Polypeptides and their use in repairing mucosal or skin lesions

Abstract

The present application relates to polypeptides and their use in repairing mucosal damage or skin damage, the polypeptides of the present application have no homology with known polypeptides, and can stably exist in vivo and in vitro, have the effect of regulating stem cell proliferation and differentiation to repair mucosal damage or skin damage; and relate to the use of the novel polypeptides to repair mucosal damage or skin damage by regulating stem cell proliferation and differentiation, and the use for preventing, alleviating or treating gastrointestinal diseases.

Description

TECHNICAL FIELD

[0001] The present application relates to polypeptides and their use in repairing mucosal injury or skin injury, the polypeptides of the present application have no homology with known polypeptides, and can stably exist in vivo and in vitro, have the effect of regulating stem cell proliferation and differentiation, repairing mucosal injury or skin injury, and relates to the use of the novel polypeptides for repairing mucosal injury or skin injury by regulating stem cell proliferation and differentiation, and for preventing, alleviating or treating gastrointestinal diseases. BACKGROUND

[0002] Skin injury and / or mucosal injury is a common pathological feature of many diseases. Skin injury refers to damage to normal skin (tissue) caused by external injury factors such as surgery, external force, heat, electric current, chemicals, low temperature and internal factors such as local blood supply disorders. Skin injury is often accompanied by damage to skin integrity and loss of a certain amount of normal tissue, and the normal function of the skin is impaired. It is also called a wound or a trauma. There are currently protein / polypeptide drugs including basic fibroblast growth factor, epidermal growth factor, platelet growth factor, granulocyte-macrophage colony-stimulating factor and growth hormone, which have obvious effects of repairing wounds, skin care, anti-wrinkle and anti-aging, but the long amino acid sequence of these protein / polypeptide drugs leads to high preparation cost, poor stability and other shortcomings, thus their application is limited to a certain extent.

[0003] Human mucosa refers to the inner layer of the respiratory system, the digestive system, the reproductive and urinary system, etc. It is the second largest barrier in the human body next to the skin, including the oral cavity, pharynx, trachea, esophagus, stomach, intestinal tract, vagina, bladder, etc. The tube walls or capsule walls of these organs have common layering rules and characteristics suitable for their functions, and have common characteristics in embryonic origin, tissue structure, pathological process, clinical manifestations, prognosis, etc.

[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 various 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 and progression 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 typically begins within minutes of injury, rapidly repairing superficial lesions through cell migration; regeneration, on the other hand, involves the differentiation and proliferation of stem cells and progenitor cells, resulting in continuous regeneration 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

[0010] 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 -

[0011] Xaa 23 Xaa 24 Xaa 25 -OH (I)

[0012] wherein

[0013] Xaa1is Ala or absent;

[0014] Xaa2is Ala or absent;

[0015] Xaa3is Ala, Arg, Glu or absent;

[0016] Xaa4is Pro, Lys, Ala or absent;

[0017] Xaa5is Glu, Val, Asp, Gin, Lys, Ala, Pro or absent;

[0018] Xaa6is Pro, Gin, Lys, Val, Ala or absent;

[0019] Xaa7is Ala, Leu, Gly, Lys, Gin, Glu, Val, Asp, Pro, Tyr or absent;

[0020] Xaa8is Pro, Leu, Lys, Glu, Gly, lie, Leu, Val, Gly, Ala or absent;

[0021] Xaa 10 Xaa 11 is Val-Lys-Gln, Ala-Gly-Leu, Ala-Ala-Val, Val-Pro-Ala;

[0022] Xaa 12 is Asp, Ala, Gin, Lys, Glu, Ala or absent;

[0023] Xaa 13 is Ala, Leu, Gly, Lys, Gin, Asp, Cys, Glu or absent;

[0024] Xaa 14 is Ala, Leu, Val, Pro, Gly, Glu or absent;

[0025] Xaa 15 -Xaa 16 is Gly-Leu, Pro-Leu, Val-Pro, Pro-Leu, Ala-Glu, Ala-Ala, Val-Pro, Cys-Gly or absent;

[0026] Xaa 17 is Asp, Leu, Pro, Glu or absent;

[0027] Xaa 18 -Xaa 19 -Xaa 20 -Xaa 21 is Val-Lys-Gln-Asp, Pro-Val-Pro-Leu, Val-Pro-Leu-Val or absent; Xaa 22 -Xaa 23 -Xaa 24 is Lys-Gln-Asp, Val-Lys-Gln or absent;

[0028] and Xaa 25 is Asp or absent;

[0029] The compound is at least 10 peptides.

[0030] In one embodiment, the compound is selected from:

[0031] Compound 1 : Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0032] Compound 2: Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0033] Compound 3: Gly-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0034] Compound 4: Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0035] Compound 5: Gln-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0036] Compound 6: Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0037] Compound 7: Glu-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0038] Compound 8: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0039] Compound 9: Val-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0040] Compound 10: Asp-Gln-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0041] Compound 11: Gln-Lys-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0042] Compound 12: Lys-Val-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0043] Compound 13: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala,

[0044] Compound 14: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu,

[0045] Compound 15: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly,

[0046] Compound 16: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Lys,

[0047] Compound 17: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gln,

[0048] Compound 18: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Asp,

[0049] Compound 19: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Ala,

[0050] Compound 20: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Gln,

[0051] Compound 21: Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0052] Compound 22: Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0053] Compound 23: Glu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0054] Compound 24: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Lys, Compound 25: Ala-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 26: Ala-Ile-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 27: Ala-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 28: Ala-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 29: Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 30: Leu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 31 : Lys-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 32: Glu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 33: Lys-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 35: Val-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,Compound 40: Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val- Lys-Gln-Asp, Compound 41 : Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu- Val-Lys-Gln-Asp,

[0055] Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 42:

[0056] Ala-Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln- Asp, Compound 43: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Gly-Leu-Asp, Compound 44: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Ala-Val-Asp, Compound 45: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu, Compound 46: Asp-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 47: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala, Compound 48: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala-Leu, Compound 49: Ala-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 50: Leu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 51 : Lys-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 52: Glu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0057] Compound 53: Lys-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0058] Compound 54: Glu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0059] Compound 55: Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0060] Compound 56: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu,

[0061] Compound 57: Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu,

[0062] Compound 58: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu,

[0063] Compound 59: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala-Gly-Leu-Asp, Compound 60: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu,

[0064] Compound 61: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Pro-Val-Pro-Leu, Compound 62:

[0065] Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu,

[0066] Compound 63:

[0067] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0068] Compound 64:

[0069] 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、

[0070] Compound 65: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Leu、

[0071] Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Ala、

[0072] Compound 67: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu、

[0073] Compound 68: Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu、

[0074] Compound 69: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln、

[0075] Compound 70: Arg-Lys-Asp-Val-Tyr-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 71 : Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Cys-Gly、

[0076] Compound 72:

[0077] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp、

[0078] Compound 73: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Glu-Cys-Gly、

[0079] Compound 74: Ala-Ala-Ala-Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val- Lys-Gln-Asp, Compound 75: Ala-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu- Val-Ala-Lys-Gln-Asp, Compound 76: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val- Lys-Gln-Asp.

[0080] For convenience, when describing the compounds of the application in the present application, the left-hand H and right-hand OH are omitted.

[0081] In one embodiment, Xaa9-Xaa 10 -Xaa 11 is Val-Lys-Gln.

[0082] In one embodiment, Xaa 12 is Asp.

[0083] In one embodiment, Xaa 12 is Glu.

[0084] In one embodiment, Xaa8is Pro, Val or Leu.

[0085] In one embodiment, the compound is selected from:

[0086] Compound 1 : Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0087] Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0088] Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp,

[0089] Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val- Lys-Gln-Asp, Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val- Lys-Gln-Asp, or

[0090] Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp.

[0091] In a second aspect, the present application provides a method for repairing a mucosal injury, which comprises administering to a subject a compound of the present application or a physiologically acceptable salt thereof or contacting the mucosal injury with a compound of the present application or a physiologically acceptable salt thereof.

[0092] In an embodiment, the repairing is performed by regulating the proliferation and differentiation of stem cells.

[0093] In an embodiment, the mucosal injury is a mucosal injury in a cavity of the digestive system, respiratory system, etc.

[0094] The mucosal injury in the digestive system is associated with oral cavity diseases, esophageal diseases and gastrointestinal diseases. The oral cavity diseases include oral cavity ulcer, oral cavity inflammation, gingivitis, periodontitis, etc. The esophageal diseases include esophagitis, esophageal ulcer, etc. The gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal disease, indigestion, precancerous lesion, digestive system tumor, gastrointestinal hemorrhage, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease and mucosal injury caused by radiotherapy and chemotherapy, but are not limited thereto.

[0095] In a preferred embodiment, the mucosa of the digestive tract includes gastric mucosa and intestinal mucosa.

[0096] In a preferred embodiment, the chronic gastritis includes chronic atrophic gastritis.

[0097] In a preferred embodiment, the mucosal injury is gastric mucosal injury caused by irritant substances or drugs, stress, etc. The irritant substances are, for example, hydrochloric acid, ethanol or alcohol, etc. The drugs are, for example, non-steroidal anti-inflammatory drugs such as aspirin or indometacin, carcinogens or acid suppressants, etc.

[0098] The present application provides a method for preventing, alleviating or treating a disease of the digestive tract or eliminating inflammatory edema, which comprises administering to a subject a compound of the present application or a physiologically acceptable salt thereof.

[0099] The disease of the digestive tract is associated with oral cavity diseases, esophageal diseases and gastrointestinal diseases. The oral cavity diseases include oral cavity ulcer, oral cavity inflammation, gingivitis, periodontitis, etc. The esophageal diseases include esophagitis, esophageal ulcer, etc. The gastrointestinal diseases include chronic gastritis, chronic atrophic gastritis, acute gastritis, gastroduodenal ulcer, functional gastrointestinal disease, indigestion, precancerous lesion, digestive system tumor, gastrointestinal hemorrhage, gastroesophageal reflux disease, acute and chronic enteritis, ulcerative colitis, Crohn's disease and mucosal injury caused by radiotherapy and chemotherapy, but are not limited thereto.

[0100] In one embodiment, the prevention, alleviation or treatment of gastrointestinal disease is carried out by regulating the proliferation and differentiation of stem cells. The method protects the gastrointestinal mucosa such as gastric mucosa or intestinal mucosa or repairs the damage of the gastrointestinal mucosa such as gastric mucosa or intestinal mucosa by the compound of the present application or a physiologically compatible salt thereof, thereby playing a role in the prevention, alleviation or treatment of gastrointestinal disease.

[0101] The present application provides a method for repairing a mucosal or skin wound, which comprises administering to a subject the compound of the present application or a physiologically compatible salt thereof. In one embodiment, the repair of a mucosal or skin wound comprises regulating the proliferation and differentiation of stem cells.

[0102] In the above method of the present application, the compound of the present application or a physiologically compatible salt thereof is administered by oral administration, injection, subcutaneous administration, etc.

[0103] In a third aspect, the present application provides a method for repairing a skin wound, which comprises contacting the skin wound with the compound of the present application or a physiologically compatible salt thereof.

[0104] In a preferred embodiment, the skin wound is associated with, but not limited to, epidermal inflammation, mechanical and surgical wounds, burns and scalds, ulcers, fistulae, bedsores, and skin damage caused by radiotherapy and chemotherapy.

[0105] In one embodiment, the skin wound refers to the damage of normal skin caused by external injury factors such as surgery, external force, heat, electric current, chemicals, low temperature, and internal factors of the body such as local blood supply disorder, etc.

[0106] In one embodiment, the skin wound is often accompanied by the destruction of skin integrity and the loss of a certain amount of normal tissue.

[0107] In another embodiment, the skin wound comprises the impairment of normal functions of the skin.

[0108] In one embodiment, the recovery of the skin wound is carried out by regulating the proliferation and differentiation of stem cells.

[0109] The present application provides a method for promoting the proliferation of HaCAT cells, which comprises contacting the cells with the compound of the present application or a physiologically compatible salt thereof.

[0110] In a fourth aspect, the present application provides a method for regenerating a damaged blood vessel, which comprises contacting the damaged blood vessel with the compound of the present application or a physiologically compatible salt thereof.

[0111] In a preferred embodiment, the damaged blood vessel comprises the blood vessel damage caused by gastrointestinal mucosal damage and skin damage.

[0112] In a fifth aspect, the present application provides a pharmaceutical, food, health care, cosmetic, or daily use composition, which comprises at least one compound of the present application or a physiologically compatible salt thereof and a physiologically acceptable carrier.

[0113] In one embodiment, the physiologically acceptable carrier comprises a pharmaceutically acceptable carrier or a cosmetically acceptable carrier. The pharmaceutical, food, health care, cosmetic, or daily use composition can be prepared according to conventional techniques of pharmacy or cosmetics, including mixing the compound of the present application as an active ingredient with a carrier to form a desired dosage form according to conventional techniques. The composition of the present application can be formulated into oral administration preparations, mucosal administration preparations, injection preparations, inhalation preparations, and external use preparations as needed.

[0114] The polypeptide of the present application has no homology with known polypeptides, and is easy to be artificially synthesized to obtain a high-purity polypeptide. The polypeptide of the present application is composed of at most 25 amino acid residues, which is less than that of an epidermal growth factor polypeptide, is stable in vivo, and can promote the proliferation and differentiation of stem cells, especially the proliferation and differentiation of gastric organoids, participate in and regulate the proliferation and differentiation of gastric epithelial stem cells, thereby repairing gastrointestinal stem cell and epidermal stem cell damage, and has the effects of significantly reducing the pathological development of gastrointestinal diseases such as chronic gastritis and digestive tract ulcers, eliminating inflammation and edema, promoting the repair of digestive tract mucosa damage and skin damage, shortening the wound healing time, regulating immune function, and the like. In addition, the polypeptide of the present application can function even after being sterilized by iodine preparations or hydrogen peroxide, or can stably exist in artificial gastric juice, artificial intestinal juice, and the like, while the epidermal growth factor cannot function after being sterilized by iodine preparations or hydrogen peroxide. BRIEF DESCRIPTION OF DRAWINGS

[0115] Figure 1 A schematic diagram showing the solid-phase synthesis steps of the polypeptide is shown;

[0116] Figure 2 Effects of compound 34 on the viability of mouse gastric organoids are shown;

[0117] Figure 3 Effects of compound 36 on the viability of mouse gastric organoids are shown;

[0118] Figure 4 Effects of compound 38 on the viability of mouse gastric organoids are shown;

[0119] Figure 5 Effects of compound 39 on the viability of mouse gastric organoids are shown. DETAILED DESCRIPTION

[0120] The term "physiologically compatible salts" refers to salts which are physiologically compatible (i.e. pharmacologically acceptable) and substantially non-toxic to the individual to whom the compounds of the present application will be administered. Physiologically compatible salts of the compounds of the present application include conventional and stoichiometric acid addition salts or base addition salts formed from suitable, non-toxic organic or inorganic acids or inorganic bases.

[0121] The term "subject" refers to an animal, preferably a mammal, most preferably a human. In particular, the term "subject" relates to a mammal or human having a skin lesion and / or a mucosal lesion. It will be understood by those skilled in the art that the repair of skin lesions and / or mucosal lesions according to the present application can be applied for cosmetic purposes (i.e. non-therapeutic purposes) and therapeutic purposes. For this reason, the term "skin lesion" according to the present application also includes skin lesions which are repaired for cosmetic purposes such as, for example, wrinkles (e.g. wrinkles caused by UV radiation), skin lines, cracks, bumps, large pores (e.g. associated with accessory structures such as sweat ducts, sebaceous glands or hair follicles), or uneven or rough, loss of skin elasticity (loss and / or inactivation of functional skin elastin), sagging (including eye and jaw puffiness), loss of skin firmness, loss of skin tightness, loss of skin's ability to recover after deformation, discoloration (including dark circles under the eyes), blemishes, sallow complexion, areas of excess pigmentation such as age spots and freckles, keratinous material, abnormal differentiation, hyperkeratinization, elastosis, destruction of collagen, and other tissue changes in the skin keratin, dermis, epidermis layer, skin vasculature (e.g. telangiectasia or arborizing blood vessels), and subcutaneous tissue, in particular close to the skin.

[0122] The following is a description of the application in connection with specific experiments, which is not intended to limit the scope of the application.

[0123] Table 1. English, abbreviation and corresponding Chinese name of solvents and reagents

[0124] English, abbreviations Chinese name 2-Chlorotrityl Chloride Resin 2-Chlorotriphenylmethyl chloride resin DMF N,N-Dimethylformamide DCM dichloromethane PIP Piperidine HOBt 1-Hydroxybenzotriazole DIPEA N,N-Diisopropylethylamine Methanol methanol tert-Butyl methyl ether Methyl tert-butyl ether TFA Trifluoroacetic acid TIS Triisopropylsilane DIC N,N'-Diisopropylcarbodiimide Ethanol ethanol Aa amino acids

[0125] Example 1: Chemical synthesis of polypeptides

[0126] The synthesis of polypeptide compounds is carried out by conventional solid phase synthesis method, through multiple cycles of resin swelling, amino acid substitution, deprotection, washing, and amino acid activation, condensation, washing, deprotection, and finally cleavage and side chain deprotection.

[0127] The schematic diagram of polypeptide solid phase synthesis steps is shown in Figure 1 . Figure 1 In the above, Cl-2-Cl-Resin represents 2-chlorotrityl chloride resin (2-Chlorotrityl Chloride Resin); Fmoc-Aa(n) etc. represents 9-fluorenylmethoxycarbonyl amino acid; TIPS is triisopropylsilane.

[0128] The following is an example of the synthesis and purification of compound 14 (Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu) using a polypeptide synthesizer of CS BIO Co., Ltd. with model number CS 136M.

[0129] The method comprises steps 1, preparation of a fully protected peptide resin; 2, cleavage and deprotection; 3, purification (salt exchange) and lyophilization.

[0130] Step 1, preparation of a fully protected peptide resin

[0131] (1) Preparation of Fmoc-Leu-Resin resin: 2.67 g of 2-Chlorotrityl Chloride Resin (SD = 0.75 mmol / g) was weighed into a synthesis tube of an automatic polypeptide synthesizer CS 136M, and the first amino acid substitution reaction and removal of the Fmoc protecting group were carried out using the program set on the polypeptide synthesizer. The specific reaction process is as follows: after the resin was swelled with DCM for 20 minutes, it was drained. Fmoc-Leu-OH (3 eq, 6 mmol) was dissolved in DMF (40 mL), and then DIPEA (7 eq, 14 mmol) was added. The Fmoc-Leu-OH / DIPEA DMF mixed solution was added to the reaction bottle containing the resin and reacted for 1 hour, and then drained. 40 mL of 20% MeOH / DMF was added and reacted for 30 minutes to cap, and then washed with DMF 3 times, and then removed the Fmoc protecting group with 20% PIP / DMF (v / v) and washed with DMF solution 5 times.

[0132] (2) Preparation of a fully protected peptide resin: adjust the circulating water bath temperature to 35°C, and use the coupling program set on the polypeptide synthesizer to sequentially couple the amino acids from the (n-1)th amino acid according to the polypeptide sequence. 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 bottle, and then DIC (4 eq, 8 mmol) was added to activate the amino acid. The Fmoc-Asp(OtBu)-OH / HOBt / DIC DMF mixed solution was added to the amino acid resin in the reaction bottle, and reacted for 1 hour. After the solvent was drained, the solid resin was washed with DMF solution 3 times, and then the Fmoc protecting group was removed with 20% PIP / DMF (v / v) and washed with DMF solution 5 times. Repeat the above steps until the entire amino acid sequence is coupled.

[0133] Step 2, cleavage

[0134] (1) Transfer the resin from the polypeptide synthesizer to a hand-tube with a frit and wash 5 times with DCM. Add 200 mL cleavage reagent (TFA:TIS:H20 = 95:2.5:2.5, v / v) to the hand-tube and bubble with N2for 1.5-3 hours.

[0135] (2) After the cleavage reaction is complete, filter the cleavage reagent into a 250 mL round bottom flask. After concentrating to one quarter of the original volume under vacuum, add 10 volumes of methyl tert-butyl ether and allow the white solid to settle. Filter the resulting mixture and rinse 3 times with 20 mL of methyl tert-butyl ether. Place the crude peptide product in a vacuum oven to remove excess solvent until the crude peptide is a powder. Obtain 1.70 g of crude peptide with a 61.7% crude yield.

[0136] Step 3, Purification, Salt Exchange and Lyophilization

[0137] Chromatography Parameters

[0138] Column: YMC-Actus Triart C18 30*250mm (L.D S-5um, 12nm)

[0139] Eluent Al: 0.1 M Acetic Acid

[0140] Eluent A2: 0.025 M Acetic Acid - 0.1 M Ammonium Acetate

[0141] Eluent B: Acetonitrile

[0142] Flow Rate: 25 mL / min

[0143] UV Detection Wavelength: 220 nm

[0144] Procedure Steps

[0145] a) Equilibrate column with 95% Al + 5% B

[0146] b) Inject, 0.464 g sample dissolved in 8 mL purified water and filtered through a 0.45 um filter.

[0147] c) Equilibrate column with 95% A2 + 5% B

[0148] d) Gradient elution of Al and B with the following gradient

[0149] time min A1% (0.1M acetic acid) Acetonitrile 0 95 5 15 70 30 17 5 95 20 5 95

[0150] e) Collect peptide of interest eluent

[0151] f) Concentrate by rotary evaporation: water bath temperature 40°C

[0152] g) Lyophilize

[0153] Purification of crude 0.464 g, pure product 0.371 g, purity: 100%, yield: 79.95%.

[0154] Other compounds were synthesized in a similar manner to that of compound 14. See Table 2 and other parts of the specification for results.

[0155] Table 2. Synthesized compounds

[0156]

[0157]

[0158]

[0159]

[0160] Note: Doublet charge peak indicates the target molecule binds 2 protons, triplet charge peak indicates the target molecule binds 3 protons; N / A represents crude product was not weighed, and the purification yield was not calculated.

[0161] Compound 1: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0162] High resolution mass spectrum (TOF-HRMS), molecular formula: C 60 H 99 N 15 O 19 ; m / z: 667.86710 ([M+2H 2+ ), 1334.72627 ([M+H + ).

[0163] Compound 2: Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0164] High resolution mass spectrum (TOF-HRMS), molecular formula: C 63 H 105 N 15 O 19 ; m / z: 688.89313 ([M+2H 2+ ). 1H NMR (600 MHz, D20) 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).

[0165] Compound 3: Gly-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0166] 1 H NMR (600 MHz, D20) 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 -

[0167] 1.42 (m, 29H, AcOH), 1.39 - 1.30 (m, 2H), 1.30 - 1.24 (m, 6H), 0.92 - 0.76 (m, 18H).

[0168] Compound 4: Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0169] 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 + ).

[0170] 1H NMR (600 MHz, D20) 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).

[0171] Compound 5: Gln-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0172] High resolution mass spectrum (TOF-HRMS), molecular formula: C 62 H 102 N 16 O 20 ; m / z: 696.38223 ([M+2H] 2+ ). 1 H NMR (600 MHz, D20) 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 = 8.2 Hz, 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).

[0173] Compound 6: Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0174] High resolution mass spectrum (TOF-HRMS), molecular formula: C 62 H 101 N 15 O 21; m / z: 786.95519 ([M+2H] 2+ ), 1392.73264 ([M+H] + ).

[0175] 1 H NMR (600 MHz, D20) 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).

[0176] Compound 7: Glu-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0177] 1 H NMR (600 MHz, D20) 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). 73 H 121 N 17 O 21 ; m / z: 786.95519 ([M+2H]2+ ). 1 H NMR (600 MHz, D20) 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).

[0178] Compound 9: Val-Pro-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0179] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 72 H 119 N 17 O 21 ; m / z: 779.94770 ([M+2H] 2+ ). 1 H NMR (600 MHz, D20) 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).

[0180] Compound 10: Asp-Gln-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0181] 1 H NMR (600 MHz, D20) 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).

[0182] Compound 11 : Gln-Lys-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0183] 1 H NMR (600 MHz, D20) 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).

[0184] Compound 12: Lys-Val-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0185] 1H NMR (600 MHz, D20) 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).

[0186] Compound 13: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala (acetate salt)

[0187] 1 H NMR (600 MHz, D20) 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).

[0188] Compound 14: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate salt)

[0189] 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 + ).

[0190] 1 H NMR (600 MHz, D20) δ 4.61 - 4.52 (m, 2H), 4.34 (dd, J = 8.4, 5.8 Hz, 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).

[0191] Compound 15: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly (acetate salt)

[0192] 1 H NMR (600 MHz, D20) δ 4.61 - 4.52 (m, 2H), 4.34 (dd, J = 8.4, 5.8 Hz, 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).

[0193] Compound 16: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Lys (acetate salt)

[0194] 1 H NMR (600 MHz, D20) δ 4.56 - 4.50 (m, 2H), 4.34 (dd, J = 8.4, 5.8 Hz, 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).

[0195] Compound 17: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gln (acetate salt)

[0196] 1 H NMR (600 MHz, D20) δ 4.58 - 4.52 (m, 2H), 4.34 (dd, J = 8.3, 5.8 Hz, 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).

[0197] Compound 18: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Asp (acetate salt)

[0198] 1 H NMR (600 MHz, D20) 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).

[0199] Compound 19: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Ala (acetate salt)

[0200] 1 H NMR (600 MHz, D20) 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).

[0201] Compound 20: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Gln (acetate salt)

[0202] 1 H NMR (600 MHz, D20) 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).

[0203] Compound 21 : Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0204] 1 H NMR (600 MHz, D20) 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).

[0205] Compound 22: Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0206] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 58 H 99 N 15O 18 ; m / z: 647.87059 ([M+2H] 2+ ), 1294.73375 ([M+H] + ).

[0207] 1 H NMR (600 MHz, D20) 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).

[0208] Compound 23: Glu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0209] 1 H NMR (600 MHz, D20) 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).

[0210] Compound 24: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Lys (acetate salt)

[0211] 1H NMR (600 MHz, D20) δ 4.53 - 4.48 (m, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 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).

[0212] Compound 25: Ala-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0213] 1 H NMR (600 MHz, D20) δ 4.53 - 4.48 (m, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 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).

[0214] Compound 26: Ala-Ile-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0215] 1H NMR (600 MHz, D20) 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).

[0216] Compound 27: Ala-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0217] 1 H NMR (600 MHz, D20) 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).

[0218] Compound 28: Ala-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0219] 1H NMR (600 MHz, D20) 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).

[0220] Compound 29: Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt)

[0221] 1 H NMR (600 MHz, D20) 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 = 7.4 Hz, 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).

[0222] Compound 30: Leu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt)

[0223] 1H NMR (600 MHz, D20) 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). Compound 31 : Lys-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0224] 1 H NMR (600 MHz, D20) 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). Compound 31 : Lys-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0225] Compound 32: Glu-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0226] 1H NMR (600 MHz, D20) δ 4.66 - 4.59 (m, 1H), 4.55 (dd, J = 9.5, 4.8 Hz, 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). Compound 33: Lys-Ala-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0227] 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] + ).

[0228] 1 H 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).

[0229] Compound 34: Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0230] High resolution mass spectrum (TOF-HRMS), molecular formula: C 63 H 104 N 16 O 20 ; m / z: 703.38943 ([M+2H] 2+ ).

[0231] 1 H NMR (600 MHz, D20) 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).

[0232] Compound 35: Val-Lys-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0233] High resolution mass spectrum (TOF-HRMS), molecular formula: C 68 H 115 N 17 O 20 ; m / z: 745.93036 ([M+2H] 2+ ), 1490.85402 ([M+H] + ).

[0234] 1H NMR (600 MHz, D20) δ 4.59 - 4.54 (m, 1H), 4.49 (dd, J = 9.4, 4.9 Hz, 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).

[0235] Compound 36: Ala-Glu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0236] High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 65 H 106 N 16 O 22 ; m / z: 732.38868 ([M+2H 2+ ), 1463.76896 ([M+H + ).

[0237] 1 H NMR (600 MHz, D20) 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).

[0238] Compound 37: Val-Pro-Leu-Val-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt)

[0239] 1 H NMR (600 MHz, D20) 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).

[0240] Compound 38: Pro-Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt) High resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 121 N 17 O 21 ; m / z: 786.95783 ([M+2H] 2+ ).

[0241] 1H NMR (600 MHz, D20) 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).

[0242] Compound 39: Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt) High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 78 H 128 N 18 O 22 ; m / z: 835.48070 ([M+2H] 2+ ).

[0243] 1 H NMR (600 MHz, D20) 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).

[0244] Compound 40: Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0245] 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 + ).

[0246] 1 H NMR (600 MHz, D20) 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).

[0247] Compound 41: Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0248] 1H NMR (600 MHz, D20) δ 4.64 - 4.53 (m, 2H), 4.49 (dd, J = 9.7, 4.8 Hz, 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).

[0249] Compound 42:

[0250] Ala-Ala-Glu-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt) 1 H NMR (600 MHz, D20) 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).

[0251] Compound 43: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Gly-Leu-Asp (acetate salt)

[0252] 1H NMR (600 MHz, D20) 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).

[0253] Compound 44: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Ala-Ala-Val-Asp (acetate salt)

[0254] 1 H NMR (600 MHz, D20) 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 - 2.29 (m, 3H), 2.22 - 2.12 (m, 2H), 2.05 - 1.83 (m, 15H, AcOH), 1.82 - 1.72 (m, 3H), 1.61 - 1.43 (m, 3H), 1.33 - 1.23 (m, 12H), 0.93 - 0.77 (m, 18H).

[0255] Compound 45: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate salt)

[0256] 1H NMR (600 MHz, D20) 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).

[0257] Compound 46: Asp-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0258] 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] + ).

[0259] 1H NMR (600 MHz, D20) 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 = 7.5 Hz, 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).

[0260] Compound 47: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala (acetate salt)

[0261] 1 H NMR (600 MHz, D20) δ 4.58 - 4.52 (m, 2H), 4.34 (dd, J = 8.4, 5.8 Hz, 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).

[0262] Compound 48: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Ala-Leu (acetate salt)

[0263] High resolution mass spectrum (TOF-HRMS), molecular formula: C 66 H 110 N 16 O 20 ; m / z: 724.41274 ([M+2H] 2+ ).

[0264] 1 H NMR (600 MHz, D20) δ 4.56 - 4.49 (m, 2H), 4.34 (dd, J = 8.3, 5.8 Hz, 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).

[0265] Compound 49: Ala-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0266] High resolution mass spectrum (TOF-HRMS), molecular formula: C 61 H 104 N 16 O 19 ; m / z: 683.38997 ([M+2H] 2+ ), 1365.77292 ([M+H] + ).

[0267] 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).

[0268] Compound 50: Leu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0269] 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 + ).

[0270] 1H NMR (600 MHz, D20) 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).

[0271] Compound 51 : Lys-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0272] 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 + ).

[0273] 1H NMR (600 MHz, D20) 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 (m, 2H), 2.08 - 2.00 (m, 1H), 2.00 - 1.83 (m, 16H, AcOH), 1.83 - 1.68 (m, 7H), 1.68 - 1.50 (m, 10H), 1.49 - 1.43 (m, 1H), 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).

[0274] Compound 52: Glu-Lys-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (Acetate salt)

[0275] High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 63 H 106 N 16 O 21 ; m / z: 712.39490 ([M+2H 2+ ), 1423.77335 ([M+H + ).

[0276] 1 H NMR (600 MHz, D20) 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).

[0277] Compound 53: Lys-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0278] High resolution mass spectrum (TOF-HRMS), molecular formula: C 60 H 102 N 16 O 19 ; m / z: 676.38574 ([M+2H] 2+ ), 1351.75361 ([M+H] + ).

[0279] 1 H NMR (600 MHz, D20) 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).

[0280] Compound 54: Glu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0281] High resolution mass spectrum (TOF-HRMS), molecular formula: C 59 H 97 N 15 O 21 ; m / z: 676.85849 ([M+2H] 2+ ), 1352.70235 ([M+H] + ).

[0282] 1H NMR (600 MHz, D20) 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).

[0283] Compound 55: Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt) High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 70 H 117 N 17 O 21 ; m / z: 766.94110 ([M+2H] 2+ ), 1532.86012 ([M+H] + ).

[0284] 1H NMR (600 MHz, D20) 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).

[0285] Compound 56: Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate salt) High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 79 H 132 N 18 O 22 ; m / z: 843.49445 ([M+2H] 2+ ), 1685.97986 ([M+H] + ).

[0286] 1H NMR (600 MHz, D20) 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).

[0287] Compound 57: Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate salt)

[0288] 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 + ).

[0289] 1H NMR (600 MHz, D20) 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).

[0290] Compound 58: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu (acetate salt)

[0291] 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 + ).

[0292] 1H NMR (600 MHz, D20) 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).

[0293] Compound 59: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Ala-Gly-Leu-Asp (Acetate salt)

[0294] High resolution mass spectrum (TOF-HRMS), molecular formula: C 78 H 129 N 19 O 25 ; m / z: 866.97784 ([M+2H 2+ ), 1732.94507 ([M+H + ).

[0295] 1H NMR (600 MHz, D20) 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 = 8.0 Hz, 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).

[0296] Compound 60: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu (Acetate salt) High resolution mass spectrum (TOF-HRMS), molecular formula: C 79 H 132 N 18 O 22 ; m / z: 843.49530 ([M+2H 2+ ), 1685.98096 ([M+H + ).

[0297] 1H NMR (600 MHz, D20) 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).

[0298] Compound 61 : Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Pro-Val-Pro-Leu High resolution mass spectrometry (TOF-HRMS), molecular formula: C 84 H 139 N 19 O 23 ; m / z: 892.02161 ([M+2H] 2+ ).

[0299] 1H NMR (600 MHz, D20) 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 = 7.3 Hz, 3H), 1.16 (d, J = 7.2 Hz, 3H), 0.85 - 0.67 (m, 36H).

[0300] Compound 62:

[0301] Val-Pro-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Val-Pro-Leu (acetate salt)

[0302] High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 92 H 155 N 21 O 25 ; m / z: 978.08408 ([M+2H] 2+ ), 1955.14559 ([M+H] + ).

[0303] 1H NMR (600 MHz, D20) 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).

[0304] Compound 63:

[0305] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp

[0306] High resolution mass spectrum (TOF-HRMS), molecular formula: C 111 H 182 N 28 O 35 ; m / z: 823.79035 ([M+3H 3+ ), 1235.17867 ([M+2H 2+ ).

[0307] 1H NMR (600 MHz, D20) δ 4.59 - 4.51 (m, 3H), 4.39 (dd, J = 6.8, 5.2 Hz, 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).

[0308] Compound 64:

[0309] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Gly-Ala-Ala-Glu-Pro-Val-Pro-Le u-Val-Lys-Gln-Asp( Acetate salt)

[0310] 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+ ).

[0311] 1H NMR (600 MHz, D20) δ 4.59 - 4.52 (m, 3H), 4.39 (dd, J = 6.9, 5.1 Hz, 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).

[0312] Compound 65: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Leu

[0313] High resolution mass spectrum (TOF-HRMS) for the molecular formula: C 64 H 107 N 15 O 19 ; m / z: 695.90275 ([M+2H 2+ ), 1390.78841 ([M+H + ).

[0314] Compound 66: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Ala (acetate)

[0315] High resolution mass spectrum (TOF-HRMS) for the molecular formula: C 61 H 101 N 15 O 19 ; m / z: 674.87902 ([M+2H 2+ ).

[0316] 1H NMR (600 MHz, D20) 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 = 7.2 Hz, 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).

[0317] Compound 67: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate salt)

[0318] High resolution mass spectrometry (TOF-HRMS) for the molecular formula: C 53 H 89 N 13 O 17 ; m / z: 590.83474 ([M+2H] 2+ ), 1180.65606 ([M+H] + ).

[0319] 1 H NMR (600 MHz, D20) 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).

[0320] Compound 68: Val-Pro-Leu-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu (acetate salt)

[0321] High resolution mass spectrum (TOF-HRMS), molecular formula: C 69 H 116 N 16 O 20 ; m / z: 745.43743 ([M+2H] 2+ ), 1489.85546 ([M+H] + ).

[0322] 1 H NMR (600 MHz, D20) 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).

[0323] Compound 69: Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln (acetate salt)

[0324] High resolution mass spectrum (TOF-HRMS), molecular formula: C 48 H 82 N 12 O 14 ; m / z: 526.31294 ([M+2H] 2+ ), 1051.61322 ([M+H] + .

[0325] 1H NMR (600 MHz, D20) 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).

[0326] Compound 70: Arg-Lys-Asp-Val-Tyr-Gly-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp 1 H NMR (600 MHz, D20) 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).

[0327] Compound 71: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Glu-Cys-Gly (Acetate)

[0328] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 63 H 104 N 16 O20 S; m / z: 719.37693 ([M+2H] 2+ ), 1437.73683 ([M+H] + ).

[0329] 1 H NMR (600 MHz, D20) 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).

[0330] Compound 72:

[0331] Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0332] 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+ ).

[0333] 1H NMR (600 MHz, D20) 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).

[0334] Compound 73: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu-Glu-Cys-Gly

[0335] High resolution mass spectrum (TOF-HRMS) for the molecular formula: C 73 H 120 N 18 O 24 S; m / z: 833.42972 ([M+2H] 2+ ), 1665.83408 ([M+H] + ).

[0336] Compound 74: Ala-Ala-Ala-Ala-Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate)

[0337] High resolution mass spectrum (TOF-HRMS) for the molecular formula: C 72 H 119 N 19 O 23 ; m / z: 809.94612 ([M+2H] 2+ ), 1618.87350 ([M+H]+ ).

[0338] 1 H NMR (600 MHz, D20) 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).

[0339] Compound 75: Ala-Pro-Val-Pro-Leu-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp (acetate salt)

[0340] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 81 H 133 N 19 O 23 ; m / z: 870.99892 ([M+2H] 2+ ).

[0341] 1H NMR (600 MHz, D20) 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). Compound 76: Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp acetate 1 H NMR (600 MHz, DMSO) δ 8.27 (d, J = 7.6 Hz, 1H), 8.21 (d, J = 7.8 Hz, 1H), 8.09 (d, J = 7.5 Hz, 1H), 8.03 (d, J = 7.9 Hz, 1H), 7.99 (d, J = 7.4 Hz, 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),

[0342] 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).

[0343] Example 2: Anti-ulcer effect of polypeptide (compound 76) on ethanol-induced mouse gastric ulcer model

[0344] 1. Experimental animals: SPF C57BL / 6 mice, Chengdu Yakang Biotechnology Co., Ltd., Animal License No.: SCXK (Chuan) 2020-034.

[0345] 2. Method: After adaptive feeding of experimental animals, mice were randomly divided into 4 groups, 10 in each group, namely: control group (blank group), model group (absolute ethanol modeling), positive drug group (Teprenone 160 mg / kg), compound 76 group (1 mg / kg). After animal grouping, the control group and the model group were treated with pure water, and the other drug groups were treated with the corresponding drugs, once a day, for 8 consecutive days. All animals were fasted but not watered for 24 h after drug administration on the 7th day, and 0.15 mL of absolute ethanol was orally administered to each group (except the control group) of mice 30 min after drug administration on the 8th day to model the animals, and they were sacrificed by CO2 overexposure 1 h later. 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 body of the stomach, the cardia was ligated, and the stomach was removed and fixed in 1% formaldehyde solution for 25 min. The greater curvature of the stomach was cut open, the gastric contents were washed clean with physiological saline, and the ulcer index was calculated after flattening. The ulcer index calculation method: for the length of the cord-like injury greater than 1 mm, measure its length, and score 1 point per mm; if its width is greater than 1 mm, double the score according to the number of mm; if the length is less than 1 mm, score 0.5 points, and the ulcer index of the animal is obtained by adding the scores.

[0346] 3. Results:

[0347] In the ethanol-induced gastric ulcer model of mice, compound 76 can significantly reduce the gastric ulcer index of mice when orally administered once a day for 8 consecutive days, and the effect is better than that of the positive drug group (Table 3), indicating that compound 76 has a significant effect on treating gastric ulcer.

[0348] Table 3. Effect of test drugs on ulcer index of ethanol-induced gastric ulcer mice (n=10, )

[0349]

[0350]

[0351] Note: compared with the control group, ## P<0.01; compared with the model group, *P<0.05, **P<0.01

[0352] Example 3: Anti-ulcer activity of compound 1-76 samples on ethanol-induced mouse gastric ulcer model

[0353] 1. Experimental animals: SPF C57BL / 6 mice, Chengdu Yakang Biotechnology Co., Ltd., Animal License No.: SCXK (Chuan) 2020-034

[0354] 2. Method:

[0355] After adaptive feeding of experimental animals, all animals started fasting without water for 24 h after drug administration 1 day before the experiment. Before modeling, the experimental mice were randomly divided into groups: 5 in the blank group, 10 in the model group, and 10 in each drug administration group. Except for the blank group and the model group, which were given purified water by gavage, the drug administration groups were given different test samples by gavage at a dose of 0.2 mg / kg. One hour after administration, each group of mice was given 0.9 ml / kg of anhydrous ethanol by oral gavage to model the mice. One hour later, the animals were sacrificed by the decapitation method, the gastric cardia was ligated, and the pylorus was clamped. The whole stomach was removed. 1 mL of 1% formaldehyde solution was injected into the stomach body, the cardia was ligated, and the stomach was removed and placed in 1% formaldehyde solution. After soaking for 30 min, the stomach tissue was removed, cut along the greater curvature of the stomach, and the contents were washed clean with physiological saline. After flattening, the mouse gastric mucosa damage was observed and measured, and the ulcer index and ulcer inhibition rate were calculated.

[0356] Ulcer index calculation method: for strip-like damage with a length greater than 1 mm, measure its length, and score 1 point per mm; if the width is greater than 1 mm, double the score according to the number of mm; for a length less than 1 mm, score 0.5 points, and add the scores to obtain the ulcer index of the animal.

[0357] Ulcer inhibition rate = (model group ulcer index - drug administration group ulcer index) / model group ulcer index x 100%;

[0358] Relative ulcer inhibition rate = (test compound ulcer inhibition rate) / (compound 76 ulcer inhibition rate).

[0359] 3. Results: Table 5 shows the relative anti-ulcer activity of compounds 1-76 relative to compound 76:

[0360] Table 5 Anti-ulcer activity of single administration of mice ethanol modeling

[0361]

[0362]

[0363] *Note: The anti-ulcer effect of each compound was completed through multiple batches of experiments. For ease of comparison, the anti-ulcer activity is represented by the average relative ulcer inhibition rate (compound 76 was used as the control group in each batch of experiments).

[0364] Relative ulcer inhibition rate = (test compound ulcer inhibition rate) / (compound 76 ulcer inhibition rate)

[0365] >1.50, represented as "+++++";

[0366] >1.20, represented as "++++";

[0367] 0.9-1.20, represented as "+++";

[0368] 0.6-0.9, represented as "++";

[0369] "NA" means not detected.

[0370] Example 4: Whether the samples of compounds 34, 36, 38, and 39 promote the growth of mouse gastric organoids

[0371] Experimental method: After the cryopreserved mouse organoids were recovered, they were expanded in a 6-well plate. When the organoids grew to a sufficient amount, the 6-well plate to be treated was removed, the old culture medium was removed, Dispase II was added to each well, the Matrigel droplet in the 6-well plate was recovered with a 1 mL pipette tip, and transferred to a 15 mL centrifuge tube, and digested into single cells with L TrypLE. After centrifugation, the supernatant was removed, 1-3 mL of DMEM / F-12 was added, mixed well, and 10 μL was taken for cell counting to calculate the total number of cells in the resuspension.

[0372] The corresponding volume of cell suspension was taken and mixed with an appropriate amount of Matrigel, and 30 μL of Matrigel (containing about 500 cells) was inoculated in a 96-well plate; the inoculated 96-well plate was placed in a 37°C incubator for 20 min to allow the Matrigel to solidify. The control group was added with 140 μL of organoid culture medium, and the drug group was added with 140 μL of organoid culture medium containing different concentrations of extended peptides. Three concentrations of each extended peptide were set, which were 1 μM, 5 μM, and 10 μM. The well plate was placed in a 37°C incubator for 9 days, and the liquid was changed every 48 hours. On the 9th day, the well plate was taken out, and the CelltiterGlo (CTG) was used to analyze the viability of the organoids.

[0373] The experimental results are shown in Figures 2-5 . Among them, Figure 2 (*p<0.05,**p<0.01,***p<0.001 compared with the control group, one-way ANOVA) and Figure 4 (*p<0.05,**p<0.01 compared with the control group, one-way ANOVA) each concentration significantly increased the CTG reading compared with the control group, with a certain dose-dependent, and the trend was optimal at a concentration of 5 μM. Figure 3(*p<0.05,**p<0.01 compared with control group, one-way ANOVA) 1 μM and 5 μM significantly increased CTG readout compared with control group in a dose-dependent manner; 10 μM showed a trend of increase but no significant difference. Figure 5 (no significant difference compared with control group, one-way ANOVA) 1 μM and 5 μM showed a trend of increase in CTG readout but no significant difference; 10 μM showed no significant trend compared with control group. It is suggested that compounds 34, 36 and 38 promote the growth of mouse gastric organoids in a dose-dependent manner.

[0374] Although the above-mentioned embodiments are disclosed in the present application, the embodiments of the present application are not limited to the above-mentioned embodiments, and any changes, modifications, substitutions, combinations, simplifications of other embodiments that do not deviate from the present application shall be equivalent replacement methods and shall be included in the protection scope of the present application.

Claims

1. A compound of formula (I) or a physiologically compatible salt thereof, wherein the compound of formula (I) is selected from the group consisting of: Compound 1 : Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp, Compound 2: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Leu, Compound 3: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe, Compound 4: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu, Compound 5: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe, Compound 6: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe, Compound 7: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe, Compound 8: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe, Compound 9: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe-Phe, Compound 10: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe-Phe-Phe, Compound 11 : Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe-Phe-Phe-Phe, Compound 12: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe-Phe-Phe-Phe-Phe, Compound 13: Ala-Pro-Ala-Ala-Glu-Pro-Val-Pro-Leu-Val-Lys-Gln-Asp-Phe-Leu-Phe-Phe-Phe-Phe-Phe-Phe-Phe-Phe-P ​ ​ ​ ​ ​ ​

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