz, 2H), 2.75 – 2.65 (m, 2H), 2.42 – 2.31 (m, 5H), 2.28 (t, J = 7.6 Hz, 3H), 2.22 – 2.13 (m, 5H), 2.07 –1.83 (m, 30H, AcOH), 1.83 – 1.74 (m, 7H),1.73 – 1.69 (m, 1H), 1.68 – 1.62 (m, 1H), 1.62 – 1.50 (m, 6H), 1.50 – 1.42(m, 2H), 1.39 – 1.31 (m, 2H), 1.31 – 1.25 (m, 12H), 0.90 – 0.86 (m, 12H), 0.85 – 0.77 (m, 24H).

[0380] Compound 73: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Glu-Cys-Gly

[0381] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 120 N 18 O 24 S; m / z: 833.42972 ([M+2H]) 2+ ), 1665.83408 ([M+H] + ).

[0382] Compound 74: Ala-Ala-Ala-Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0383] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 72 H 119 N 19 O 23 m / z: 809.94612 ([M+2H]) 2+ ), 1618.87350 ([M+H] + ).

[0384] 1 H NMR (600 MHz, D2O) δ 4.57 – 4.45 (m, 2H), 4.39 – 4.31 (m, 2H), 4.31– 4.13 (m, 11H), 3.98 (dd, J = 7.8, 5.9 Hz, 2H), 3.80 – 3.74 (m, 1H), 3.73 –3.66 (m, 2H), 3.63 – 3.47 (m, 3H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 – 2.61 (m,2H), 2.39 – 2.29 (m, 2H), 2.27 (t, J = 7.6 Hz, 2H), 2.24 – 2.12 (m, 3H), 2.08– 1.68 (m, 21H, AcOH), 1.68 – 1.44 (m, 6H), 1.43 (d, J = 7.1 Hz, 3H), 1.40 –1.30 (m, 2H), 1.30 – 1.23 (m, 18H), 0.92 – 0.77 (m, 18H).

[0385] Compound 75: Ala-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0386] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 81 H 133 N 19 O 23 m / z: 870.99892 ([M+2H]) 2+ ).

[0387] 1H NMR (600 MHz, D2O) δ 4.54 (dd, J = 9.5, 4.9 Hz, 1H), 4.49 (dd, J =9.7, 4.9 Hz, 1H), 4.42 (dd, J = 8.3, 6.4 Hz, 1H), 4.40 – 4.24 (m, 9H), 4.23 –4.10 (m, 4H), 3.99 (d, J = 8.2 Hz, 1H), 3.80 – 3.67 (m, 3H), 3.64 – 3.43 (m,6H), 2.89 (t, J = 7.4 Hz, 2H), 2.73 – 2.61 (m, 2H), 2.40 – 2.29 (m, 2H), 2.27(t, J = 7.6 Hz, 2H), 2.25 – 2.08 (m, 5H), 2.07 – 1.68 (m, 29H, AcOH), 1.68 –1.44 (m, 9H), 1.42 (d, J = 7.1 Hz, 3H), 1.37 – 1.29 (m, 2H), 1.29 – 1.22 (m, 6H), 0.92 – 0.76 (m, 30H).

[0388] Compound 76: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp acetate

[0389] 11H NMR (600 MHz, DMSO) δ 8.27 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 7.8Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.4Hz, 1H), 7.94 (dd, J = 16.7, 8.0 Hz, 2H), 7.58 (d, J = 6.3 Hz, 1H), 7.51 (d,J = 8.6 Hz, 1H), 7.16 (s, 1H), 6.70 (s, 1H), 4.48 (dd, J = 13.3, 7.9 Hz, 1H),4.39 (dd, J = 8.2, 4.2 Hz, 1H), 4.35-4.21 (m, 6H), 4.18-4.03 (m, 3H), 3.71-3.47 (m, 5H), 2.93-2.69 (m, 4H), 2.45-2.32 (m, 2H), 2.25 (t, J = 7.7 Hz, 2H),2.08 (t, J = 7.9 Hz, 2H), 2.01-1.93 (m, 3H), 1.93-1.84 (m, 14H, AcOH), 1.84-1.76 (m, 3H), 1.75-1.57 (m, 8H), 1.54-1.39 (m, 5H), 1.36-1.27 (m, 2H), 1.21-1.10 (m, 6H), 0.91-0.74 (m, 18H).

[0390] Example 2: Anti-ulcer effect of polypeptide (Compound 76) on ethanol-induced gastric ulcer model in mice

[0391] 1. Experimental animals: SPF-grade C57BL / 6 mice, Chengdu Yakang Biotechnology Co., Ltd., animal license number: SCXK(Sichuan)2020-034.

[0392] 2. Method: After the experimental animals were adaptively fed, the mice were randomly divided into 4 groups with 10 mice in each group, namely: control group (blank group), model group (modeled with absolute ethanol), positive drug group (tiopronin 160 mg / kg), and compound 76 group (1 mg / kg). After the animals were grouped, except for the control group and the model group which were treated with pure water, the other dosing groups were treated with the corresponding drugs once a day for 8 consecutive days. After dosing on the 7th day, all animals were fasted but allowed to drink water for 24 h. 30 min after dosing on the 8th day, 0.15 mL of absolute ethanol was orally administered to the mice in each group (except the control group) for modeling. 1 h later, the animals were sacrificed by excessive inhalation of CO2. The gastric cardia was ligated and the pylorus was clamped, and the whole stomach was removed. 1 mL of 1% formaldehyde solution was injected into the gastric body, the cardia was ligated, and the stomach was immediately placed in 1% formaldehyde solution for fixation for 25 min. The stomach was cut along the greater curvature, the gastric contents were washed clean with normal saline, and the ulcer index was calculated after spreading. Method for calculating the ulcer index: For linear lesions with a length greater than 1 mm, measure the length and count 1 point per millimeter; if the width is greater than 1 mm, double the score according to the number of millimeters of the width; for lesions with a length less than 1 mm, count 0.5 points, and add up the scores to obtain the ulcer index of the animal.

[0393] 3. Results:

[0394] In the ethanol-induced gastric ulcer model of mice, oral gavage of compound 76 once a day for 8 consecutive days could significantly reduce the gastric ulcer index of mice, and the effect was better than that of the positive drug group (Table 3). The results showed that compound 76 had a significant effect on the treatment of gastric ulcers.

[0395] Table 3. Effects of the test drugs on the ulcer index of mice with ethanol-induced gastric ulcers (n = 10, ±s)

[0396] Grouping Ulcer Index control group 1.84±1.62 Model group <![CDATA[35.32±23.30 ## ]]> Teprenone group 13.42±7.61* Group 76 of compounds 8.13±4.17**

[0397] Note: Compared with the control group, ## P < 0.01; compared with the model group, *P < 0.05, **P < 0.01

[0398] Example 3: Anti-ulcer activity of compound 1-76 samples on the ethanol-induced gastric ulcer model in mice

[0399] 1. Experimental animals: SPF-grade C57BL / 6 mice, Chengdu Yakang Biotech Co., Ltd., animal license number: SCXK (Sichuan) 2020-034

[0400] 2. Method:

[0401] After acclimatization, all experimental animals were fasted for 24 hours with free access to water one day before the experiment. Before modeling, mice were randomly divided into three groups: a control group (n=5), a model group (n=10), and each of the drug-treated groups (n=10). Except for the control and model groups, which were administered purified water by gavage, the drug-treated groups were administered different test samples by gavage at a dose of 0.2 mg / kg. One hour after administration, each group of mice was orally administered 0.9 ml / kg of anhydrous ethanol to induce the model. One hour later, the animals were sacrificed by cervical dislocation, the gastric cardia and pylorus were ligated, and the entire stomach was removed. 1 mL of 1% formaldehyde solution was injected into the stomach, the cardia was ligated, and the stomach was immediately immersed in 1% formaldehyde solution after removal. After soaking for 30 minutes, the stomach tissue was removed, cut along the greater curvature, and the stomach contents were rinsed clean with physiological saline. The stomach was then laid flat to observe and measure the damage to the gastric mucosa, and the ulcer index and ulcer inhibition rate were calculated.

[0402] Ulcer Index Calculation Method: For linear lesions longer than 1 mm, measure their length and score 1 point per millimeter; if their width is greater than 1 mm, double the score based on the width in millimeters; if the length is less than 1 mm, score 0.5 points. Add the scores together to obtain the ulcer index of the animal.

[0403] Ulcer inhibition rate = (Ulcer index of model group - Ulcer index of treatment group) / Ulcer index of model group × 100%;

[0404] Relative ulcer inhibition rate = (ulcer inhibition rate of test compound) / (ulcer inhibition rate of compound 76).

[0405] 3. Results: Table 5 shows the relative anti-ulcer activity of compounds 1-76 relative to compound 76:

[0406]

[0407] *Note: The anti-ulcer activity of each compound was determined through multiple batches of experiments. For ease of comparison, the anti-ulcer activity is expressed as the average of the relative ulcer inhibition rate (compound 76 was used as the control group in each batch of experiments).

[0408] Relative ulcer inhibition rate = (ulcer inhibition rate of test compound) / (ulcer inhibition rate of compound 76)

[0409] A relative ulcer inhibition rate >1.50 is indicated as "+++++";

[0410] A relative ulcer inhibition rate >1.20 is indicated as "++++";

[0411] The relative ulcer inhibition rate was 0.9-1.20, denoted as "+++";

[0412] The relative ulcer inhibition rate is 0.6-0.9, indicated by "++";

[0413] “NA” indicates that it was not detected.

[0414] Example 4: Do compounds 34, 36, 38, and 39 promote the growth of gastric organoids in mice?

[0415] Experimental Methods: After thawing cryopreserved mouse organoids, they were expanded in 6-well plates. Once the organoids reached sufficient quantity, the 6-well plates were removed, the old culture medium was discarded, and Dispase II was added to each well. Matrigel droplets in the 6-well plates were collected using a 1 mL pipette tip and transferred to 15 mL centrifuge tubes. The cells were then digested into single cells using L-TrypLE. After centrifugation, the supernatant was discarded, and the cells were resuspended in 1-3 mL of DMEM / F-12 solution. The mixture was stirred, and 10 µL was taken for cell counting. The total number of cells in the resuspended solution was calculated.

[0416] Take an appropriate volume of cell suspension and mix well with an appropriate amount of Matrigel. Seed 30 µL of Matrigel (containing approximately 500 cells) into 96-well plates. Incubate the 96-well plates at 37°C for 20 min to allow the Matrigel to solidify. The control group received 140 µL of organoid culture medium, while the treatment groups received 140 µL of organoid culture medium containing different concentrations of elongation peptides. Each elongation peptide was prepared at three concentrations: 1 µM, 5 µM, and 10 µM. Incubate the plates at 37°C for 9 days, changing the medium every 48 hours. On day 9, remove the plates and analyze organoid viability using CelltiterGlo (CTG).

[0417] The experimental results are shown in Figures 2-5 .in, Figure 2 (*p<0.05, **p<0.01, ***p<0.001 compared to the control group, one-way ANOVA) and Figure 4 (*p<0.05, **p<0.01, one-way ANOVA compared with the control group) Each concentration significantly increased CTG readings compared with the control group, showing a certain dose-dependent effect, with the best trend at 5µM concentration. Figure 3 (*p<0.05, **p<0.01 compared with the control group, one-way ANOVA) 1µM and 5µM significantly increased CTG readings compared with the control group, showing a certain dose-dependent effect; at 10µM, there was a trend of increasing but no significant difference. Figure 5 (No significant difference compared to the control group, one-way ANOVA) CTG readings showed a trend of increasing at 1 µM and 5 µM concentrations, but no significant difference was observed; at 10 µM concentration, there was no obvious trend compared to the control group. This suggests that compounds 34, 36, and 38 promote the growth of mouse gastric organoids in a dose-dependent manner.

[0418] Although the present invention has disclosed the above embodiments, the implementation of the present invention is not limited to the above embodiments. Any other changes, modifications, substitutions, combinations, or simplifications that do not depart from the present invention should be considered as equivalent substitutions and are included within the protection scope of the present invention.

Claims

1. A compound of formula (I) or a physiologically compatible salt thereof, wherein the compound of formula (I) is selected from: Compound 67: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu Compound 57: Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Ala or Compound 68: Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu.

2. Use of the compound of claim 1 or a physiologically compatible salt thereof in the preparation of a medicament for repairing gastric ulcers.

3. A food product for the auxiliary protection of the gastric mucosa, the food product comprising at least one compound of claim 1 or a physiologically compatible salt thereof and a physiologically acceptable carrier.

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