Polypeptide compound and its use in treating enteritis

Abstract

The present invention relates to a new polypeptide and its application. The polypeptide provided by the present invention has a short peptide chain and is absorbed faster and better. Experimental results show that the polypeptide provided in this application exhibits an obvious effect of alleviating intestinal lumen dilation in the zebrafish inflammatory bowel disease model and the rat inflammatory bowel disease model. The polypeptide provided by the present invention has a significant effect of alleviating colitis and can be used to prepare drugs for treating enteritis, especially drugs for ulcerative colitis.

Description

Technical Field

[0001] The present invention relates to a new polypeptide and its application. The polypeptide of the present invention has a significant effect in treating inflammatory bowel disease, especially in treating ulcerative colitis. Background Art

[0002] Enteritis is an intestinal inflammatory reaction caused by various reasons, such as pathogenic vitamin infections of intestinal bacteria, viruses, etc., or factors such as immune damage, radiation damage, dietary stimulation, and drug stimulation. The clinical manifestations mainly include fever, nausea, vomiting, abdominal pain, diarrhea, loose stools or mucus bloody stools, and some patients may also have a sense of tenesmus.

[0003] Enteritis can be classified into specific enteritis and non-specific enteritis according to the inflammatory manifestations. Specific enteritis includes inflammatory bowel disease, necrotizing enteropathy, and dysbacteriosis enteritis. Among them, as a relatively common inflammatory bowel disease, it is a chronic, persistent, recurrent, inflammatory disease of the intestine that is idiopathic and non-infectious. The clinical manifestations are abdominal pain and diarrhea, testing bloody stools, and even symptoms such as fever, abdominal mass, weight loss, and malnutrition. Inflammatory bowel disease is a chronic and long-term disease that requires long-term and active treatment.

[0004] General specific enteritis has a clear etiology. For example, bacterial enteritis, pseudomembranous enteritis, viral enteritis, radiation enteritis, etc. are all types of enteritis with a clear etiology. Non-specific enteritis has no clear etiology and is considered to be caused by immune system diseases, such as ulcerative colitis, Crohn's disease, and so on. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. Ulcerative colitis is a chronic non-specific intestinal inflammatory disease with an unclear etiology, most commonly occurring in young and middle-aged people. The clinical manifestations are persistent or recurrent diarrhea, mucus purulent bloody stools accompanied by abdominal pain, tenesmus, and varying degrees of systemic symptoms. There may be extra-intestinal manifestations such as skin, mucosa, joints, eyes, liver, and gallbladder. Complications include toxic megacolon, intestinal perforation, lower gastrointestinal hemorrhage, intraepithelial neoplasia, and canceration. There is a lack of accurate incidence data of UC in China. Regional epidemiological surveys suggest that the incidence of UC in China is 0.42 - 2.22 / 100,000. Although the incidence is still lower compared with Western countries, it shows an obvious upward trend compared with 20 years ago. The lesions mainly involve the colonic mucosa and submucosa. The range starts from the distal rectum and colon and develops retrogradely towards the proximal end, even involving the entire colon. 5% can involve the terminal ileum, showing a continuous distribution. The main clinical manifestations of ulcerative colitis are diarrhea, abdominal pain, and mucus purulent bloody stools. The etiology has not been fully understood. Currently, it is considered to be related to infection, immune abnormalities, genetics, and mental factors. In addition, enteritis patients usually have symptoms such as intestinal lumen dilation (also known as intestinal dilation or bowel dilation), which may be due to inflammation destroying the nerve and muscle regulation mechanism that controls the normal intestine, and the pressure in the intestinal lumen causes the intestinal wall to dilate beyond its normal range of activity. Or it is caused by overgrowth of microorganisms and the toxins they produce, mucus exudation, etc. Relieving or inhibiting intestinal lumen dilation helps in the treatment of enteritis.

[0005] Although the drugs currently commonly used for the treatment of ulcerative colitis have certain preventive and therapeutic effects, they still have disadvantages such as slow absorption, long treatment cycles, and unclear treatment effects. Summary of the Invention

[0006] In order to overcome the deficiencies and defects of the prior art, the purpose of the present invention is to provide a new polypeptide compound and its application. The inventors of the present invention found that the polypeptide compound of the present invention can effectively or significantly relieve or inhibit intestinal lumen dilation, thereby playing a role in the treatment of enteritis.

[0007] In the first aspect, the present invention relates to a compound of formula (I) or its physiologically compatible salt, wherein the compound of formula (I) is as follows:

[0008] H-X a -Z1-Z2-Z3-Z4-X b -OH (I)

[0009] Wherein

[0010] Z1 is Pro, Ala, Gly, D-Pro or absent;

[0011] Z2 is Val, Ala, D-Val, Ile or absent;

[0012] Z3 is Pro, Ala, Gly, D-Pro or absent;

[0013] Z4 is Gln, Ala, Glu, Ile, D-Gln or absent;

[0014] Provided that at most 2 of Z1, Z2, Z3 and Z4 are absent.

[0015] X a is a sequence containing 0 - 10 amino acid residues;

[0016] X b is a sequence containing 0 - 9 amino acid residues.

[0017] In one embodiment, 2 of Z1, Z2, Z3 and Z4 are absent. In one embodiment, Z1 and Z2 are absent. In one embodiment, Z3 and Z4 are absent. In one embodiment, 1 of Z1, Z2, Z3 and Z4 is absent. In one embodiment, Z1 is absent. In one embodiment, Z4 is absent. In one embodiment, 0 of Z1, Z2, Z3 and Z4 are absent.

[0018] In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is D-Pro; Z2 is Val; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Ala; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Ile; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is absent. In one embodiment, Z1 is Pro; Z2 is Ala; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is Gly; Z2 is Val; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Gly; and Z4 is Gln. In one embodiment, Z1 is Ala; Z2 is Val; Z3 is Pro; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is Glu. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is D-Pro; and Z4 is Gln. In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is D-Gln.

[0019] In one embodiment, X a is X a10 -X a9 -X a8 -X a7 -X a6 -X a5 -X a4 -X a3 -X a2 -X a1 -*, where * represents the position of attachment to Z1-Z2-Z3-Z4, where

[0020] X a10 is Gly or absent,

[0021] X a9 is Gly, Pro, Ser or absent,

[0022] X a8 is Pro, Glu, Ser or absent,

[0023] X a7 is Arg, Glu, Thr, Ser or absent,

[0024] X a6 is Lys, Thr, Ala, Asp, Glu, Arg, Ser or absent,

[0025] X a5 is Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or absent,

[0026] X a4 is Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or absent,

[0027] X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or absent,

[0028] X a2 is D-Lys, Lys, Ala, Arg, Val, Glu, Tyr or absent, and

[0029] X a1 is Glu, Ala, D-Glu, Tyr, Gln, Asp, Asn or absent.

[0030] In one embodiment, X a is X aa -X a2 -X a1 -*, where * represents the position connected to Z1-Z2-Z3-Z4, X a2 -X a1 is Lys-Glu-*, Arg-Glu-*, Val-Tyr-*, Glu-Glu-*, Lys-Gln-*, Lys-D-Glu-* or Tyr-Glu-*, and X aa is X a10 -X a9 -X a8 -X a7 -X a6 -X a5 -X a4 -X a3 -, where X a10 is Gly or absent, X a9 is Gly, Pro, Ser or absent, X a8 is Pro, Glu, Ser or absent, X a7 is Arg, Glu, Thr, Ser or absent, X a6 is Lys, Thr, Ala, Asp, Glu, Arg, Ser or absent, X a5 is Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or absent, X a4is Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or absent, and X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or absent. In one embodiment, X aa is Arg-Lys-Asp-Val-Tyr-, Gly-Pro-Glu-Thr-Ala-Phe-Leu-, Val-Pro-Pro-, Pyro-Glu-Leu-, Arg-Lys-Asp-, Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-, Ser-Ser-Glu-Asp-Ile-Lys-Glu-, Ser-Ser-Glu-Asp-Ile-Lys-, Val-Pro-Tys-, Pro-Ala-Tys-, Arg-Lys-Asp-Val-, Ser-Ser-Glu-Asp-Ile- or absent, where the rightmost linker - indicates connection to -X a2 -X a1 connection. In one embodiment, X a is X aa -X a2 -X a1 -*, where * indicates the position of connection to Z1-Z2-Z3-Z4, where X a2 -X a1 is Lys-Glu-*, and X aa is as defined above.

[0031] In one embodiment, X a is X a1 -*, where * indicates the position of connection to Z1-Z2-Z3-Z4, where X a1 is Glu, Ala, D-Glu, Asp, Asn or absent.

[0032] In one embodiment, X a is X a2 -X a1 -*, where * indicates the position of connection to Z1-Z2-Z3-Z4, where X a2 is Lys, and X a1 is Glu, D-Glu or Gln.

[0033] In one embodiment, X ais Glu-*, Ala-*, D-Glu-*, Asp-*, Asn-*, Lys-Glu-*, D-Lys-Glu-*, Ala-Glu-*, Lys-Gln-*, Lys-D-Glu-*, Lys-Ala-*, Arg-Lys-Asp-Val-Tyr-Lys-Glu-*, Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-*, Val-Pro-Pro-Lys-Glu-*, Pyro-Glu-Leu-Lys-Glu-*, Arg-Lys-Asp-Val-Tyr-*, Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-*, Val-Pro-Tys-Lys-Glu-*, Pro-Ala-Tys-Lys-Glu-*, Arg-Lys-Asp-Val-Tyr-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-* or missing, where * represents the position connected to Z1-Z2-Z3-Z4.

[0034] In one embodiment, X b is **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 , where ** represents the position connected to Z1-Z2-Z3-Z4, where

[0035] X b1 is Ala, D-Ala or missing,

[0036] X b2 is Lys, Ala, D-Lys, Arg or missing,

[0037] X b3 is Pro, Gly, D-Pro, Ser, Val, Ala or missing,

[0038] X b4 is Arg, Ala, Ser, Pro, D-Arg or missing,

[0039] X b5is Lys, Ala, D-Lys, Glu, Tyr or absent,

[0040] X b6 is Val, Asp, D-Val, Ala or absent,

[0041] X b7 is Ala, D-Ala, Ile or absent,

[0042] X b8 is Ala, D-Ala, Lys or absent, and

[0043] X b9 is Gln, Ala, Glu, Asn, D-Gln or absent.

[0044] In one embodiment, X b is **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 where ** represents the position connected to Z1-Z2-Z3-Z4, where

[0045] X b1 is Ala or D-Ala,

[0046] X b2 is Lys, Ala or D-Lys,

[0047] X b3 is Pro, Gly, or Ala,

[0048] X b4 is Arg or D-Arg,

[0049] X b5 is Lys or absent,

[0050] X b6 is Val, D-Val, Ala or absent,

[0051] X b7 is Ala or absent,

[0052] X b8 is Ala or absent, and

[0053] X b9 is Gln, Asn, D-Gln or absent.

[0054] In one embodiment, Xb is -X b1 -X b2 -X bb , where ** represents the position connected to Z1-Z2-Z3-Z4, and X b1 -X b2 - is -Ala-Lys-, -Ala-Lys-, -Ala-D-Lys-, -Ala-Ala- or -D-Ala-Lys-, and X bb is -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 , where X b3 is Pro, Gly, D-Pro, Ser, Val, Ala or absent, and X b4 is Arg, Ala, Ser, Pro, D-Arg or absent, and X b5 is Lys, Ala, D-Lys, Glu, Tyr or absent, and X b6 is Val, Asp, D-Val, Ala or absent, and X b7 is Ala, D-Ala, Ile or absent, and X b8 is Ala, D-Ala, Lys or absent, and X b9 is Gln, Ala, Glu, Asn, D-Gln or absent; or X b3 is Pro, Gly, or Ala, and X b4 is Arg or D-Arg, and X b5 is Lys or absent, and X b6 is Val, D-Val, Ala or absent, and X b7 is Ala or absent, and X b8 is Ala or absent, and X b9 is Gln, Asn, D-Gln or absent. In one embodiment, X bb is -Pro-Arg-Lys-Val, -Pro-Arg-Lys, -Pro-Arg, -Ala-Gln, -Ala-Ala, -Pro, -Lys-Val, -Val-Pro-Tyr, -Arg-Lys, -Val-Ala, -Pro-Arg-Lys-Val-Ala, -Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Gln,

[0055] -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Ala-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Ala-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Ala, -Gly-Arg-Lys-Val-Ala-Ala-Gln, -D-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-D-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-D-Ala-Ala-Gln,

[0056] -Pro-Arg-Lys-Val-Ala-D-Ala-Gln, -Ser-Ser-Glu-Asp-Ile-Lys-Glu, -Pro-Arg-Lys-Val-Ala-Ala-Asn, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-D-Val-Ala-Ala-Gln, -Ala-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Ala-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-D-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-D-Gln or deletion, where the leftmost linker - represents a linkage to X b1 -X b2 is linked. In one embodiment, X b is **-X b1 -X b2 -X bb where ** represents the position linked to Z1-Z2-Z3-Z4, and X b1 -X b2 - is **-Ala-Lys-, and X bb is defined as above.

[0057] In one embodiment, X b is **-Ala-.

[0058] In one embodiment, X b-Ala-, -Ala-Lys, -Ala-D-Lys-, -Ala-Ala, -D-Ala-Lys, -Ala-Arg, -Ala-Lys-Pro-Arg-Lys-Val, -Ala-Lys-Pro-Arg-Lys, -Ala-Lys-Pro-Arg,

[0059] -Val-Ala-Ala-Gln, -Lys-Val-Ala-Ala, -Ala-Lys-Pro, -Pro-Arg-Lys-Val,

[0060] -Ala-Lys-Val-Pro-Tyr, -Lys-Pro-Arg-Lys, -Arg-Lys-Val-Ala,

[0061] -Ala-Lys-Pro-Arg-Lys-Val-Ala, -Pro-Arg-Lys-Val-Ala-Ala-Gln,

[0062] -Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln,

[0063] -Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln, -Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln,

[0064] -Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala, -Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln,

[0065] -Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln,

[0066] -Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln, -Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln,

[0067] **-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu, -Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn,

[0068] **-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln,

[0069] **-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln, -Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln,

[0070] **-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln,

[0071] **-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln or deletion, where ** represents the position connected to Z1-Z2-Z3-Z4.

[0072] In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is Gln; X a is X aa -X a2 -X a1 -*, where * represents the position connected to Z1-Z2-Z3-Z4, where X a2 -X a1 is Lys-Glu-*, and X b is **-X b1 -X b2 -X bb , where ** represents the position connected to Z1-Z2-Z3-Z4, X b1 -X b2 - is **-Ala-Lys-, where X aa and X bb are defined as above.

[0073] In one embodiment, the compound is selected from:

[0074] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1);

[0075] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 2);

[0076] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 3);

[0077] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4);

[0078] Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 5);

[0079] Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6);

[0080] Lys-Glu-Pro-Val (Compound 7);

[0081] Val-Ala-Ala-Gln (Compound 8);

[0082] Glu-Pro-Val-Pro (Compound 9);

[0083] Lys-Pro-Arg-Lys (Compound 10);

[0084] Ala-Lys-Pro-Arg (Compound 11);

[0085] Pro-Val-Pro-Gln (Compound 12);

[0086] Val-Pro-Gln-Ala (Compound 13);

[0087] Pro-Gln-Ala-Lys (Compound 14);

[0088] Arg-Lys-Val-Ala (Compound 15);

[0089] Lys-Val-Ala-Ala (Compound 16);

[0090] Gln-Ala-Lys-Pro (Compound 17);

[0091] Pro-Arg-Lys-Val (Compound 18);

[0092] Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 19);

[0093] Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 20);

[0094] Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 21);

[0095] Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 22);

[0096] Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 23);

[0097] Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 24);

[0098] Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 25);

[0099] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (Compound 26);

[0100] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln (Compound 27);

[0101] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln (Compound 28);

[0102] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (Compound 29);

[0103] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala (Compound 30);

[0104] Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 31);

[0105] Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 32);

[0106] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 33);

[0107] Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 34);

[0108] Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 35);

[0109] Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 36);

[0110] Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 37);

[0111] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 38);

[0112] Pro-Val-Pro-Gln-Ala (Compound 39);

[0113] Pro-Val-Pro-Glu-Ala (Compound 40);

[0114] Pro-Val-Pro-Ile-Ala (Compound 41);

[0115] Pro-Val-Pro-Ala (Compound 42);

[0116] Glu-Pro-Val-Pro-Gln-Ala (Compound 43);

[0117] Pro-Val-Pro-Gln-Ala-Lys (Compound 44);

[0118] Glu-Pro-Val-Pro-Gln-Ala-Arg (Compound 45);

[0119] Ala-Pro-Val-Pro-Gln-Ala-Lys (Compound 46);

[0120] Glu-Pro-Val-Pro-Ala-Ala-Lys (Compound 47);

[0121] Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48);

[0122] Asp-Pro-Val-Pro-Gln-Ala-Lys (Compound 49);

[0123] Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50);

[0124] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51);

[0125] Glu-Pro-Ala-Pro-Gln-Ala-Lys (Compound 52);

[0126] Glu-Ala-Val-Pro-Gln-Ala-Lys (Compound 53);

[0127] Glu-Pro-Val-Ala-Gln-Ala-Lys (Compound 54);

[0128] Glu-Pro-Val-Pro-Glu-Ala-Lys (Compound 55);

[0129] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val (Compound 56);

[0130] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57);

[0131] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 58);

[0132] Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 59);

[0133] Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 60);

[0134] D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 61);

[0135] Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 62);

[0136] Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 63);

[0137] Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 64);

[0138] Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 65);

[0139] Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 66);

[0140] Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 67);

[0141] Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 68);

[0142] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 69);

[0143] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (Compound 70);

[0144] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (Compound 71);

[0145] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (Compound 72);

[0146] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (Compound 73);

[0147] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (Compound 74);

[0148] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (Compound 75);

[0149] Glu-Gly-Val-Pro-Gln-Ala-Lys (Compound 76);

[0150] Glu-Pro-Val-Gly-Gln-Ala-Lys (Compound 77);

[0151] D-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 78);

[0152] Glu-D-Pro-Val-Pro-Gln-Ala-Lys (Compound 79);

[0153] Glu-Pro-D-Val-Pro-Gln-Ala-Lys (Compound 80);

[0154] Glu-Pro-Val-D-Pro-Gln-Ala-Lys (Compound 81);

[0155] Glu-Pro-Val-Pro-D-Gln-Ala-Lys (Compound 82);

[0156] Glu-Pro-Val-Pro-Gln-D-Ala-Lys (Compound 83);

[0157] Glu-Pro-Val-Pro-Gln-Ala-D-Lys (Compound 84);

[0158] Lys-Glu-Pro-Val-Pro (Compound 85);

[0159] Glu-Pro-Val-Pro-Gln (Compound 86);

[0160] Lys-Glu-Pro-Val-Pro-Gln (Compound 87);

[0161] Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 88);

[0162] Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 89);

[0163] Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 90);

[0164] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 91);

[0165] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 92);

[0166] Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93);

[0167] Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (Compound 94);

[0168] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 95);

[0169] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96);

[0170] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 97);

[0171] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 98);

[0172] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (Compound 99);

[0173] Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 100);

[0174] Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (Compound 101);

[0175] Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (Compound 102);

[0176] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (Compound 103);

[0177] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (Compound 104);

[0178] Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 105);

[0179] Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 106);

[0180] Val-Pro-Gln-Ala (Compound 107); or

[0181] Val-Pro-Gln-Ala-Lys (Compound 108).

[0182] In one embodiment, the compound is selected from:

[0183] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1);

[0184] Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 63);

[0185] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96);

[0186] Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 100);

[0187] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (Compound 104);

[0188] Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6);

[0189] Pro-Val-Pro-Gln (Compound 12);

[0190] Glu-Pro-Val-Ala-Gln-Ala-Lys (Compound 54);

[0191] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57);

[0192] Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 68);

[0193] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (Compound 72);

[0194] Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 89);

[0195] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 92);

[0196] Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (Compound 94);

[0197] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 95);

[0198] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 97);

[0199] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 98);

[0200] Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 105);

[0201] Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 106);

[0202] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4);

[0203] Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 5);

[0204] Glu-Pro-Val-Pro (Compound 9);

[0205] Lys-Pro-Arg-Lys (Compound 10);

[0206] Arg-Lys-Val-Ala (Compound 15);

[0207] Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 25);

[0208] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (Compound 26);

[0209] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (Compound 29);

[0210] Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 31);

[0211] Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 34);

[0212] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 38);

[0213] Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48);

[0214] Asp-Pro-Val-Pro-Gln-Ala-Lys (Compound 49);

[0215] Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50);

[0216] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51);

[0217] Glu-Ala-Val-Pro-Gln-Ala-Lys (Compound 53);

[0218] Glu-Pro-Val-Pro-Glu-Ala-Lys (Compound 55);

[0219] Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 62);

[0220] Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 65);

[0221] Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 66);

[0222] Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 67);

[0223] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (Compound 70);

[0224] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (Compound 75);

[0225] Glu-Pro-Val-Pro-Gln-D-Ala-Lys (Compound 83);

[0226] Lys-Glu-Pro-Val-Pro (Compound 85);

[0227] Glu-Pro-Val-Pro-Gln (Compound 86);

[0228] Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 88);

[0229] Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 90);

[0230] Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93);

[0231] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (Compound 99); or

[0232] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (Compound 103).

[0233] In a second aspect, the present invention provides the use of the polypeptide compound or a physiologically compatible salt thereof in the preparation of a medicament for treating enteritis; or a method for treating enteritis, the method comprising administering to a subject a therapeutically effective amount of the polypeptide compound or a physiologically compatible salt thereof; or the polypeptide compound or a physiologically compatible salt thereof for treating enteritis.

[0234] Further, enteritis includes specific enteritis and non-specific enteritis. Further, specific enteritis includes inflammatory bowel disease, necrotizing enteropathy, and dysbacteriosis enteritis.

[0235] Further, inflammatory bowel disease includes ulcerative colitis.

[0236] Further, the present invention provides a pharmaceutical composition comprising the polypeptide compound of the present invention or a physiologically compatible salt thereof, and a pharmaceutically acceptable excipient.

[0237] Further, the dosage forms of the medicament include tablets, capsules, solutions, powders, and pills.

[0238] Beneficial effects of the novel polypeptide provided by the present invention and its applications:

[0239] The peptide chain of the above polypeptide of the present invention is short, so it is absorbed faster and better. Experimental results show that the polypeptide provided in this application demonstrated an obvious effect of alleviating intestinal lumen dilation in the rat acute inflammatory bowel disease model test; and had a significant therapeutic effect in the rat acute inflammatory bowel disease model test. The above polypeptide of the present invention has a significant effect of alleviating colitis and can be used to prepare drugs for treating enteritis, especially drugs for ulcerative colitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0240] Figure 1 Shows a schematic diagram of the solid-phase synthesis steps of the polypeptide;

[0241] Figure 2 Shows the mass spectrum of the polypeptide. DETAILED DESCRIPTION OF THE INVENTION

[0242] The following is an illustration of the present invention in combination with specific tests, which does not limit the protection scope of the present invention.

[0243] As used in this application (including the appended claims), unless the context clearly indicates otherwise, singular terms such as "a / an" and "the" include their corresponding plural referents.

[0244] Unless the context clearly indicates otherwise, the term "or" is used to mean "and / or" and can be used interchangeably with the term "and / or".

[0245] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (such as a compound) that is sufficient to affect the treatment of a disease or at least one clinical symptom of a disease or disorder when administered to a subject to treat the disease, disorder or symptom. The "therapeutically effective amount" can vary with the compound, the disease, disorder and / or the symptom of the disease or disorder, the severity of the disease, disorder and / or the symptom of the disease or disorder, the age of the subject to be treated and / or the weight of the subject to be treated. In any given case, the appropriate amount may be clear to those skilled in the art or can be determined by routine experimentation. In some embodiments, the "therapeutically effective amount" is the amount of at least one compound disclosed in this application and / or at least one of its stereoisomers, and / or at least one of its pharmaceutically acceptable salts that is effective in "treating" (as defined above) the disease or disorder of the subject. In the case of combination therapy, the "therapeutically effective amount" refers to the total amount of the combination of agents used to effectively treat a disease, disorder or condition.

[0246] The term "physiologically compatible salt" refers to a salt form that is physiologically compatible (i.e., pharmaceutically acceptable) and substantially non-toxic to an individual to whom the compounds of the present invention are to 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.

[0247] The term "lumen dilation" refers to the dilation of the intestine or intestinal tube. In patients with enteritis, due to intestinal damage, mucus exudation, intestinal gas accumulation or fluid accumulation, overgrowth of microorganisms and other factors, the lumen of the intestine dilates, and the intestinal tube is thicker than the normal intestinal tube. Clinically, recurrent enteritis such as inflammatory bowel disease often causes intestinal tube dilation, or tumors cause intestinal tube dilation and intestinal obstruction.

[0248] As used in this application, the abbreviations of each amino acid are as follows

[0249] Chinese Name English Name Abbreviation Alanine Alanine Ala Arginine Arginine Arg Asparagine Asparagine Asn Aspartic acid Aspartic acid Asp Cysteine Cysteine Cys Glutamine Glutamine Gln Glutamic acid Glutamic acid Glu Glycine Glycine Gly Histidine Histidine His Isoleucine Isoleucine Ile Leucine Leucine Leu Lysine Lysine Lys Methionine Methionine Met Phenylalanine Phenylalanine Phe Proline Proline Pro Serine Serine Ser Threonine Threonine Thr Tryptophan Tryptophan Trp Tyrosine Tyrosine Tyr Valine Valine Val

[0250] Table 1 English names of solvents, reagents, etc. and their Chinese names of abbreviations

[0251]

[0252] Example 1: Chemical synthesis of polypeptides

[0253] The synthesis of polypeptide compounds adopts the conventional solid-phase synthesis method of an automatic polypeptide synthesizer, and the chemical synthesis of polypeptides is carried out through the processes of resin swelling, deprotection, washing, amino acid activation, and condensation.

[0254] Taking Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1) as an example, the schematic diagram of the solid-phase synthesis steps of polypeptides can be seen in Figure 1 .

[0255] Step 1: Preparation of fully protected peptide resin of polypeptide

[0256] (1) Resin swelling: Weigh 7.71 g of 2-Chlorotrityl Chloride Resin (SD = 0.73 mmol / g), add it to a synthesis tube with a sieve plate, and swell it with 100 ml of dichloromethane (DCM).

[0257] (2) Preparation of Fmoc-Gln(Trt)-resin: Weigh Fmoc-Gln(Trt)-OH and DIPEA according to the molar ratio of resin, Fmoc-Gln(Trt)-OH, and DIPEA of 1:1.78:4.31 and add them to the synthesis tube. Bubble nitrogen (N2) and shake at room temperature for 1 - 3 hours, then drain; then wash with dimethylformamide (DMF) 5 times, 100 ml each time, and drain the resin.

[0258] (3) Removal of the Fmoc protecting group: Add 100 ml of 20% piperidine-DMF (v / v) solution to the reactor, react with nitrogen bubbling for 20 min, then drain; then wash with DMF 5 times, 100 ml each time, for 3 minutes each time, and drain. Detect the result of Fmoc removal by the ninhydrin method.

[0259] (4) Pre-activation of amino acids: Add 15 mmol of Fmoc-protected amino acid, 15 mmol of HOBt, and 15 mmol of DIC to a 250 ml beaker, dissolve with 100 ml of DMF, stir at room temperature, and set aside.

[0260] (5) Amino acid coupling: Pour the activated protected amino acid solution into the reactor, and add an appropriate amount of DCM to wash the utensils. React with nitrogen bubbling at room temperature for 1 - 3 hours, detect whether the amino acid coupling is complete by the ninhydrin method. If complete, drain. Wash the resin with DMF 5 times, 100 ml each time, for 3 min each time, and drain. The dosage of each amino acid and condensing agent is shown in Table 2.

[0261] (6) After the condensation of the first amino acid is completed, repeat steps (4) and (5) to extend the peptide chain according to the amino acid sequence until the coupling of the last amino acid is completed.

[0262] (7) Wash the resin peptide with DMF 4 times, 150 ml each time, for 3 min each time; then wash with DCM 5 times, 150 ml each time, for 3 min each time, and drain.

[0263] Table 2 Dosage of Amino Acids and Condensing Agents

[0264]

[0265] Step 2. Cleavage

[0266] (1) Add 100 ml of cleavage agent (TFA:TIPS:H2O = 95:2.5:2.5, v / v) to the synthesis tube, and react with nitrogen bubbling for 1.5 - 3 hours.

[0267] (2) After the cleavage reaction was completed, the cleavage agent was suction filtered into a 250 ml round-bottom flask. After vacuum concentration to one-fourth of the original volume of the cleavage agent, 10 times the existing volume of methyl tert-butyl ether was added, and a white solid was obtained by sedimentation. The resulting mixture was filtered, and after washing 3 times with 50 ml of methyl tert-butyl ether respectively, the resulting crude peptide product was placed in a sintered funnel and dried with nitrogen in a fume hood until the solvent evaporated and the crude peptide became powdery. 9.04 g of crude peptide was obtained, and the crude yield was 74.7%.

[0268] Step Three: Purification, Salt Exchange and Freeze-drying

[0269] Direct Salt Exchange of Polypeptide by HPLC (Acetate)

[0270] A. Chromatographic Parameters

[0271] Chromatographic column: Dynamic axial compression column 80*250 mm, packing: Daisogel C18 (SP-100-8-ODS-P)

[0272] Eluent A1: 0.1 M acetic acid

[0273] Eluent A2: 0.025 M acetic acid - 0.1 M ammonium acetate

[0274] Eluent B: Acetonitrile

[0275] Flow rate: 180 ml / min

[0276] Ultraviolet detection wavelength: 220 nm

[0277] B. Operating Procedures

[0278] a) Dissolve the crude peptide with water and / or acetonitrile and filter through a 0.45 μm filter membrane

[0279] b) Equilibrate the chromatographic column with 95% A1 + 5% B

[0280] c) Inject the sample

[0281] d) Equilibrate the chromatographic column with 95% A2 + 5% B

[0282] e) Gradient elution with A1 and B

[0283] f) Collect the eluate of the target peptide

[0284] g) Rotary evaporation and concentration

[0285] h) Freeze-drying

[0286] 8.26 g of crude peptide was purified to obtain 4.92 g of pure peptide, and the purification yield was 59.5%.

[0287] Other compounds were synthesized in a similar manner to Compound 1. The results are shown in Table 3 and other parts of the specification.

[0288] Table 3 Synthesized Polypeptide Compounds

[0289]

[0290]

[0291]

[0292]

[0293]

[0294]

[0295] Note: The double-charged peak indicates that the target molecule binds 2 protons, and the triple-charged peak indicates that the target molecule binds 3 protons; N / A represents difficulty in weighing and the actual weight is not counted.

[0296] Compound 1: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0297] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: m / z: 549.65904 ([M + 3H] 3+ )), 823.98493 ([M + 2H] 2+ )), 1646.96346 ([M + H] + ).

[0298] 11H NMR (600 MHz, D2O + CD3CN) δ 4.48 (dd, J = 9.5, 4.1 Hz, 1H), 4.42 (dd, J = 9.2, 4.5 Hz, 1H), 4.32–4.27 (m, 1H), 4.27–4.21 (m, 3H), 4.20–4.07 (m, 6H), 4.00 (dd, J = 8.3, 4.8 Hz, 1H), 3.95 (d, J = 7.5 Hz, 1H), 3.86 (t, J = 6.7 Hz, 1H), 3.77–3.62 (m, 3H), 3.59–3.43 (m, 3H), 3.04 (t, J = 6.7 Hz, 2H), 2.87–2.78 (m, 6H), 2.28–2.08 (m, 9H), 2.00–1.80 (m, 31H, AcOH), 1.80–1.41 (m, 23H), 1.40–1.24 (m, 6H), 1.24–1.18 (m, 9H), 0.87–0.73 (m, 12H).

[0299] Compound 2: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (acetate)

[0300] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 57 H 100 N 18 O 15 ; m / z: 426.59680 ([M + 3H] 3+ ),639.39021 ([M + 2H] 2+ ),1277.77023 ([M + H] + ).

[0301] 1H NMR (600 MHz, DMSO-d6) δ 4.57 (dd, J = 8.7, 4.9 Hz, 1H), 4.41–4.11 (m, 10H), 3.83 (s, 1H), 3.78 (t, J = 6.5 Hz, 1H), 3.54 (d, J = 73.5 Hz, 7H), 3.08 (d, J = 7.0 Hz, 2H), 2.74–2.68 (m, 7H), 2.32 (d, J = 9.1 Hz, 2H), 2.23–2.17 (m, 2H), 2.05–1.46 (m, AcOH, 56H), 1.43–1.22 (m, 7H), 1.17 (d, J = 7.0 Hz, 3H), 0.82 (dd, J = 19.6, 6.7 Hz, 6H).

[0302] Compound 3: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0303] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 51 H 88 N 16 O 14 ; m / z: 383.89927 ([M + 3H] 3+ ),575.34276 ([M + 2H] 2+ ),1149.67551 ([M + H] + ).

[0304] 1 H NMR (600 MHz, DMSO-d6) δ 4.58–4.55 (m, 1H), 4.44–4.37 (m, 2H), 4.33 (dd, J = 8.4, 4.2 Hz, 1H), 4.30–4.22 (m, 3H), 4.16–4.12 (m, 2H), 3.79 (d, J = 6.1 Hz, 1H), 3.64–3.48 (m, 6H), 3.08 (t, J = 7.0 Hz, 2H), 2.71 (d, J = 8.2 Hz, 5H), 2.36–2.30 (m, 2H), 2.15 (t, J = 7.6 Hz, 2H), 2.09–1.41 (m, AcOH, 46H), 1.37–1.29 (m, 4H), 1.16 (d, J = 7.1 Hz, 3H), 0.85 (dd, J = 20.7, 6.7 Hz, 6H).

[0305] Compound 4: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0306] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 40 H 69 N 11 O 12 ; m / z: 448.76653 ([M + 2H] 2+ ),896.52058 ([M + H] + ).

[0307] 11H NMR (600 MHz, DMSO-d6) δ 4.56 (dd, J = 9.0, 4.9 Hz, 1H), 4.39 (dd, J = 8.3, 4.4 Hz, 1H), 4.31–4.24 (m, 3H), 4.13 (dd, J = 9.1, 5.1 Hz, 2H), 3.78 (dd, J = 7.9, 4.3 Hz, 1H), 3.67–3.51 (m, 4H), 2.75–2.70 (m, 4H), 2.38–2.29 (m, 2H), 2.14 (t, J = 7.8 Hz, 2H), 2.04–1.47 (m, AcOH, 33H), 1.35–1.28 (m, 4H), 1.19 (d, J = 7.2 Hz, 3H), 0.85 (dd, J = 22.1, 6.8 Hz, 6H).

[0308] Compound 5: Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0309] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 33 H 60 N 12 O9; m / z: 385.24021 ([M + 2H] 2+ ),769.46971 ([M + H] + ).

[0310] 1 1H NMR (600 MHz, D2O) δ 4.23–4.17 (m, 1H), 4.15–4.07 (m, 4H), 3.95 (dd, J = 8.5, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.25–3.15 (m, 2H), 3.00 (t, J = 7.0 Hz, 2H), 2.78 (t, J = 7.7 Hz, 2H), 2.30–2.22 (m, 1H), 2.12–2.05 (m, 2H), 1.93–1.80 (m, 5H), 1.75 (s, AcOH, 10H), 1.62–1.40 (m, 8H), 1.19 (d, J = 7.2 Hz, 8H), 0.73 (dd, J = 6.7, 4.0 Hz, 6H).

[0311] Compound 6: Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0312] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 768.42641 ([M + H] + ).

[0313] 1 1H NMR (600 MHz, D2O) δ 4.46 (dd, J = 8.4, 6.4 Hz, 1H), 4.35–4.27 (m, 3H), 4.26–4.18 (m, 2H), 4.09 (dd, J = 8.2, 5.1 Hz, 1H), 3.84–3.77 (m, 1H), 3.68–3.52 (m, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.39 (t, J = 7.2 Hz, 2H), 2.33 (t, J = 7.6 Hz, 2H), 2.27–2.17 (m, 2H), 2.12–1.87 (m, AcOH, 13H), 1.83–1.72 (m, 3H), 1.66–1.57 (m, 3H), 1.32 (dd, J = 11.8, 7.5 Hz, 5H), 0.92 (dd, J = 12.6, 6.7 Hz, 6H).

[0314] Compound 7: Lys-Glu-Pro-Val (acetate)

[0315] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 21 H 37 N5O7; m / z: 472.27768 ([M+H] + ).

[0316] 1 1H NMR (600 MHz, D2O) δ 4.43 (dd, J = 10.2, 4.0 Hz, 1H), 4.27 (dd, J = 8.3, 5.3 Hz, 1H), 3.85–3.80 (m, 2H), 3.68–3.60 (m, 1H), 3.59–3.46 (m, 1H), 2.80 (t, J = 7.6 Hz, 2H), 2.22–2.14 (m, 2H), 2.10–2.06 (m, 1H), 1.96–1.64 (m, AcOH, 11H), 1.52–1.47 (m, 2H), 1.29–1.22 (m, 2H), 0.71 (dd, J = 15.3, 6.9 Hz, 6H).

[0317] Compound 8: Val-Ala-Ala-Gln (acetate)

[0318] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 16 H 29 N5O6; m / z: 388.2187 ([M+H] + ).

[0319] 11H NMR (600 MHz, D2O) δ 4.25 (q, J = 7.2 Hz, 1H), 4.17 (q, J = 7.2 Hz, 1H), 4.05 (dd, J = 8.5, 4.8 Hz, 1H), 3.67 (d, J = 6.0 Hz, 1H), 2.23–2.14 (m, 2H), 2.13–2.05 (m, 1H), 2.04–1.95 (m, 1H), 1.85–1.76 (m, 1H), 1.28 (dd, J = 7.2, 5.0 Hz, 6H), 0.90 (dd, J = 10.3, 6.9 Hz, 6H).

[0320] Compound 9: Glu - Pro - Val - Pro (acetate)

[0321] High resolution mass spectrometry (TOF - HRMS), molecular formula: C 20 H 32 N4O7; 441.23562 ([M + H] + ).

[0322] 1 1H NMR (600 MHz, DMSO - d6) δ 4.42 (dd, J = 8.4, 4.6 Hz, 1H), 4.28 (t, J = 8.3 Hz, 1H), 4.17 (dd, J = 8.5, 4.7 Hz, 1H), 3.78 (dd, J = 8.3, 4.2 Hz, 1H), 3.64–3.45 (m, 4H), 2.37–2.27 (m, 2H), 2.08–1.58 (m, AcOH, 16H), 0.87 (dd, J = 25.7, 6.7 Hz, 6H).

[0323] Compound 10: Lys - Pro - Arg - Lys (acetate)

[0324] High resolution mass spectrometry (TOF - HRMS), molecular formula: C 23 H 45 N9O5; 264.68527 ([M + 2H] 2+ ),528.36210 ([M + H] + ).

[0325] 11H NMR (600 MHz, DMSO-d6) δ 4.42 (dd, J = 8.2, 5.2 Hz, 1H), 4.23 (t, J = 6.7 Hz, 1H), 4.14 (dd, J = 8.9, 5.2 Hz, 1H), 4.09 (d, J = 7.9 Hz, 1H), 3.64 (dd, J = 9.9, 6.6 Hz, 1H), 3.45–3.40 (m, 1H), 3.07 (s, 2H), 2.72 (t, J = 6.3 Hz, 4H), 2.11–2.04 (m, 1H), 1.92–1.66 (m, AcOH, 18H), 1.56–1.48 (m, 8H), 1.45–1.38 (m, 2H), 1.33–1.29 (m, 2H).

[0326] Compound 11: Ala-Lys-Pro-Arg (acetate)

[0327] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 38 N8O5; 236.15638 ([M + 2H] 2+ ), 471.30462 ([M + H] + ).

[0328] 1 1H NMR (600 MHz, D2O)) δ 4.55 (dd, J = 8.3, 5.6 Hz, 1H), 4.34 (dd, J = 8.4, 5.9 Hz, 1H), 4.09–3.96 (m, 2H), 3.82–3.74 (m, 1H), 3.64–3.55 (m, 1H), 3.12 (t, J = 6.9 Hz, 2H), 2.93 (t, J = 7.6 Hz, 2H), 2.28–2.20 (m, 1H), 2.04–1.83 (m, 3H), 1.82 (s, AcOH, 6H), 1.79–1.60 (m, 6H), 1.58–1.51 (m, 2H), 1.42 (d, J = 7.1 Hz, 5H).

[0329] Compound 12: Pro-Val-Pro-Gln (acetate)

[0330] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 33 N5O6; m / z: 440.25122 ([M + H] + ).

[0331] 11H NMR (600 MHz, D2O) δ 4.33–4.18 (m, 3H), 3.97 (dd, J = 8.9, 4.8 Hz, 1H), 3.74–3.65 (m, 1H), 3.53–3.46 (m, 1H), 3.25–3.16 (m, 2H), 2.29–2.22 (m, 1H), 2.17–2.10 (m, 3H), 1.99–1.66 (m, AcOH, 12H), 0.82 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H).

[0332] Compound 13: Val-Pro-Gln-Ala (acetate)

[0333] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.23575 ([M+H] + ).

[0334] 1 1H NMR (600 MHz, D2O) δ 4.37 (t, J = 7.5 Hz, 1H), 4.15 (dd, J = 8.6, 6.0 Hz, 1H), 4.07 (d, J = 5.5 Hz, 1H), 4.03 (t, J = 7.2 Hz, 1H), 3.68–3.61 (m, 1H), 3.55–3.48 (m, 1H), 2.35–2.26 (m, 2H), 2.26–2.15 (m, 2H), 2.04–1.74 (m, AcOH, 7H), 1.22 (d, J = 7.2 Hz, 3H), 0.98 (d, J = 7.0 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).

[0335] Compound 14: Pro-Gln-Ala-Lys (acetate)

[0336] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 19 H 34 N6O6; m / z: 222.13480 ([M+2H] 2+ ),443.26183 ([M+H] + ).

[0337] 11H NMR (600 MHz, D2O) δ 4.28 (dd, J = 8.7, 6.1 Hz, 1H), 4.25–4.15 (m, 2H), 4.01 (dd, J = 8.1, 5.2 Hz, 1H), 3.34–3.22 (m, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.37–2.29 (m, 1H), 2.26 (t, J = 7.6 Hz, 2H), 2.00–1.84 (m, 5H), 1.73–1.64 (m, 1H), 1.62–1.50 (m, 3H), 1.30–1.24 (m, 5H).

[0338] Compound 15: Arg-Lys-Val-Ala (acetate)

[0339] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 40 N8O5; m / z: 237.16465 ([M + 2H] 2+ ),473.32087 ([M + H] + ).

[0340] 1 1H NMR (600 MHz, D2O) δ 4.28 (t, J = 7.3 Hz, 1H), 4.00–3.94 (m, 2H), 3.90 (t, J = 6.4 Hz, 1H), 3.07 (t, J = 7.0 Hz, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.01–1.92 (m, 1H), 1.80–1.75 (m, AcOH, 8H), 1.73–1.59 (m, 2H), 1.59–1.40 (m, 4H), 1.35–1.22 (m, 2H), 1.19 (d, J = 7.2 Hz, 3H), 0.81 (t, J = 6.9 Hz, 6H).

[0341] Compound 16: Lys-Val-Ala-Ala (acetate)

[0342] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 17 H 33 N5O5; m / z: 388.25660 ([M + H] + ).

[0343] 11H NMR (600 MHz, D2O) δ 4.18 (q, J = 7.1 Hz, 1H), 4.03–3.91 (m, 3H), 2.87 (t, J = 7.7 Hz, 2H), 1.98–1.89 (m, 1H), 1.83–1.74 (m, AcOH, 6H), 1.60–1.53 (m, 2H), 1.36–1.27 (m, 2H), 1.26 (d, J = 7.2 Hz, 3H), 1.19 (d, J = 7.2 Hz, 3H), 0.83 (d, J = 6.8 Hz, 6H).

[0344] Compound 17: Gln-Ala-Lys-Pro (acetate)

[0345] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 19 H 34 N6O6; m / z: 443.26161 ([M+H] + ).

[0346] 1 1H NMR (600 MHz, D2O) δ 4.48 (dd, J = 8.2, 5.6 Hz, 1H), 4.26–4.20 (m, 1H), 4.10 (dd, J = 8.5, 5.4 Hz, 1H), 3.91 (t, J = 6.6 Hz, 1H), 3.68–3.61 (m, 1H), 3.55–3.43 (m, 1H), 2.88 (t, J = 7.5 Hz, 2H), 2.39–2.27 (m, 2H), 2.15–1.96 (m, 3H), 1.92–1.69 (m, 8H), 1.66–1.49 (m, 3H), 1.43–1.29 (m, 2H), 1.28–1.22 (m, 3H).

[0347] Compound 18: Pro-Arg-Lys-Val (acetate)

[0348] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 22 H 42 N8O5; m / z: 250.17158 ([M+2H] 2+ ),499.33464 ([M+H] + ).

[0349] 11H NMR (600 MHz, D2O) δ 4.27 (dd, J = 8.7, 6.0 Hz, 1H), 4.24–4.17 (m, 2H), 3.88 (d, J = 6.2 Hz, 1H), 3.33–3.20 (m, 2H), 3.09–3.02 (m, 2H), 2.85 (t, J = 7.5 Hz, 2H), 2.37–2.28 (m, 1H), 1.98–1.86 (m, 4H), 1.78 (s, AcOH, 6H), 1.72–1.42 (m, 8H), 1.38–1.23 (m, 2H), 0.75 (dd, J = 11.2, 6.8 Hz, 6H).

[0350] Compound 19: Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0351] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 530.64499 ([M + 3H] 3+ ),795.46224 ([M + 2H] 2+ ),1589.91350 ([M + H] + ).

[0352] 1 1H NMR (600 MHz, D2O) δ 4.53–4.43 (m, 2H), 4.33 (dd, J = 8.3, 6.0 Hz, 1H), 4.27 (t, J = 7.7 Hz, 3H), 4.24–4.12 (m, 6H), 4.06–3.94 (m, 3H), 3.77 (q, J = 7.6 Hz, 1H), 3.73–3.67 (m, 2H), 3.63–3.53 (m, 2H), 3.51 (q, J = 7.6 Hz, 1H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 4H), 2.29 (t, J = 7.6 Hz, 2H), 2.26–2.12 (m, 7H), 2.03–1.46 (m, AcOH, 38H), 1.39 (d, J = 7.1 Hz, 4H), 1.36–1.30 (m, 2H), 1.30–1.22 (m, 10H), 0.92–0.77 (m, 12H).

[0353] Compound 20: Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0354] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 18 ; m / z: 530.32804 ([M + 3H] 3+ ), 794.98683 ([M + 2H] 2+ ), 1588.96546 ([M + H] + ).

[0355] 1 H NMR (600 MHz, D2O) δ 4.51 (q, J = 7.1 Hz, 1H), 4.48–4.43 (m, 1H), 4.31–4.25 (m, 3H), 4.24–4.11 (m, 6H), 4.03 (dd, J = 8.4, 4.9 Hz, 1H), 3.98 (d, J = 7.6 Hz, 1H), 3.87 (t, J = 6.7 Hz, 1H), 3.79–3.67 (m, 3H), 3.60–3.47 (m, 3H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 6H), 2.28 (t, J = 7.6 Hz, 2H), 2.21–2.13 (m, 5H), 2.03–1.64 (m, AcOH, 33H), 1.64–1.47 (m, 11H), 1.44–1.28 (m, 6H), 1.28–1.21 (m, 12H), 0.89–0.76 (m, 12H).

[0356] Compound 21: Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0357] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 540.99125 ([M + 3H] 3+ ), 810.98235 ([M + 2H] 2+ ), 1620.94722 ([M + H] + ).

[0358] 11H NMR (600 MHz, D2O) δ 4.45 (dd, J = 9.4, 4.9 Hz, 1H), 4.30–4.24 (m, 3H), 4.24–4.11 (m, 8H), 4.02 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.89 (t, J = 6.7 Hz, 1H), 3.79–3.66 (m, 2H), 3.60–3.47 (m, 2H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 6H), 2.28 (t, J = 7.6 Hz, 2H), 2.22–2.12 (m, 6H), 2.02–1.46 (m, AcOH, 41H), 1.43–1.28 (m, 6H), 1.28–1.20 (m, 12H), 0.88–0.75 (m, 12H).

[0359] Compound 22: Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0360] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 540.99088 ([M + 3H] 3+ ),810.98168 ([M + 2H] 2+ ),1620.95237 ([M + H] + ).

[0361] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.46 (dd, J = 9.4, 4.8 Hz, 1H), 4.35 (dd, J = 8.4, 5.8 Hz, 1H), 4.28 (dd, J = 8.3, 6.1 Hz, 1H), 4.25–4.13 (m, 7H), 4.03 (dd, J = 8.3, 4.9 Hz, 1H), 3.98 (d, J = 7.6 Hz, 1H), 3.94–3.88 (m, 2H), 3.75–3.67 (m, 2H), 3.63–3.56 (m, 1H), 3.51 (q, J = 7.3 Hz, 1H), 3.09 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 6H), 2.29–2.21 (m, 4H), 2.21–2.13 (m, 4H), 2.03–1.65 (m, AcOH, 31H), 1.64–1.46 (m, 11H), 1.45–1.28 (m, 6H), 1.28–1.22 (m, 12H), 0.89–0.78 (m, 12H).

[0362] Compound 23: Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0363] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 124 N 22 O 19 ; m / z: 398.24191 ([M + 4H] 4+ ),530.65344 ([M + 3H] 3+ ),795.97791 ([M + 2H] 2+ ).

[0364] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.44 (dd, J = 9.4, 4.9 Hz, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.08 (m, 9H), 4.03 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.92–3.87 (m, 1H), 3.79–3.73 (m, 1H), 3.73–3.66 (m, 2H), 3.62–3.52 (m, 2H), 3.51–3.46 (m, 1H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.81 (m, 6H), 2.29–2.21 (m, 2H), 2.21–2.10 (m, 5H), 2.02–1.64 (m, AcOH, 37H), 1.64–1.45 (m, 11H), 1.44–1.27 (m, 6H), 1.27–1.20 (m, 12H), 0.91–0.74 (m, 12H).

[0365] Compound 24: Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0366] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 398.23245 ([M + 4H] 4+ ), 530.64075 ([M + 3H] 3+ ), 795.45752 ([M + 2H] 2+ ).

[0367] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.7, 4.4 Hz, 1H), 4.45 (q, J = 7.1 Hz, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.24 (m, 3H), 4.23–4.12 (m, 6H), 4.03 (dd, J = 8.4, 4.8 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.92–3.87 (m, 1H), 3.79–3.73 (m, 1H), 3.73–3.64 (m, 2H), 3.62–3.48 (m, 3H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 4H), 2.32–2.21 (m, 4H), 2.20–2.11 (m, 5H), 2.03–1.71 (m, AcOH, 32H), 1.71–1.45 (m, 10H), 1.37–1.27 (m, 4H), 1.27–1.17 (m, 12H), 0.90–0.76 (m, 12H).

[0368] Compound 25: Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0369] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 123 N 23 O 20 ; m / z: 405.48935 ([M + 4H] 4+ ),540.31677 ([M + 3H] 3+ ),809.97144 ([M + 2H] 2+ ).

[0370] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.5, 4.4 Hz, 1H), 4.48–4.41 (m, 2H), 4.32–4.25 (m, 3H), 4.21 (dd, J = 8.1, 6.7 Hz, 1H), 4.19–4.12 (m, 5H), 4.02 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.92–3.85 (m, 1H), 3.74–3.64 (m, 3H), 3.60–3.46 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.83 (m, 6H), 2.30–2.20 (m, 4H), 2.20–2.12 (m, 5H), 2.02–1.45 (m, AcOH, 48H), 1.43–1.27 (m, 6H), 1.27–1.21 (m, 12H), 0.80 (dd, J = 6.8, 4.4 Hz, 6H).

[0371] Compound 26: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0372] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 405.99350 ([M + 4H] 4+ ),540.98883 ([M + 3H] 3+ ),810.97961 ([M + 2H] 2+ ).

[0373] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.23 (m, 2H), 4.23–4.09 (m, 8H), 4.03 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.93–3.86 (m, 1H), 3.81–3.66 (m, 2H), 3.62–3.52 (m, 2H), 3.07 (t, J = 6.9 Hz, 2H), 2.86 (m, 6H), 2.31–2.11 (m, 8H), 2.03–1.41 (m, AcOH, 48H), 1.40–1.27 (m, 6H), 1.25 (dd, J = 13.7, 7.3 Hz, 12H), 0.90–0.76 (m, 12H).

[0374] Compound 27: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln (acetate)

[0375] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 20 O 20 ; m / z: 391.23177 ([M + 4H] 4+ ),781.45496 ([M + 2H] 2+ ).

[0376] 1 1H NMR (600 MHz, D2O) δ 4.52–4.43 (m, 2H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.22 (m, 3H), 4.21–4.10 (m, 6H), 4.02 (dd, J = 8.5, 4.8 Hz, 1H), 3.96 (d, J = 7.7 Hz, 1H), 3.92–3.84 (m, 1H), 3.81–3.73 (m, 1H), 3.73–3.65 (m, 2H), 3.61–3.52 (m, 2H), 3.52–3.45 (m, 1H), 2.91–2.81 (m, 6H), 2.30–2.10 (m, 9H), 2.02–1.62 (m, AcOH, 31H), 1.62–1.51 (m, 8H), 1.41–1.27 (m, 6H), 1.27–1.20 (m, 12H), 0.90–0.75 (m, 12H).

[0377] Compound 28: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln (acetate)

[0378] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 398.23303 ([M + 4H] 4+ ), 530.64142 ([M + 3H] 3+ ), 795.45850 ([M + 2H] 2+ ).

[0379] 1 H NMR (600 MHz, D2O) δ 4.52–4.42 (m, 2H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.30–4.24 (m, 3H), 4.23–4.09 (m, 6H), 4.02 (dd, J = 8.5, 4.8 Hz, 1H), 3.95 (d, J = 7.5 Hz, 1H), 3.92–3.85 (m, 1H), 3.79–3.73 (m, 1H), 3.72–3.67 (m, 2H), 3.62–3.42 (m, 3H), 3.08 (t, J = 6.9 Hz, 2H), 2.87 (t, J = 7.6 Hz, 4H), 2.30–2.25 (m, 2H), 2.24–2.10 (m, 7H), 2.02–1.65 (m, AcOH, 29H), 1.64–1.48 (m, 8H), 1.42–1.29 (m, 4H), 1.28–1.19 (m, 12H), 0.90–0.75 (m, 12H).

[0380] Compound 29: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (acetate)

[0381] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 123 N 23 O 20 ; m / z: 405.48969 ([M + 4H] 4+ ), 540.31714 ([M + 3H] 3+ ), 809.97205 ([M + 2H] 2+ ).

[0382] 1 1H NMR (600 MHz, D2O) δ 4.49 (dd, J = 9.6, 4.3 Hz, 1H), 4.45 (dd, J = 9.3, 4.9 Hz, 1H), 4.33 (dd, J = 8.4, 5.8 Hz, 1H), 4.29–4.24 (m, 3H), 4.19–4.13 (m, 7H), 4.02 (dd, J = 8.4, 4.8 Hz, 1H), 3.89 (t, J = 6.8 Hz, 1H), 3.79–3.66 (m, 3H), 3.61–3.47 (m, 3H), 3.08 (t, J = 6.9 Hz, 2H), 2.86 (q, J = 8.0 Hz, 6H), 2.28 (t, J = 7.6 Hz, 2H), 2.23–2.13 (m, 7H), 2.02–1.46 (m, AcOH, 47H), 1.42–1.18 (m, 20H), 0.85 (dd, J = 14.2, 6.7 Hz, 6H).

[0383] Compound 30: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala (acetate)

[0384] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 124 N 22 O 19 ; m / z: 398.24493 ([M + 4H] 4+ ),530.65551 ([M + 3H] 3+ ),795.47815 ([M + 2H] 2+ ),1589.94194 ([M + H] + ).

[0385] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.46 (dd, J = 9.4, 4.9 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.24 (m, 3H), 4.24–4.20 (m, 1H), 4.20–4.09 (m, 5H), 4.02–3.96 (m, 2H), 3.93–3.86 (m, 1H), 3.80–3.74 (m, 1H), 3.74–3.67 (m, 2H), 3.63–3.43 (m, 3H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.82 (m, 6H), 2.31–2.12 (m, 7H), 2.01–1.65 (m, AcOH, 34H), 1.64–1.46 (m, 11H), 1.35 (dd, J = 16.0, 8.1 Hz, 6H), 1.27–1.20 (m, 12H), 0.92–0.77 (m, 12H).

[0386] Compound 31: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0387] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.49240 ([M + 4H] 4+ ),536.31955 ([M + 3H] 3+ ),803.97442 ([M + 2H] 2+ ),1606.91471 ([M + H] + ).

[0388] 11H NMR (600 MHz, D2O) δ 4.45 (dd, J = 9.4, 4.9 Hz, 1H), 4.32 (d, J = 8.1 Hz, 1H), 4.30–4.25 (m, 2H), 4.24–4.19 (m, 2H), 4.19–4.11 (m, 5H), 4.02 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.91–3.84 (m, 2H), 3.82–3.73 (m, 2H), 3.69 (q, J = 7.7, 7.0 Hz, 1H), 3.59–3.52 (m, 1H), 3.52–3.46 (m, 1H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.82 (m, 6H), 2.28 (t, J = 7.6 Hz, 2H), 2.23–2.12 (m, 6H), 2.02–1.64 (m, AcOH, 35H), 1.63–1.45 (m, 11H), 1.44–1.27 (m, 6H), 1.27–1.21 (m, 9H), 0.88–0.73 (m, 12H).

[0389] Compound 32: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0390] High-resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.49278 ([M + 4H] 4+ ),536.31975 ([M + 3H] 3+ ),803.97422 ([M + 2H] 2+ ),1606.92969 ([M + H] + ).

[0391] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.7, 4.4 Hz, 1H), 4.46 (dd, J = 9.4, 4.9 Hz, 1H), 4.36 (dd, J = 8.3, 5.9 Hz, 1H), 4.28 (dd, J = 8.3, 6.1 Hz, 1H), 4.24–4.14 (m, 6H), 4.03 (dd, J = 8.3, 4.9 Hz, 1H), 3.97 (dd, J = 10.0, 7.5 Hz, 2H), 3.90 (t, J = 6.8 Hz, 1H), 3.87–3.78 (m, 2H), 3.76–3.67 (m, 2H), 3.61–3.54 (m, 1H), 3.54–3.47 (m, 1H), 3.08 (t, J = 6.9 Hz, 2H), 2.91–2.83 (m, 6H), 2.26–2.13 (m, 8H), 2.03–1.87 (m, 9H), 1.87–1.45 (m, AcOH, 33H), 1.44–1.28 (m, 6H), 1.26 (dd, J = 18.4, 7.2 Hz, 9H), 0.89–0.79 (m, 12H).

[0392] Compound 33: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0393] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.48917 ([M + 4H] 4+ ),536.31647 ([M + 3H] 3+ ),803.97101 ([M + 2H] 2+ ).

[0394] 11H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.34 (dd, J = 8.4, 5.8 Hz, 1H), 4.31–4.11 (m, 9H), 4.03 (dd, J = 8.4, 4.9 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.92–3.86 (m, 1H), 3.85–3.74 (m, 3H), 3.74–3.66 (m, 1H), 3.62–3.52 (m, 2H), 3.06 (t, J = 7.0 Hz, 2H), 2.91–2.83 (m, 6H), 2.31–2.11 (m, 8H), 2.03–1.43 (m, AcOH, 45H), 1.40–1.27 (m, 6H), 1.27–1.23 (m, 9H), 0.91–0.77 (m, 12H).

[0395] Compound 34: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0396] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48178 ([M + 4H] 4+ ),522.97314 ([M + 3H] 3+ ),784.45752 ([M + 2H] 2+ ).

[0397] 1 1H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.6, 4.4 Hz, 1H), 4.35 (dd, J = 8.3, 5.9 Hz, 1H), 4.25–4.12 (m, 7H), 4.03 (dd, J = 8.4, 4.8 Hz, 1H), 3.96 (dd, J = 10.6, 7.5 Hz, 2H), 3.92–3.86 (m, 1H), 3.85–3.77 (m, 4H), 3.75–3.68 (m, 1H), 3.60–3.53 (m, 1H), 3.06 (t, J = 7.0 Hz, 2H), 2.92–2.83 (m, 6H), 2.28–2.12 (m, 7H), 2.05–1.41 (m, AcOH, 42H), 1.40–1.27 (m, 6H), 1.27–1.24 (m, 9H), 0.85 (dd, J = 11.0, 6.7 Hz, 6H), 0.80 (dd, J = 6.8, 5.1 Hz, 6H).

[0398] Compound 35: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0399] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 64 H 115 N 23 O 20 ; m / z: 382.47363 ([M+4H] 4+ ),509.62903 ([M+3H] 3+ ),763.93982 ([M+2H] 2+ ).

[0400] 1 1H NMR (600 MHz, D2O) δ 4.27–4.13 (m, 8H), 4.05–4.00 (m, 2H), 3.97 (d, J = 7.6 Hz, 1H), 3.93–3.87 (m, 2H), 3.85–3.76 (m, 5H), 3.06 (t, J = 7.0 Hz, 2H), 2.90–2.83 (m, 6H), 2.24–2.12 (m, 6H), 2.02–1.41 (m, AcOH, 40H), 1.39–1.27 (m, 6H), 1.27–1.22 (m, 9H), 0.85–0.76 (m, 12H).

[0401] Compound 36: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0402] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48172 ([M+4H] 4+ ),522.97314 ([M+3H] 3+ ),783.95605 ([M+2H] 2+ ).

[0403] 11H NMR (600 MHz, D2O) δ 4.32 (d, J = 8.0 Hz, 1H), 4.28 (dd, J = 8.2, 6.7 Hz, 1H), 4.25–4.12 (m, 8H), 4.03 (dd, J = 8.4, 4.8 Hz, 1H), 3.97 (d, J = 7.6 Hz, 1H), 3.92–3.83 (m, 2H), 3.83–3.73 (m, 4H), 3.60–3.53 (m, 1H), 3.06 (t, J = 7.0 Hz, 2H), 2.91–2.83 (m, 6H), 2.28 (t, J = 7.5 Hz, 2H), 2.24–2.12 (m, 5H), 2.02–1.42 (m, AcOH, 43H), 1.41–1.27 (m, 6H), 1.27–1.22 (m, 9H), 0.91–0.72 (m, 12H).

[0404] Compound 37: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0405] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48172 ([M + 4H] 4+ ),522.97314 ([M + 3H] 3+ ),783.95605 ([M + 2H] 2+ ).

[0406] 1 1H NMR (600 MHz, D2O) δ 4.44 (dd, J = 9.4, 4.9 Hz, 1H), 4.29–4.12 (m, 8H), 4.04–3.99 (m, 2H), 3.96 (d, J = 7.6 Hz, 1H), 3.91–3.82 (m, 3H), 3.81 (s, 2H), 3.72–3.65 (m, 1H), 3.52–3.44 (m, 1H), 3.06 (t, J = 6.9 Hz, 2H), 2.89–2.81 (m, 6H), 2.23–2.12 (m, 7H), 2.01–1.45 (m, AcOH, 43H), 1.42–1.26 (m, 6H), 1.26–1.20 (m, 9H), 0.83–0.77 (m, 12H).

[0407] Compound 38: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (acetate)

[0408] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 51 H 88 N 16 O 14 ; m / z: 383.89569 ([M + 3H] 3+ ),575.33978 ([M + 2H] 2+ ).

[0409] 1 1H NMR (600 MHz, D2O) δ 4.45 (dd, J = 9.2, 5.0 Hz, 1H), 4.39 (dd, J = 8.3, 6.4 Hz, 1H), 4.29–4.21 (m, 4H), 4.19–4.12 (m, 3H), 4.01 (dd, J = 7.8, 5.5 Hz, 1H), 3.78–3.73 (m, 1H), 3.72–3.67 (m, 1H), 3.61–3.48 (m, 4H), 3.08 (t, J = 6.8 Hz, 2H), 2.88–2.83 (m, 4H), 2.30–2.26 (m, 4H), 2.20–2.13 (m, 3H), 2.08–1.46 (m, AcOH, 38H), 1.39–1.22 (m, 7H), 0.86 (dd, J = 10.3, 6.7 Hz, 6H).

[0410] Compound 39: Pro-Val-Pro-Gln-Ala (acetate)

[0411] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 23 H 38 N6O7; m / z: 511.2871 ([M + H] + ).

[0412] 1 1H NMR (600 MHz, D2O) δ 4.41 (d, J = 7.3 Hz, 1H), 4.38–4.32 (m, 2H), 4.20 (dd, J = 8.7, 5.9 Hz, 1H), 4.11–4.04 (m, 1H), 3.85–3.77 (m, 1H), 3.62 (dt, J = 10.3, 7.2 Hz, 1H), 3.39–3.29 (m, 2H), 2.39–2.31 (m, 3H), 2.28–2.20 (m, 1H), 2.08–1.90 (m, AcOH, 10H), 1.86–1.80 (m, 1H), 1.26 (d, J = 7.3 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.88 (d, J = 6.8 Hz, 3H).

[0413] Compound 40: Pro-Val-Pro-Glu-Ala (acetate)

[0414] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 23 H 37 N5O8; m / z: 512.27081 ([M+H] + ).

[0415] 1 1H NMR (600 MHz, D2O) δ 4.41 (d, J = 7.3 Hz, 1H), 4.38–4.32 (m, 2H), 4.23 (dd, J = 8.9, 5.6 Hz, 1H), 4.13–4.09 (m, 1H), 3.86–3.76 (m, 1H), 3.62 (dt, J = 10.2, 7.2 Hz, 1H), 3.38–3.28 (m, 2H), 2.43–2.35 (m, 3H), 2.26–2.16 (m, 1H), 2.12–1.72 (m, AcOH, 12H), 1.28 (d, J = 7.2 Hz, 3H), 0.94 (d, J = 6.8 Hz, 3H), 0.87 (d, J = 6.8 Hz, 3H).

[0416] Compound 41: Pro-Val-Pro-Ile-Ala (acetate)

[0417] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 24 H 41 N5O6; m / z: 496.31158 ([M+H] + ).

[0418] 11H NMR (600 MHz, D2O) δ 4.36–4.27 (m, 3H), 4.03 (q, J = 7.2 Hz, 1H), 3.98 (d, J = 7.8 Hz, 1H), 3.79–3.72 (m, 1H), 3.60–3.53 (m, 1H), 3.34–3.21 (m, 2H), 2.36–2.25 (m, 1H), 2.21–2.12 (m, 1H), 2.03–1.96 (m, 1H), 1.96–1.81 (m, AcOH, 7H), 1.80–1.69 (m, 2H), 1.43–1.33 (m, 1H), 1.20 (d, J = 7.2 Hz, 3H), 1.13–1.02 (m, 1H), 0.88 (d, J = 6.8 Hz, 3H), 0.85–0.80 (m, 6H), 0.80–0.77 (m, 1H), 0.74 (t, J = 7.4 Hz, 3H).

[0419] Compound 42: Pro-Val-Pro-Ala

[0420] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 18 H 30 N4O5; m / z: 383.22791 ([M+H] + ).

[0421] 1 1H NMR (600 MHz, D2O) δ 4.36 (d, J = 7.2 Hz, 1H), 4.30 (dd, J = 8.5, 6.3 Hz, 1H), 4.24 (dd, J = 8.1, 6.5 Hz, 1H), 4.00 (q, J = 7.2 Hz, 1H), 3.79–3.72 (m, 1H), 3.60–3.52 (m, 1H), 3.31–3.23 (m, 2H), 2.33–2.26 (m, 1H), 2.20–2.13 (m, 1H), 2.09–1.69 (m, AcOH, 10H), 1.21 (d, J = 7.3 Hz, 3H), 0.88 (d, J = 6.9 Hz, 3H), 0.81 (d, J = 6.8 Hz, 3H).

[0422] Compound 43: Glu-Pro-Val-Pro-Gln-Ala (acetate)

[0423] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 28 H 45 N7O 10 ; m / z: 640.32892 ([M+H] + ).

[0424] 1 1H NMR (600 MHz, D2O) δ 4.34 (dd, J = 8.3, 6.5 Hz, 1H), 4.25–4.15 (m, 3H), 4.08 (dd, J = 8.8, 5.9 Hz, 1H), 4.04–4.00 (m, 1H), 3.73–3.65 (m, 1H), 3.57–3.41 (m, 3H), 2.35 (t, J = 7.3 Hz, 2H), 2.24–2.20 (m, 2H), 2.16–2.07 (m, 2H), 2.04–1.75 (m, AcOH, 11H), 1.73–1.63 (m, 2H), 1.17 (d, J = 7.2 Hz, 3H), 0.80 (dd, J = 12.9, 6.8 Hz, 6H).

[0425] Compound 44: Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0426] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 29 H 50 N8O8; m / z: 320.19421 ([M + 2H] 2+ ).

[0427] 1 1H NMR (600 MHz, D2O) δ 4.29–4.19 (m, 3H), 4.13–4.06 (m, 2H), 3.95 (dd, J = 8.2, 5.1 Hz, 1H), 3.73–3.68 (m, 1H), 3.52–3.47 (m, 1H), 3.24–3.16 (m, 2H), 2.79 (t, J = 7.5 Hz, 2H), 2.25–2.19 (m, 3H), 2.14–2.08 (m, 1H), 1.97–1.57 (m, AcOH, 17H), 1.53–1.45 (m, 3H), 1.21–1.17 (m, 5H), 0.82 (d, J = 6.8 Hz, 3H), 0.75 (d, J = 6.7 Hz, 3H).

[0428] Compound 45: Glu-Pro-Val-Pro-Gln-Ala-Arg (acetate)

[0429] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N 11 O 11 ; m / z: 398.71835 ([M + 2H] 2+ ),796.42944 ([M + H]+ ).

[0430] 1 1H NMR (600 MHz, D2O) δ 4.38 (dd, J = 8.3, 6.4 Hz, 1H), 4.27–4.19 (m, 3H), 4.19–4.10 (m, 2H), 4.03 (dd, J = 8.3, 4.9 Hz, 1H), 3.78–3.70 (m, 1H), 3.60–3.46 (m, 3H), 3.07–3.02 (m, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.25 (t, J = 7.6 Hz, 2H), 2.19–2.11 (m, 2H), 2.06–1.78 (m, AcOH, 12H), 1.76–1.67 (m, 3H), 1.60–1.53 (m, 1H), 1.48–1.42 (m, 2H), 1.24 (d, J = 7.1 Hz, 3H), 0.85 (dd, J = 12.8, 6.7 Hz, 6H).

[0431] Compound 46: Ala - Pro - Val - Pro - Gln - Ala - Lys (acetate)

[0432] High resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 32 H 55 N9O9; m / z: 355.71259 ([M + 2H] 2+ ),710.41809 ([M + H] + ).

[0433] 11H NMR (600 MHz, DMSO-d6) δ 8.23 (d, J = 7.7 Hz, 1H), 8.08 (d, J = 8.1 Hz, 1H), 7.87 (d, J = 8.4 Hz, 1H), 7.68 (s, 1H), 7.38 (d, J = 6.4 Hz, 1H), 6.75 (s, 1H), 4.40–4.37 (m, 1H), 4.33–4.25 (m, 3H), 4.15 (t, J = 7.2 Hz, 3H), 3.78 (d, J = 6.4 Hz, 1H), 3.66 (dd, J = 32.4, 8.0 Hz, 2H), 3.58–3.51 (m, 2H), 3.43 (d, J = 7.0 Hz, 1H), 3.36–3.27 (m, 1H), 2.67 (t, J = 7.7 Hz, 3H), 2.19–2.07 (m, 4H), 2.01–1.69 (m, AcOH, 24H), 1.63–1.60 (m, 1H), 1.55–1.41 (m, 5H), 1.26 (d, 1H), 1.18 (d, J = 7.2 Hz, 6H), 1.11 (d, J = 6.7 Hz, 3H), 1.04 (d, J = 6.6 Hz, 1H), 0.87 (d, J = 6.7 Hz, 3H), 0.83 (d, J = 6.9 Hz, 3H).

[0434] Compound 47: Glu-Pro-Val-Pro-Ala-Ala-Lys (acetate)

[0435] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 54 N8O 10 ; m / z: 356.20514 ([M + 2H] 2+ ), 711.40198 ([M + H] + ).

[0436] 1 1H NMR (600 MHz, D2O) δ 4.45 (dd, J = 8.4, 6.4 Hz, 1H), 4.33–4.27 (m, 3H), 4.21 (dd, J = 15.1, 7.2 Hz, 2H), 4.07 (dd, J = 8.1, 5.1 Hz, 1H), 3.86–3.75 (m, 1H), 3.67–3.54 (m, 3H), 2.91 (t, J = 7.5 Hz, 2H), 2.37 (t, J = 6.9 Hz, 2H), 2.26–2.18 (m, 2H), 2.14–1.69 (m, AcOH, 13H), 1.65–1.58 (m, 3H), 1.35–1.29 (m, 9H), 0.92 (dd, J = 13.6, 6.8 Hz, 6H).

[0437] Compound 48: Glu-Pro-Val-Pro-Gln-Ala-Ala (acetate)

[0438] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 50 N8O 11 ; m / z: 356.18692 ([M + 2H] 2+ ), 711.36597 ([M + H] + ).

[0439] 1 1H NMR (600 MHz, D2O) δ 4.34 (dd, J = 8.3, 6.5 Hz, 1H), 4.24–4.16 (m, 3H), 4.12–4.06 (m, 2H), 4.03–3.99 (m, 1H), 3.73–3.65 (m, 1H), 3.56–3.41 (m, 3H), 2.35 (t, J = 7.3 Hz, 2H), 2.22–2.18 (m, 2H), 2.15–2.07 (m, 2H), 2.04–1.73 (m, AcOH, 11H), 1.71–1.63 (m, 2H), 1.18 (dd, J = 11.2, 7.2 Hz, 6H), 0.80 (dd, J = 13.0, 6.8 Hz, 6H).

[0440] Compound 49: Asp-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0441] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 33 H 55 N9O 11 ; m / z: 377.70767 ([M + 2H] 2+ ), 754.40814 ([M + H] + ).

[0442] 11H NMR (600 MHz, D2O) δ 4.36–4.29 (m, 2H), 4.23–4.14 (m, 2H), 4.13–4.06 (m, 2H), 3.97 (dd, J = 8.3, 5.0 Hz, 1H), 3.74–3.65 (m, 1H), 3.56–3.46 (m, 2H), 3.44–3.39 (m, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.65 (dd, J = 17.5, 3.3 Hz, 1H), 2.38 (dd, J = 17.5, 10.7 Hz, 1H), 2.21 (t, J = 7.6 Hz, 2H), 2.15–2.06 (m, 2H), 1.93–1.75 (m, AcOH, 9H), 1.72–1.61 (m, 3H), 1.54–1.45 (m, 3H), 1.21 (dd, J = 13.1, 7.5 Hz, 5H), 0.80 (dd, J = 11.0, 6.7 Hz, 6H).

[0443] Compound 50: Asn-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0444] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 33 H 56 N 10 O 10 ; m / z: 377.21542 ([M + 2H] 2+ ),753.42365 ([M + H] + ).

[0445] 1 1H NMR (600 MHz, D2O) δ 4.55 (dd, J = 9.3, 4.0 Hz, 1H), 4.47 (dd, J = 8.4, 6.1 Hz, 1H), 4.34–4.29 (m, 2H), 4.26–4.19 (m, 2H), 4.07 (dd, J = 8.1, 5.1 Hz, 1H), 3.83–3.77 (m, 1H), 3.69–3.53 (m, 3H), 2.94–2.90 (m, 3H), 2.72 (dd, J = 17.0, 9.3 Hz, 1H), 2.33 (t, J = 7.6 Hz, 2H), 2.27–2.19 (m, 2H), 2.05–1.71 (m, AcOH, 15H), 1.65–1.57 (m, 3H), 1.34–1.30 (m, 5H), 0.91 (dd, J = 13.4, 6.7 Hz, 6H).

[0446] Compound 51: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (acetate)

[0447] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 59 H 102 N 18 O 16 ; m / z: 440.59735 ([M+3H] 3+ ),660.39252 ([M+2H] 2+ ).

[0448] 1 H NMR (600 MHz, D2O) δ 4.38 (dd, J = 9.3, 4.8 Hz, 1H), 4.33 (dd, J = 8.3, 6.5 Hz, 1H), 4.22–4.12 (m, 5H), 4.10–4.04 (m, 3H), 3.93–3.88 (m, 2H), 3.75–3.67 (m, 1H), 3.66–3.58 (m, 1H), 3.56–3.41 (m, 4H), 3.00 (t, J = 6.9 Hz, 2H), 2.82–2.76 (m, 4H), 2.24–2.19 (m, 4H), 2.14–2.06 (m, 3H), 1.97–1.41 (m, AcOH, 37H), 1.33–1.12 (m, 10H), 0.80 (dd, J = 9.7, 6.7 Hz, 6H), 0.74 (dd, J = 11.0, 6.8 Hz, 6H).

[0449] Compound 52: Glu-Pro-Ala-Pro-Gln-Ala-Lys (acetate)

[0450] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 53 N9O 11 ; m / z: 370.6998 ([M+2H] 2+ ),740.39221 ([M+H] + ).

[0451] 11H NMR (600 MHz, D2O) δ 4.43 (q, J = 7.1 Hz, 1H), 4.33 (dd, J = 8.4, 6.5 Hz, 1H), 4.26 (dd, J = 8.4, 5.8 Hz, 1H), 4.22 (dd, J = 7.6, 4.6 Hz, 1H), 4.18–4.11 (m, 2H), 4.01 (dd, J = 8.3, 5.0 Hz, 1H), 3.67 (dt, J = 10.0, 6.7 Hz, 1H), 3.61–3.54 (m, 1H), 3.53–3.44 (m, 2H), 2.84 (t, J = 7.5 Hz, 2H), 2.30 (t, J = 7.2 Hz, 2H), 2.25 (t, J = 7.6 Hz, 2H), 2.21–2.12 (m, 2H), 2.08–1.77 (m, AcOH, 11H), 1.77–1.63 (m, 3H), 1.60–1.49 (m, 3H), 1.24 (dd, J = 10.4, 7.1 Hz, 6H).

[0452] Compound 53: Glu-Ala-Val-Pro-Gln-Ala-Lys (acetate)

[0453] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O 11 ; m / z: 371.7081 ([M + 2H] 2+ ), 742.4089 ([M + H] + ).

[0454] 1 1H NMR (600 MHz, D2O) δ 4.23–4.18 (m, 3H), 4.13–4.06 (m, 2H), 3.95 (dd, J = 8.3, 5.0 Hz, 1H), 3.85–3.82 (m, 1H), 3.73–3.66 (m, 1H), 3.53–3.47 (m, 1H), 2.79 (t, J = 7.5 Hz, 2H), 2.22–2.17 (m, 4H), 2.13–2.07 (m, 1H), 1.99–1.70 (m, AcOH, 9H), 1.69–1.59 (m, 2H), 1.53–1.45 (m, 3H), 1.26–1.12 (m, 9H), 0.79 (d, J = 6.7 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H).

[0455] Compound 54: Glu-Pro-Val-Ala-Gln-Ala-Lys (acetate)

[0456] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O 11 ; m / z: 371.70767 ([M+2H] 2+ ),742.40802 ([M+H] + ).

[0457] 1 1H NMR (600 MHz, DMSO-d6 + D2O) δ 4.34 (dd, J = 8.3, 6.0 Hz, 1H), 4.15–4.05 (m, 4H), 3.97–3.87 (m, 2H), 3.51 (d, J = 9.8 Hz, 1H), 3.46–3.38 (m, 1H), 2.74 (t, J = 7.5 Hz, 2H), 2.23 (t, J = 7.1 Hz, 2H), 2.17–2.06 (m, 3H), 1.95–1.67 (m, AcOH, 10H), 1.65–1.59 (m, 1H), 1.53–1.42 (m, 3H), 1.22–1.13 (m, 8H), 0.78 (d, J = 6.8 Hz, 6H).

[0458] Compound 55: Glu-Pro-Val-Pro-Glu-Ala-Lys (acetate)

[0459] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 56 N8O 12 ; m / z: 385.2083 ([M+2H] 2+ ),769.4092 ([M+H] + ).

[0460] 11H NMR (600 MHz, D2O) δ 4.33 (dd, J = 8.3, 6.5 Hz, 1H), 4.21–4.16 (m, 3H), 4.11 (t, J = 7.1 Hz, 1H), 4.07 (dd, J = 8.8, 5.7 Hz, 1H), 3.98 (dd, J = 8.5, 4.8 Hz, 1H), 3.71–3.66 (m, 1H), 3.55–3.41 (m, 3H), 2.78 (t, J = 7.5 Hz, 2H), 2.36–2.14 (m, 5H), 2.13–2.05 (m, 2H), 1.99–1.74 (m, AcOH, 11H), 1.70–1.61 (m, 3H), 1.53–1.45 (m, 3H), 1.20 (dd, J = 15.4, 7.5 Hz, 5H), 0.80 (dd, J = 12.5, 6.7 Hz, 6H).

[0461] Compound 56: Glu - Pro - Val - Pro - Gln - Ala - Lys - Pro - Arg - Lys - Val (acetate)

[0462] High resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 56 H 97 N 17 O 15 ; m / z: 416.91827 ([M + 3H] 3+ ),624.87354 ([M + 2H] 2+ ).

[0463] 1 1H NMR (600 MHz, D2O) δ 4.43 (dd, J = 9.3, 4.9 Hz, 1H), 4.38 (dd, J = 8.4, 6.4 Hz, 1H), 4.27–4.19 (m, 5H), 4.16–4.10 (m, 3H), 3.88 (d, J = 6.2 Hz, 1H), 3.74 (dt, J = 10.1, 6.9 Hz, 1H), 3.71–3.63 (m, 1H), 3.60–3.46 (m, 4H), 3.07–3.02 (m, 2H), 2.87–2.82 (m, 4H), 2.29–2.24 (m, 4H), 2.19–2.11 (m, 3H), 2.04–1.43 (m, AcOH, 37H), 1.37–1.20 (m, 7H), 0.85 (dd, J = 10.1, 6.8 Hz, 6H), 0.74 (dd, J = 11.8, 6.9 Hz, 6H).

[0464] Compound 57: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0465] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 45 H 76 N 14 O 13 ; m / z: 511.29254 ([M+2H] 2+ ).

[0466] 1 H NMR (600 MHz, D2O) δ 4.39 (dd, J = 8.6, 5.5 Hz, 1H), 4.32 (dd, J = 8.3, 6.5 Hz, 1H), 4.22–4.13 (m, 4H), 4.10–4.03 (m, 2H), 3.93 (dd, J = 7.9, 5.2 Hz, 1H), 3.72–3.60 (m, 2H), 3.54–3.40 (m, 4H), 3.00 (t, J = 6.9 Hz, 2H), 2.80 (t, J = 7.5 Hz, 2H), 2.24–2.18 (m, 4H), 2.14–2.06 (m, 3H), 1.98–1.70 (m, AcOH, 19H), 1.69–1.60 (m, 4H), 1.55–1.47 (m, 4H), 1.45–1.39 (m, 2H), 1.34–1.24 (m, 2H), 1.16 (d, J = 7.1 Hz, 3H), 0.80 (dd, J = 10.4, 6.7 Hz, 6H).

[0467] Compound 58: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (acetate)

[0468] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 39 H 64 N 10 O 12 ; m / z: 433.24188 ([M+2H] 2+ ), 865.47662 ([M+H] + ).

[0469] 11H NMR (600 MHz, D2O) δ 4.41 (dd, J = 8.5, 5.5 Hz, 1H), 4.33 (dd, J = 8.3, 6.5 Hz, 1H), 4.22–4.14 (m, 3H), 4.11–4.02 (m, 3H), 3.75–3.67 (m, 1H), 3.59–3.41 (m, 5H), 2.81 (t, J = 7.4 Hz, 2H), 2.25–2.19 (m, 4H), 2.15–1.61 (m, AcOH, 26H), 1.57–1.48 (m, 3H), 1.37–1.23 (m, 2H), 1.16 (d, J = 7.0 Hz, 3H), 0.80 (dd, J = 11.5, 6.7 Hz, 6H).

[0470] Compound 59: Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0471] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 40 H 69 N 13 O 10 ; m / z: 298.18314 ([M + 3H] 3+ ),446.77118 ([M + 2H] 2+ ),892.53497 ([M + H] + ).

[0472] 1 1H NMR (600 MHz, D2O) δ 4.40 (dd, J = 8.6, 5.5 Hz, 1H), 4.30–4.19 (m, 4H), 4.11–4.05 (m, 2H), 3.93 (dd, J = 7.9, 5.2 Hz, 1H), 3.73–3.63 (m, 2H), 3.52–3.45 (m, 2H), 3.26–3.17 (m, 2H), 3.01 (t, J = 6.9 Hz, 2H), 2.81 (t, J = 7.5 Hz, 2H), 2.26–2.19 (m, 3H), 2.14–2.09 (m, 2H), 1.94–1.62 (m, AcOH, 24H), 1.57–1.40 (m, 7H), 1.34–1.26 (m, 2H), 1.16 (d, J = 7.3 Hz, 3H), 0.82 (d, J = 6.8 Hz, 3H), 0.76 (d, J = 6.7 Hz, 3H).

[0473] Compound 60: Pro-Val-Pro-Gln-Ala-Lys-Pro (acetate)

[0474] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O9; m / z: 368.7207 ([M+2H] 2+ ),736.4343 ([M+H] + ).

[0475] 1 1H NMR (600 MHz, D2O) δ 4.46 (dd, J = 8.4, 5.6 Hz, 1H), 4.34 (d, J = 7.4 Hz, 1H), 4.29 (dd, J = 8.5, 6.2 Hz, 1H), 4.27–4.24 (m, 1H), 4.16–4.07 (m, 3H), 3.78–3.70 (m, 1H), 3.66–3.60 (m, 1H), 3.58–3.45 (m, 2H), 3.30–3.22 (m, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.32–2.24 (m, 3H), 2.19–2.13 (m, 1H), 2.12–2.03 (m, 1H), 2.02–1.69 (m, AcOH, 19H), 1.61–1.52 (m, 3H), 1.42–1.27 (m, 2H), 1.23–1.20 (m, 3H), 0.87 (d, J = 6.8 Hz, 3H), 0.81 (d, J = 6.7 Hz, 3H).

[0476] Compound 61: D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0477] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ),549.6611 ([M+3H] 3+ ),823.9882 ([M+2H] 2+ ).

[0478] 11H NMR (600 MHz, D2O) δ 4.46–4.35 (m, 2H), 4.27 (dd, J = 8.3, 6.1 Hz, 1H), 4.22–4.04 (m, 9H), 3.96 (dd, J = 8.4, 4.8 Hz, 1H), 3.90 (d, J = 7.7 Hz, 1H), 3.84 (t, J = 6.6 Hz, 1H), 3.74–3.59 (m, 3H), 3.56–3.38 (m, 3H), 3.01 (t, J = 6.9 Hz, 2H), 2.83–2.76 (m, 6H), 2.23–2.06 (m, 9H), 1.96–1.39 (m, AcOH, 48H), 1.18 (dd, J = 22.0, 7.2 Hz, 15H), 0.83–0.67 (m, 12H).

[0479] Compound 62: Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0480] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M + 4H] 4+ ),549.6608 ([M + 3H] 3+ ).

[0481] 1 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 9.8, 4.4 Hz, 1H), 4.37 (dd, J = 9.4, 4.9 Hz, 1H), 4.25–4.03 (m, 10H), 3.95 (dd, J = 8.5, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.83 (t, J = 6.6 Hz, 1H), 3.74–3.68 (m, 1H), 3.64–3.55 (m, 2H), 3.52–3.38 (m, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.83–2.75 (m, 6H), 2.20 (t, J = 7.6 Hz, 2H), 2.12–2.06 (m, 6H), 1.92–1.41 (m, AcOH, 47H), 1.32–1.13 (m, 15H), 0.78 (dd, J = 9.7, 6.7 Hz, 6H), 0.73 (dd, J = 6.8, 4.1 Hz, 6H).

[0482] Compound 63: Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0483] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6609 ([M+3H] 3+ ), 823.9878 ([M+2H] 2+ ).

[0484] 1 H NMR (600 MHz, D2O) δ 4.45 (dd, J = 9.4, 4.4 Hz, 1H), 4.37 (dd, J = 9.4, 4.9 Hz, 1H), 4.29–4.25 (m, 1H), 4.21–4.04 (m, 8H), 3.96–3.94 (m, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.79 (d, J = 6.9 Hz, 1H), 3.68–3.59 (m, 2H), 3.54–3.35 (m, 3H), 3.00 (t, J = 6.9 Hz, 2H), 2.82–2.74 (m, 6H), 2.23–2.19 (m, 2H), 2.15–2.02 (m, 6H), 1.95–1.41 (m, AcOH, 48H), 1.17 (dd, J = 21.6, 7.2 Hz, 15H), 0.83–0.64 (m, 12H).

[0485] Compound 64: Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0486] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6609 ([M+3H] 3+ ), 823.9878 ([M+2H] 2+ ).

[0487] 11H NMR (600 MHz, D2O) δ 4.46 (dd, J = 10.2, 3.9 Hz, 1H), 4.41–4.31 (m, 2H), 4.27–4.18 (m, 3H), 4.15–4.02 (m, 7H), 3.95–3.92 (m, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.83 (t, J = 6.6 Hz, 1H), 3.67–3.50 (m, 5H), 3.47–3.25 (m, 2H), 3.00 (t, J = 6.9 Hz, 2H), 2.81–2.76 (m, 6H), 2.23–2.06 (m, 10H), 1.94–1.41 (m, AcOH, 50H), 1.17 (dd, J = 19.9, 7.1 Hz, 17H), 0.76–0.68 (m, 12H).

[0488] Compound 65: Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0489] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4979 ([M + 4H] 4+ ),549.6612 ([M + 3H] 3+ ),823.9883 ([M + 2H] 2+ ).

[0490] 1 1H NMR (600 MHz, D2O) δ 4.42 (dd, J = 9.9, 4.2 Hz, 1H), 4.34 (dd, J = 9.2, 5.2 Hz, 1H), 4.31–4.23 (m, 2H), 4.22–4.18 (m, 2H), 4.15–4.05 (m, 6H), 3.94 (dd, J = 8.4, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.82 (t, J = 6.7 Hz, 1H), 3.65 (d, J = 6.8 Hz, 3H), 3.57–3.36 (m, 3H), 3.00 (t, J = 6.9 Hz, 2H), 2.82–2.75 (m, 6H), 2.18–2.03 (m, 9H), 1.95–1.40 (m, AcOH, 46H), 1.37–1.08 (m, 16H), 0.80–0.68 (m, 12H).

[0491] Compound 66: Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0492] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6611 ([M+3H] 3+ ), 823.9881 ([M+2H] 2+ ).

[0493] 1 H NMR (600 MHz, D2O) δ 4.44–4.35 (m, 2H), 4.26–4.04 (m, 10H), 3.94 (dd, J=8.5, 4.8 Hz, 1H), 3.89 (d, J=7.7 Hz, 1H), 3.82 (t, J=6.8 Hz, 1H), 3.76–3.68 (m, 1H), 3.64 (d, J=8.7 Hz, 2H), 3.55–3.37 (m, 3H), 3.00 (t, J=6.9 Hz, 2H), 2.83–2.75 (m, 6H), 2.19–2.05 (m, 9H), 2.02–1.38 (m, AcOH, 47H), 1.34–1.15 (m, 15H), 0.78 (dd, J=11.2, 6.7 Hz, 6H), 0.73 (dd, J=6.7, 3.9 Hz, 6H).

[0494] Compound 67: Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0495] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4961 ([M+4H] 4+ ), 549.6615 ([M+3H] 3+ ), 823.9886 ([M+2H] 2+ ).

[0496] 11H NMR (600 MHz, D2O) δ 4.47–4.38 (m, 2H), 4.26 (dd, J = 8.4, 5.8 Hz, 1H), 4.22–4.04 (m, 9H), 3.95 (dd, J = 8.5, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.82 (t, J = 6.8 Hz, 1H), 3.74–3.56 (m, 3H), 3.54–3.35 (m, 3H), 3.00 (t, J = 6.9 Hz, 2H), 2.86–2.74 (m, 6H), 2.23–2.05 (m, 9H), 1.94–1.38 (m, AcOH, 46H), 1.29–1.14 (m, 15H), 0.78 (dd, J = 10.5, 6.7 Hz, 6H), 0.73 (dd, J = 6.8, 3.9 Hz, 6H).

[0497] Compound 68: Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0498] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M + 4H] 4+ ),549.6615 ([M + 3H] 3+ ),823.9879 ([M + 2H] 2+ ).

[0499] 1 1H NMR (600 MHz, D2O) δ 4.47–4.40 (m, 2H), 4.26 (dd, J = 8.4, 5.9 Hz, 1H), 4.23–4.15 (m, 3H), 4.14–4.01 (m, 6H), 3.95 (dd, J = 8.5, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.82 (t, J = 6.8 Hz, 1H), 3.71–3.44 (m, 5H), 3.01 (t, J = 6.9 Hz, 2H), 2.82–2.73 (m, 6H), 2.23–2.05 (m, 9H), 1.93–1.40 (m, AcOH, 46H), 1.30–1.14 (m, 15H), 0.79 (dd, J = 12.5, 6.7 Hz, 6H), 0.73 (dd, J = 6.8, 4.6 Hz, 6H).

[0500] Compound 69: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0501] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ),549.6608 ([M+3H] 3+ ).

[0502] 1 H NMR (600 MHz, D2O) δ 4.42 (dt, J = 8.2, 4.3 Hz, 2H), 4.26 (dd, J = 8.4, 5.9 Hz, 1H), 4.23–4.14 (m, 3H), 4.14–4.05 (m, 6H), 3.94 (dd, J = 8.5, 4.8 Hz, 1H), 3.89 (d, J = 7.7 Hz, 1H), 3.81 (q, J = 7.7, 7.2 Hz, 1H), 3.74–3.58 (m, 3H), 3.55–3.38 (m, 3H), 2.98 (t, J = 7.0 Hz, 2H), 2.82–2.75 (m, 6H), 2.23–2.05 (m, 9H), 1.93–1.13 (m, AcOH, 62H), 0.79 (dd, J = 13.2, 6.7 Hz, 6H), 0.73 (dd, J = 6.8, 4.7 Hz, 6H).

[0503] Compound 70: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0504] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ),549.6611 ([M+3H] 3+ ),823.9883 ([M+2H] 2+ ).

[0505] 11H NMR (600 MHz, D2O) δ 4.45–4.36 (m, 2H), 4.27–4.14 (m, 6H), 4.12–4.05 (m, 4H), 3.95 (dd, J = 8.4, 4.8 Hz, 1H), 3.90 (d, J = 7.7 Hz, 1H), 3.82 (t, J = 6.8 Hz, 1H), 3.66 (dd, J = 35.9, 8.3 Hz, 3H), 3.55–3.39 (m, 3H), 2.99 (t, J = 7.0 Hz, 2H), 2.82–2.75 (m, 6H), 2.23–2.07 (m, 9H), 1.93–1.15 (m, AcOH, 63H), 0.79 (dd, J = 13.9, 6.7 Hz, 6H), 0.74 (dd, J = 6.8, 2.0 Hz, 6H).

[0506] Compound 71: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (acetate)

[0507] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M + 4H] 4+ ),549.6609 ([M + 3H] 3+ ),823.9878 ([M + 2H] 2+ ).

[0508] 1 1H NMR (600 MHz, D2O) δ 4.45–4.36 (m, 2H), 4.26 (dd, J = 8.4, 5.8 Hz, 1H), 4.22–4.16 (m, 3H), 4.12–4.05 (m, 6H), 3.96–3.91 (m, 2H), 3.82 (t, J = 6.8 Hz, 1H), 3.73–3.58 (m, 3H), 3.54–3.36 (m, 3H), 3.00 (t, J = 7.0 Hz, 2H), 2.82–2.75 (m, 6H), 2.22–2.06 (m, 9H), 1.93–1.41 (m, AcOH, 45H), 1.32–1.14 (m, 15H), 0.79 (dd, J = 13.8, 6.7 Hz, 6H), 0.74 (d, J = 6.8 Hz, 3H), 0.70 (d, J = 6.8 Hz, 3H).

[0509] Compound 72: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (acetate)

[0510] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6609 ([M+3H] 3+ ), 823.9876 ([M+2H] 2+ ).

[0511] 1 H NMR (600 MHz, D2O δ 4.45–4.35 (m, 2H), 4.26 (dd, J = 8.4, 5.9 Hz, 1H), 4.21–4.05 (m, 9H), 3.94–3.88 (m, 2H), 3.82 (t, J = 6.8 Hz, 1H), 3.73–3.57 (m, 3H), 3.55–3.37 (m, 3H), 2.99 (t, J = 6.8 Hz, 2H), 2.82–2.75 (m, 6H), 2.23–2.06 (m, 9H), 1.96–1.36 (m, AcOH, 50H), 1.32–1.14 (m, 15H), 0.78 (dd, J = 13.9, 6.7 Hz, 6H), 0.73 (d, J = 6.7 Hz, 6H).

[0512] Compound 73: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (acetate)

[0513] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M+4H] 4+ ), 549.6609 ([M+3H] 3+ ), 823.9879 ([M+2H] 2+ ).

[0514] 11H NMR (600 MHz, D2O) δ 4.48 (dd, J = 9.7, 4.3 Hz, 1H), 4.43 (dd, J = 9.3, 4.9 Hz, 1H), 4.32 (dd, J = 8.4, 5.8 Hz, 1H), 4.27–4.23 (m, 3H), 4.21–4.17 (m, 3H), 4.15–4.10 (m, 3H), 3.97 (dd, J = 9.2, 4.6 Hz, 1H), 3.89–3.85 (m, 2H), 3.76–3.66 (m, 3H), 3.59–3.45 (m, 3H), 3.05 (t, J = 6.9 Hz, 2H), 2.87–2.81 (m, 6H), 2.26 (t, J = 7.7 Hz, 2H), 2.22–2.12 (m, 7H), 2.00–1.48 (m, AcOH, 47H), 1.37–1.20 (m, 16H), 0.86–0.77 (m, 12H).

[0515] Compound 74: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (acetate)

[0516] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M + 4H] 4+ ),549.6610 ([M + 3H] 3+ ),823.9879 ([M + 2H] 2+ ).

[0517] 11H NMR (600 MHz, D2O) δ 4.48 (dd, J = 9.6, 4.3 Hz, 1H), 4.44 (dd, J = 9.3, 4.9 Hz, 1H), 4.32 (dd, J = 8.4, 5.8 Hz, 1H), 4.28–4.17 (m, 5H), 4.17–4.09 (m, 4H), 4.05 (dd, J = 9.1, 4.7 Hz, 1H), 3.95 (d, J = 7.7 Hz, 1H), 3.88 (t, J = 6.8 Hz, 1H), 3.78–3.63 (m, 3H), 3.60–3.37 (m, 3H), 3.06 (t, J = 6.9 Hz, 2H), 2.89–2.81 (m, 6H), 2.29–2.09 (m, 9H), 2.02–1.46 (m, AcOH, 45H), 1.39–1.19 (m, 15H), 0.84 (dd, J = 14.0, 6.7 Hz, 6H), 0.78 (dd, J = 14.3, 6.8 Hz, 6H).

[0518] Compound 75: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (acetate)

[0519] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M + 4H] 4+ ),549.6611 ([M + 3H] 3+ ) 823.9881 ([M + 2H] 2+ ).

[0520] 11H NMR (600 MHz, D2O) δ 4.49–4.42 (m, 2H), 4.32 (dd, J = 8.4, 5.8 Hz, 1H), 4.27–4.10 (m, 9H), 4.04 (dd, J = 8.4, 4.6 Hz, 1H), 3.96 (d, J = 7.4 Hz, 1H), 3.90–3.84 (m, 1H), 3.73 (d, J = 7.7 Hz, 1H), 3.71–3.64 (m, 2H), 3.60–3.32 (m, 3H), 3.06 (t, J = 6.9 Hz, 2H), 2.89–2.79 (m, 6H), 2.28–2.06 (m, 9H), 1.99–1.47 (m, AcOH, 44H), 1.39–1.18 (m, 15H), 0.84 (dd, J = 13.9, 6.7 Hz, 6H), 0.78 (dd, J = 6.8, 3.3 Hz, 6H).

[0521] Compound 76: Glu-Gly-Val-Pro-Gln-Ala-Lys (acetate)

[0522] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 364.7022 ([M + 2H] 2+ ), 728.3929 ([M + H] + ).

[0523] 1 1H NMR (600 MHz, D2O) δ 4.30 (d, J = 7.8 Hz, 1H), 4.26 (dd, J = 8.2, 6.7 Hz, 1H), 4.19–4.11 (m, 2H), 4.02 (dd, J = 8.3, 5.0 Hz, 1H), 3.95 (t, J = 6.5 Hz, 1H), 3.91–3.82 (m, 2H), 3.78–3.72 (m, 1H), 3.58–3.51 (m, 1H), 2.84 (t, J = 7.5 Hz, 2H), 2.29–2.24 (m, 4H), 2.20–2.11 (m, 1H), 2.01–1.82 (m, AcOH, 10H), 1.77–1.65 (m, 2H), 1.60–1.50 (m, 3H), 1.25 (dd, J = 7.5, 4.7 Hz, 5H), 0.84 (d, J = 6.8 Hz, 3H), 0.80 (d, J = 6.7 Hz, 3H).

[0524] Compound 77: Glu-Pro-Val-Gly-Gln-Ala-Lys (acetate)

[0525] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 364.7004 ([M+2H] 2+ ), 728.3932 ([M+H] + ).

[0526] 1 H NMR (600 MHz, D2O) δ 4.40 (dd, J = 8.3, 6.5 Hz, 1H), 4.23 (dd, J = 7.7, 4.4 Hz, 1H), 4.20–4.15 (m, 2H), 4.01 (dd, J = 8.3, 5.1 Hz, 1H), 3.95 (d, J = 7.4 Hz, 1H), 3.83–3.76 (m, 2H), 3.63–3.55 (m, 1H), 3.50–3.45 (m, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.23–2.15 (m, 3H), 2.05–1.67 (m, AcOH, 12H), 1.59–1.50 (m, 3H), 1.26 (dd, J = 9.7, 7.5 Hz, 5H), 0.84 (dd, J = 14.3, 6.8 Hz, 6H).

[0527] Compound 78: D-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0528] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 384.716 ([M+2H] 2+ ), 768.4245 ([M+H] + ).

[0529] 11H NMR (600 MHz, D2O) δ 4.36 (dd, J = 8.8, 4.3 Hz, 1H), 4.29–4.21 (m, 3H), 4.18–4.11 (m, 2H), 4.01 (dd, J = 8.2, 5.1 Hz, 1H), 3.78–3.72 (m, 1H), 3.63–3.49 (m, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.28–2.23 (m, 4H), 2.19–2.12 (m, 2H), 1.98–1.66 (m, AcOH, 15H), 1.59–1.50 (m, 3H), 1.25 (dd, J = 11.6, 7.4 Hz, 5H), 0.85 (dd, J = 15.5, 6.8 Hz, 6H).

[0530] Compound 79: Glu-D-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0531] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 384.7159 ([M + 2H] 2+ ),768.4244 ([M + H] + ).

[0532] 1 1H NMR (600 MHz, D2O) δ 4.36 (dd, J = 8.8, 3.9 Hz, 1H), 4.33 (d, J = 8.1 Hz, 1H), 4.28 (dd, J = 8.3, 6.6 Hz, 1H), 4.23 (dd, J = 7.1, 5.1 Hz, 1H), 4.19–4.13 (m, 2H), 4.02 (dd, J = 8.2, 5.1 Hz, 1H), 3.76–3.68 (m, 1H), 3.61–3.51 (m, 3H), 2.84 (t, J = 7.5 Hz, 2H), 2.31–2.06 (m, 7H), 2.00–1.66 (m, AcOH, 16H), 1.58–1.50 (m, 3H), 1.27–1.23 (m, 5H), 0.81 (dd, J = 22.8, 6.7 Hz, 6H).

[0533] Compound 80: Glu-Pro-D-Val-Pro-Gln-Ala-Lys (acetate)

[0534] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11; m / z: 384.7158 ([M+2H] 2+ ),768.4241 ([M+H] + ).

[0535] 1 1H NMR (600 MHz, D2O) δ 4.46 (d, J = 7.3 Hz, 1H), 4.36 (dd, J = 8.3, 6.6 Hz, 1H), 4.30–4.20 (m, 3H), 4.17 (dd, J = 8.1, 6.1 Hz, 1H), 4.03–4.00 (m, 1H), 3.72–3.66 (m, 1H), 3.63–3.57 (m, 2H), 3.53–3.49 (m, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.36–2.21 (m, 6H), 2.18–2.13 (m, 1H), 2.05–1.78 (m, AcOH, 17H), 1.70–1.66 (m, 1H), 1.58–1.51 (m, 3H), 1.28–1.23 (m, 6H), 0.78 (dd, J = 15.0, 6.7 Hz, 6H).

[0536] Compound 81: Glu-Pro-Val-D-Pro-Gln-Ala-Lys (acetate)

[0537] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 384.7157 ([M+2H] 2+ ),768.4240 ([M+H] + ).

[0538] 1 1H NMR (600 MHz, D2O) δ 4.43–4.30 (m, 2H), 4.28–4.21 (m, 2H), 4.21–4.13 (m, 2H), 4.03–3.98 (m, 1H), 3.72–3.53 (m, 3H), 3.50–3.44 (m, 1H), 2.85 (t, J = 7.5 Hz, 2H), 2.33 (t, J = 7.2 Hz, 2H), 2.23–2.11 (m, 4H), 2.07–1.74 (m, AcOH, 14H), 1.73–1.64 (m, 2H), 1.58–1.50 (m, 3H), 1.29–1.23 (m, 5H), 0.81 (dd, J = 15.1, 6.7 Hz, 6H).

[0539] Compound 82: Glu-Pro-Val-Pro-D-Gln-Ala-Lys (acetate)

[0540] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 384.7158 ([M+2H] 2+ ), 768.4242 ([M+H] + ).

[0541] 1 1H NMR (600 MHz, D2O) δ 4.38 (dd, J = 8.3, 6.4 Hz, 1H), 4.27–4.14 (m, 5H), 4.03 (dd, J = 8.4, 5.0 Hz, 1H), 3.80–3.75 (m, 1H), 3.62–3.45 (m, 3H), 2.85 (t, J = 7.5 Hz, 2H), 2.32 (t, J = 7.3 Hz, 2H), 2.24–2.12 (m, 4H), 2.09–1.67 (m, AcOH, 15H), 1.60–1.50 (m, 3H), 1.28 (d, J = 7.3 Hz, 5H), 0.88–0.80 (m, 6H).

[0542] Compound 83: Glu-Pro-Val-Pro-Gln-D-Ala-Lys (acetate)

[0543] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 384.7159 ([M+2H] 2+ ), 768.4243 ([M+H] + ).

[0544] 11H NMR (600 MHz, D2O) δ 4.38 (dd, J = 8.3, 6.4 Hz, 1H), 4.28–4.20 (m, 3H), 4.19–4.12 (m, 2H), 4.05 (dd, J = 8.6, 5.0 Hz, 1H), 3.77–3.72 (m, 1H), 3.60–3.45 (m, 3H), 2.85–2.80 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.26 (t, J = 8.0 Hz, 2H), 2.20–2.12 (m, 2H), 2.08–1.77 (m, AcOH, 13H), 1.75–1.66 (m, 3H), 1.57–1.47 (m, 3H), 1.26–1.18 (m, 5H), 0.85 (dd, J = 13.0, 6.7 Hz, 6H).

[0545] Compound 84: Glu - Pro - Val - Pro - Gln - Ala - D - Lys (acetate)

[0546] High - resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 384.7160 ([M + 2H] 2+ ),768.4246 ([M + H] + ).

[0547] 1 1H NMR (600 MHz, D2O) δ 4.39 (dd, J = 8.3, 6.4 Hz, 1H), 4.30–4.20 (m, 3H), 4.19–4.11 (m, 2H), 4.05 (dd, J = 8.3, 4.8 Hz, 1H), 3.79–3.71 (m, 1H), 3.61–3.47 (m, 3H), 2.86–2.81 (m, 2H), 2.32 (t, J = 7.2 Hz, 2H), 2.27 (t, J = 7.5 Hz, 2H), 2.21–2.12 (m, 2H), 2.05–1.78 (m, AcOH, 12H), 1.78–1.68 (m, 3H), 1.60–1.50 (m, 3H), 1.27–1.20 (m, 5H), 0.86 (dd, J = 12.5, 6.7 Hz, 6H).

[0548] Compound 85: Lys - Glu - Pro - Val - Pro (acetate)

[0549] High - resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 26 H 44N6O8; m / z: 454.2655 ([M+2H] 2+ ), 569.3287 ([M+H] + ).

[0550] 1 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 9.9, 4.2 Hz, 1H), 4.36–4.22 (m, 3H), 4.09 (dd, J = 8.5, 5.8 Hz, 1H), 3.89 (t, J = 6.7 Hz, 1H), 3.70–3.65 (m, 2H), 3.60–3.53 (m, 2H), 3.51–3.26 (m, 1H), 2.87 (d, J = 7.5 Hz, 2H), 2.28–2.09 (m, 5H), 2.00–1.68 (m, AcOH, 18H), 1.58–1.55 (m, 2H), 1.35–1.29 (m, 2H), 0.88 (d, J = 6.8 Hz, 3H), 0.82 (d, J = 6.7 Hz, 3H).

[0551] Compound 86: Glu-Pro-Val-Pro-Gln (acetate)

[0552] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 25 H 40 N6O9; m / z: 569.2919 ([M+H] + ).

[0553] 1 1H NMR (600 MHz, D2O) δ 4.40 (dd, J = 8.3, 6.4 Hz, 1H), 4.31–4.23 (m, 3H), 4.09 (dd, J = 9.0, 4.8 Hz, 1H), 3.78–3.72 (m, 1H), 3.61–3.48 (m, 3H), 2.41 (t, J = 7.3 Hz, 2H), 2.25–2.14 (m, 4H), 2.09–1.70 (m, AcOH, 13H), 0.86 (dd, J = 15.3, 6.7 Hz, 6H).

[0554] Compound 87: Lys-Glu-Pro-Val-Pro-Gln (acetate)

[0555] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 52 N8O 10 ; m / z: 349.1971 ([M+2H] 2+ ),697.3868 ([M+H]+ ).

[0556] 1 1H NMR (600 MHz, D2O) δ 4.51 (dd, J = 9.8, 4.3 Hz, 1H), 4.34–4.25 (m, 3H), 4.03 (dd, J = 8.8, 4.7 Hz, 1H), 3.89 (t, J = 6.7 Hz, 1H), 3.79–3.65 (m, 2H), 3.63–3.52 (m, 2H), 2.86 (t, J = 7.5 Hz, 2H), 2.28–2.13 (m, 6H), 2.00–1.73 (m, AcOH, 17H), 1.60–1.54 (m, 2H), 1.36–1.28 (m, 2H), 0.86 (d, J = 6.8 Hz, 3H), 0.83 (d, J = 6.6 Hz, 3H).

[0557] Compound 88: Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0558] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 92 H 152 N 26 O 24 ; m / z: 502.2934 ([M + 4H] 4+ ),669.3699 ([M + 3H] 3+ ).

[0559] 11H NMR (600 MHz, D2O) δ 6.97–6.94 (m, 2H), 6.70–6.66 (m, 2H), 4.44 (dd, J = 9.4, 4.8 Hz, 1H), 4.35–4.08 (m, 17H), 4.05–4.00 (m, 2H), 3.96 (d, J = 7.6 Hz, 1H), 3.76–3.67 (m, 3H), 3.64–3.53 (m, 3H), 3.48 (dd, J = 10.2, 6.3 Hz, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.94 (dd, J = 13.6, 6.6 Hz, 1H), 2.88–2.79 (m, 7H), 2.76 (dd, J = 13.6, 9.2 Hz, 1H), 2.27 (t, J = 7.6 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 2.18–2.08 (m, 8H), 2.01–1.45 (m, AcOH, 59H), 1.30–1.10 (m, 16H), 0.95 (d, J = 6.9 Hz, 3H), 0.87–0.77 (m, 18H).

[0560] Compound 89: pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0561] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 84 H 145 N 25 O 24 ; m / z: 468.7766 ([M + 4H] 4+ ),624.6998 ([M + 3H] 3+ ),936.5460 ([M + 2H] 2+ ).

[0562] 11H NMR (600 MHz, D2O) δ 4.47–4.42 (m, 2H), 4.32–4.10 (m, 13H), 4.02 (dd, J = 8.4, 4.8 Hz, 1H), 3.96 (d, J = 7.6 Hz, 1H), 3.82–3.60 (m, 3H), 3.58–3.45 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.80 (m, 6H), 2.45–2.36 (m, 1H), 2.31–2.24 (m, 4H), 2.23–2.03 (m, 7H), 1.99–1.44 (m, AcOH, 47H), 1.39–1.19 (m, 15H), 0.85 (dd, J = 12.5, 6.8 Hz, 6H), 0.81–0.77 (m, 9H), 0.75 (d, J = 6.0 Hz, 3H).

[0563] Compound 90: Pro - Ala - Tyr - Lys - Glu - Pro - Val - Pro - Gln - Ala - Lys - Pro - Arg - Lys - Val - Ala - Ala - Gln (acetate)

[0564] High resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 90 H 148 N 26 O 24 ; m / z: 495.2855 ([M + 4H] 4+ ),660.0449 ([M + 3H] 3+ ),989.5637 ([M + 2H] 2+ ).

[0565] 1 1H NMR (600 MHz, D2O) δ 6.99–6.92 (m, 2H), 6.71–6.64 (m, 2H), 4.47–4.42 (m, 1H), 4.36 (t, J = 7.8 Hz, 1H), 4.32–4.06 (m, 15H), 4.04–3.99 (m, 1H), 3.96 (d, J = 7.6 Hz, 1H), 3.79–3.65 (m, 3H), 3.60–3.46 (m, 3H), 3.30–3.22 (m, 2H), 3.07 (t, J = 6.9 Hz, 2H), 2.89–2.79 (m, 8H), 2.33–2.06 (m, 11H), 1.99–1.45 (m, AcOH, 51H), 1.39–1.14 (m, 19H), 0.87–0.77 (m, 12H).

[0566] Compound 91:

[0567] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0568] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 103 H 174 N 32 O 28 ; m / z: 578.0856 ([M+4H] 4+ ),770.4463 ([M+3H] 3+ ),1155.1642 ([M+2H] 2+ ).

[0569] 1 H NMR (600 MHz, D2O) δ6.96 (d, J = 8.5 Hz, 2H), 6.70–6.64 (m, 2H), 4.50–4.43 (m, 2H), 4.38 (t, J = 8.0 Hz, 1H), 4.30–4.11 (m, 13H), 4.02 (dd, J = 8.4, 4.9 Hz, 1H), 3.96 (d, J = 7.6 Hz, 1H), 3.94–3.90 (m, 2H), 3.79–3.65 (m, 3H), 3.62–3.46 (m, 3H), 3.11–3.05 (m, 4H), 2.88–2.79 (m, 10H), 2.51 (dd, J = 15.9, 5.3 Hz, 1H), 2.42 (dd, J = 16.0, 8.5 Hz, 1H), 2.29–2.11 (m, 9H), 1.99–1.64 (m, AcOH, 45H), 1.63–1.45 (m, 19H), 1.41–1.14 (m, 18H), 0.87–0.77 (m, 12H), 0.72 (d, J = 6.7 Hz, 6H).

[0570] Compound 92: Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0571] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 116 N 20 O 20 ; m / z: 390.2233 ([M+4H] 4+ ),519.9619 ([M+3H] 3+ ),779.4393 ([M+2H]2+ ).

[0572] 1 1H NMR (600 MHz, D2O) δ 6.96 (d, J = 8.6 Hz, 2H), 6.67 (d, J = 8.5 Hz, 2H), 4.49 (dd, J = 8.4, 5.3 Hz, 1H), 4.38 (t, J = 8.0 Hz, 1H), 4.31–4.23 (m, 5H), 4.19–4.10 (m, 3H), 4.01 (dd, J = 8.2, 5.1 Hz, 1H), 3.93–3.89 (m, 2H), 3.77–3.67 (m, 2H), 3.61–3.50 (m, 2H), 3.10–3.05 (m, 2H), 2.86–2.79 (m, 8H), 2.51 (dd, J = 16.0, 5.3 Hz, 1H), 2.42 (dd, J = 15.9, 8.5 Hz, 1H), 2.28–2.20 (m, 4H), 2.18–2.10 (m, 2H), 1.97–1.65 (m, AcOH, 29H), 1.61–1.45 (m, 13H), 1.26 (dd, J = 11.1, 7.4 Hz, 10H), 0.83 (dd, J = 19.0, 6.7 Hz, 6H), 0.72 (d, J = 5.6 Hz, 6H).

[0573] Compound 93: Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0574] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 64 H 104 N 18 O 19 ; m / z: 715.3917 ([M + 2H] 2+ ).

[0575] 11H NMR (600 MHz, D2O) δ 6.96 (d, J = 8.6 Hz, 2H), 6.66 (d, J = 8.5 Hz, 2H), 4.48–4.42 (m, 3H), 4.26–4.12 (m, 6H), 4.02 (dd, J = 8.2, 5.0 Hz, 1H), 3.95–3.89 (m, 2H), 3.77–3.68 (m, 1H), 3.56–3.47 (m, 2H), 3.43–3.36 (m, 1H), 3.10–3.04 (m, 2H), 2.87–2.80 (m, 6H), 2.54 (dd, J = 16.0, 5.1 Hz, 1H), 2.45 (dd, J = 16.0, 8.4 Hz, 1H), 2.27 (t, J = 7.6 Hz, 2H), 2.17–2.08 (m, 4H), 1.98–1.66 (m, AcOH, 27H), 1.65–1.45 (m, 9H), 1.26 (dd, J = 11.3, 7.4 Hz, 7H), 0.84 (dd, J = 13.0, 6.7 Hz, 6H), 0.70 (dd, J = 6.8, 2.8 Hz, 6H).

[0576] Compound 94: Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (acetate)

[0577] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 50 H 80 N 14 O 14 ; m / z: 367.8727 ([M + 3H] 3+ ),551.3051 ([M + 2H] 2+ ),1101.6030 ([M + H] + ).

[0578] 11H NMR (600 MHz, D2O) δ 4.45 (dd, J = 8.9, 4.8 Hz, 1H), 4.36–4.22 (m, 4H), 4.04–3.98 (m, 1H), 3.90 (dd, J = 7.0, 5.8 Hz, 2H), 3.76 (dd, J = 10.1, 6.4 Hz, 1H), 3.69–3.63 (m, 1H), 3.60–3.43 (m, 2H), 3.09–3.05 (m, 2H), 2.95 (dd, J = 14.3, 5.2 Hz, 1H), 2.86–2.82 (m, 2H), 2.74–2.67 (m, 1H), 2.52–2.31 (m, 2H), 2.22–2.08 (m, 4H), 1.99–1.46 (m, AcOH, 29H), 1.32–1.23 (m, 2H), 0.90–0.81 (m, 6H), 0.75 (dd, J = 10.3, 6.8 Hz, 2H), 0.67 (dd, J = 17.1, 6.7 Hz, 4H).

[0579] Compound 95:

[0580] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0581] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 113 H 188 N 34 O 31 ; m / z: 504.6906 ([M + 5H] 5+ ),630.6115 ([M + 4H] 4+ ),840.4796 ([M + 3H] 3+ ).

[0582] 11H NMR (600 MHz, D2O) δ 7.22 (t, J = 7.4 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.12–7.07 (m, 2H), 4.47–4.41 (m, 3H), 4.35–4.03 (m, 19H), 4.02 (dd, J = 8.4, 4.8 Hz, 1H), 3.95 (d, J = 3.6 Hz, 1H), 3.86 (s, 1H), 3.75 (s, 1H), 3.68 (t, J = 8.5 Hz, 2H), 3.58–3.42 (m, 5H), 3.06 (t, J = 6.9 Hz, 4H), 2.91–2.81 (m, 7H), 2.29–2.11 (m, 12H), 2.00–1.19 (m, AcOH, 80H), 1.14 (d, J = 7.1 Hz, 3H), 1.06 (d, J = 6.3 Hz, 3H), 0.84 (dd, J = 13.7, 6.7 Hz, 6H), 0.81–0.76 (m, 9H), 0.72 (d, J = 5.6 Hz, 3H).

[0583] Compound 96: Gly - Pro - Glu - Thr - Ala - Phe - Leu - Arg - Glu - Pro - Val - Pro - Gln - Ala - Lys (acetate)

[0584] High - resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 74 H 118 N 20 O 22 ; m / z: 547.2972 ([M + 3H] 3+ ), 820.4424 ([M + 2H] 2+ ).

[0585] 11H NMR (600 MHz, D2O) δ 7.21 (dd, J = 8.2, 6.6 Hz, 2H), 7.16 (t, J = 7.3 Hz, 1H), 7.12–7.07 (m, 2H), 4.50–4.42 (m, 2H), 4.36–4.22 (m, 4H), 4.21–4.09 (m, 7H), 4.07–4.00 (m, 2H), 3.93 (d, J = 16.5 Hz, 1H), 3.84 (d, J = 16.5 Hz, 1H), 3.78–3.70 (m, 1H), 3.68–3.60 (m, 1H), 3.56–3.42 (m, 4H), 3.10–2.97 (m, 3H), 2.90–2.82 (m, 3H), 2.29–2.09 (m, 9H), 2.00–1.81 (m, AcOH, 19H), 1.77–1.66 (m, 5H), 1.61–1.37 (m, 9H), 1.26 (dd, J = 11.9, 7.4 Hz, 5H), 1.14 (d, J = 7.2 Hz, 3H), 1.05 (d, J = 6.4 Hz, 3H), 0.84 (dd, J = 15.5, 6.7 Hz, 6H), 0.77 (d, J = 5.9 Hz, 3H), 0.72 (d, J = 5.7 Hz, 3H).

[0586] Compound 97:

[0587] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0588] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 105 H 179 N 31 O 35 ; m / z: 488.0708 ([M + 5H] 5+ ),609.8367 ([M + 4H] 4+ ),812.7799 ([M + 3H] 3+ ).

[0589] 11H NMR (600 MHz, D2O) δ 4.48–4.41 (m, 3H), 4.34 (t, J = 5.4 Hz, 1H), 4.31 (dd, J = 8.4, 5.8 Hz, 1H), 4.28–4.22 (m, 3H), 4.22–4.09 (m, 11H), 4.04–3.88 (m, 5H), 3.81–3.72 (m, 3H), 3.71–3.62 (m, 2H), 3.59–3.43 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.80 (m, 8H), 2.58 (dd, J = 16.0, 6.3 Hz, 1H), 2.48 (dd, J = 16.0, 7.9 Hz, 1H), 2.29–2.09 (m, 13H), 2.00–1.47 (m, AcOH, 51H), 1.40–1.20 (m, 18H), 1.12–1.05 (m, 1H), 0.89–0.70 (m, 18H).

[0590] Compound 98: Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0591] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ; m / z: 519.5973 ([M + 3H] 3+ ),778.8925 ([M + 2H] 2+ ).

[0592] 1 1H NMR (600 MHz, D2O) δ 4.54–4.47 (m, 2H), 4.37–4.30 (m, 2H), 4.27–4.10 (m, 8H), 4.05–3.99 (m, 2H), 3.94–3.88 (m, 2H), 3.79–3.73 (m, 3H), 3.70–3.62 (m, 1H), 3.61–3.50 (m, 2H), 2.85 (t, J = 7.6 Hz, 4H), 2.63 (dd, J = 16.2, 6.2 Hz, 1H), 2.51 (dd, J = 16.2, 7.9 Hz, 1H), 2.37–2.06 (m, 11H), 1.99–1.49 (m, AcOH, 30H), 1.34–1.24 (m, 8H), 1.10–1.01 (m, 1H), 0.84 (dd, J = 13.8, 6.7 Hz, 6H), 0.77–0.71 (m, 6H).

[0593] Compound 99: Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (acetate)

[0594] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 52 H 85 N 13 O 21 ; m / z: 614.806 ([M + 2H] 2+ ),1228.605 ([M + H] + ).

[0595] 1 1H NMR (600 MHz, D2O) δ 4.54–4.48 (m, 2H), 4.36 (t, J = 5.5 Hz, 1H), 4.34–4.24 (m, 3H), 4.23–4.18 (m, 2H), 4.12–4.05 (m, 2H), 4.01 (d, J = 7.9 Hz, 1H), 3.94–3.88 (m, 2H), 3.79–3.72 (m, 3H), 3.70–3.62 (m, 1H), 3.60–3.50 (m, 2H), 2.85 (t, J = 7.6 Hz, 2H), 2.65 (dd, J = 16.3, 6.0 Hz, 1H), 2.53 (dd, J = 16.4, 8.0 Hz, 1H), 2.40–2.03 (m, 9H), 2.01–1.51 (m, AcOH, 21H), 1.34–1.22 (m, 3H), 1.08–1.01 (m, 1H), 0.89–0.80 (m, 6H), 0.76–0.70 (m, 6H).

[0596] Compound 100: Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0597] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 88 H 150 N 26 O 23 ; m / z: 389.0348 ([M + 5H] 5+ ),480.0415 ([M + 4H] 4+ ),647.7197 ([M + 3H] 3+ ).

[0598] 11H NMR (600 MHz, D2O) δ 4.49–4.42 (m, 2H), 4.34–4.06 (m, 13H), 4.05–4.00 (m, 2H), 3.96 (d, J = 7.6 Hz, 1H), 3.80–3.73 (m, 1H), 3.69 (d, J = 9.8 Hz, 4H), 3.58–3.45 (m, 5H), 3.07 (t, J = 6.9 Hz, 2H), 2.88–2.83 (m, 6H), 2.27 (t, J = 7.7 Hz, 3H), 2.20–2.11 (m, 9H), 2.01–1.45 (m, AcOH, 55H), 1.24 (dd, J = 21.5, 7.2 Hz, 16H), 0.97 (d, J = 6.9 Hz, 3H), 0.88–0.78 (m, 15H).

[0599] Compound 101: Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (acetate)

[0600] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ; m / z: 519.5978 ([M + 3H] 3+ ),778.8933 ([M + 2H] 2+ ).

[0601] 1 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 8.0, 6.0 Hz, 1H), 4.40 (dd, J = 8.4, 6.4 Hz, 1H), 4.36–4.30 (m, 2H), 4.27–4.19 (m, 6H), 4.18–4.11 (m, 2H), 4.08 (dd, J = 8.8, 4.9 Hz, 1H), 4.01 (d, J = 8.1 Hz, 1H), 3.82–3.71 (m, 5H), 3.62–3.47 (m, 3H), 2.86 (t, J = 7.5 Hz, 4H), 2.65 (dd, J = 16.4, 6.0 Hz, 1H), 2.51 (dd, J = 16.3, 8.1 Hz, 1H), 2.34 (t, J = 7.2 Hz, 2H), 2.31–2.10 (m, 9H), 2.06–1.52 (m, AcOH, 28H), 1.35–1.23 (m, 8H), 1.08–1.00 (m, 1H), 0.86 (dd, J = 11.5, 6.7 Hz, 6H), 0.76–0.70 (m, 6H).

[0602] Compound 102 Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (acetate)

[0603] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 53 H 82 N 12 O 15 ; m / z: 564.3073 ([M+2H] 2+ ).

[0604] 1 H NMR (600 MHz, D2O) δ 7.01–6.95 (m, 2H), 6.69 (d, J = 8.5 Hz, 2H), 4.40 (dd, J = 8.3, 6.4 Hz, 1H), 4.29–4.10 (m, 9H), 3.79–3.71 (m, 1H), 3.68–3.45 (m, 5H), 2.92–2.81 (m, 4H), 2.33 (t, J = 7.3 Hz, 2H), 2.26 (t, J = 7.7 Hz, 2H), 2.20–2.13 (m, 2H), 2.06–1.52 (m, AcOH, 25H), 1.33–1.21 (m, 5H), 0.86 (dd, J = 11.3, 6.7 Hz, 6H), 0.77 (dd, J = 17.6, 6.7 Hz, 6H).

[0605] Compound 103: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (acetate)

[0606] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 126 N 22 O 21 ; m / z: 824.4799 ([M+2H] 2+ ).

[0607] 11H NMR (600 MHz, D2O) δ 4.49 (dd, J = 9.6, 4.4 Hz, 1H), 4.45 (dd, J = 9.4, 4.9 Hz, 1H), 4.36–4.05 (m, 11H), 4.01–3.96 (m, 2H), 3.92–3.87 (m, 1H), 3.82–3.64 (m, 3H), 3.60–3.46 (m, 3H), 3.07 (t, J = 7.0 Hz, 2H), 2.88–2.83 (m, 6H), 2.29–2.09 (m, 9H), 1.99–1.46 (m, AcOH, 47H), 1.39–1.20 (m, 16H), 0.85 (dd, J = 14.2, 6.7 Hz, 6H), 0.80 (dd, J = 6.7, 3.7 Hz, 6H).

[0608] Compound 104: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (acetate)

[0609] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 72 H 125 N 23 O 20 ; m / z: 408.9938 ([M + 4H] 4+ ),544.9891 ([M + 3H] 3+ ),816.9801 ([M + 2H] 2+ ).

[0610] 1 1H NMR (600 MHz, D2O) δ 4.49 (dd, J = 9.7, 4.4 Hz, 1H), 4.45 (dd, J = 9.4, 4.8 Hz, 1H), 4.34–4.10 (m, 11H), 3.96 (d, J = 7.6 Hz, 1H), 3.92–3.84 (m, 1H), 3.78–3.66 (m, 3H), 3.62–3.43 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.82 (m, 6H), 2.63 (dd, J = 15.1, 4.9 Hz, 1H), 2.53 (dd, J = 15.1, 8.1 Hz, 1H), 2.30–2.11 (m, 7H), 2.03–1.42 (m, AcOH, 44H), 1.39–1.19 (m, 15H), 0.85 (dd, J = 14.0, 6.7 Hz, 6H), 0.80 (dd, J = 6.8, 3.0 Hz, 6H).

[0611] Compound 105: Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0612] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 128 N 24 O 19 ; m / z: 412.2515 ([M+4H] 4+ ), 549.3327 ([M+3H] 3+ ), 823.4955 ([M+2H] 2+ ).

[0613] 1 H NMR (600 MHz, D2O) δ 4.53 (dd, J = 9.0, 5.0 Hz, 1H), 4.44 (dd, J = 9.4, 4.8 Hz, 1H), 4.34 (dd, J = 8.4, 6.0 Hz, 1H), 4.30–4.23 (m, 3H), 4.22–4.11 (m, 6H), 4.02 (dd, J = 8.4, 4.8 Hz, 1H), 3.96 (d, J = 7.6 Hz, 1H), 3.90 (t, J = 6.7 Hz, 1H), 3.80–3.63 (m, 3H), 3.60–3.42 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.89–2.82 (m, 6H), 2.34–2.24 (m, 4H), 2.22–2.07 (m, 5H), 2.01–1.45 (m, AcOH, 50H), 1.39–1.20 (m, 15H), 0.85 (dd, J = 15.5, 6.7 Hz, 6H), 0.80 (dd, J = 6.8, 4.3 Hz, 6H).

[0614] Compound 106: Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0615] High-resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 74 H 129 N 23 O 20 ; m / z: 416.0015 ([M+4H] 4+ ), 554.3328 ([M+3H] 3+ ), 830.9956 ([M+2H] 2+ ).

[0616] 1 1H NMR (600 MHz, D2O) δ 4.50 (dd, J = 9.6, 4.4 Hz, 1H), 4.45 (dd, J = 9.3, 4.9 Hz, 1H), 4.36–4.22 (m, 4H), 4.22–4.10 (m, 6H), 4.02 (dd, J = 8.4, 4.9 Hz, 1H), 3.96 (d, J = 7.6 Hz, 1H), 3.92–3.84 (m, 1H), 3.82–3.74 (m, 1H), 3.73–3.63 (m, 2H), 3.61–3.41 (m, 3H), 3.07 (t, J = 6.9 Hz, 2H), 2.90–2.82 (m, 6H), 2.32–2.12 (m, 9H), 2.00–1.46 (m, AcOH, 46H), 1.43–1.05 (m, 17H), 0.84 (d, J = 6.8 Hz, 3H), 0.80 (dd, J = 6.8, 4.3 Hz, 6H), 0.75 (t, J = 7.4 Hz, 3H).

[0617] Compound 107: Val - Pro - Gln - Ala (acetate)

[0618] High - resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.2341 ([M + 1H] + ).

[0619] 1 1H NMR (600 MHz, D2O) δ 4.29 (t, J = 7.6 Hz, 1H), 4.07 (dd, J = 8.5, 6.1 Hz, 1H), 4.01–3.91 (m, 2H), 3.61–3.53 (m, 1H), 3.46–3.41 (m, 1H), 2.24–2.10 (m, 4H), 1.95–1.69 (m, AcOH, 6H), 1.14 (d, J = 7.3 Hz, 3H), 0.91 (d, J = 7.0 Hz, 3H), 0.80 (d, J = 6.8 Hz, 3H).

[0620] Compound 108: Val - Pro - Gln - Ala - Lys (acetate)

[0621] High - resolution mass spectrometry (Orbitrap - HRMS), molecular formula: C 24 H 43 N7O7; m / z: 271.6681 ([M + 2H]2+), 542.3289 ([M + 1H] + ).

[0622] 1 1H NMR (600 MHz, D2O) δ 4.28 (t, J = 7.6 Hz, 1H), 4.13–4.06 (m, 2H), 3.99 (d, J = 5.5 Hz, 1H), 3.94 (dd, J = 8.2, 5.1 Hz, 1H), 3.60–3.54 (m, 1H), 3.46–3.41 (m, 1H), 2.78 (t, J = 7.5 Hz, 2H), 2.21 (t, J = 7.6 Hz, 2H), 2.17–2.09 (m, 2H), 1.93–1.58 (m, AcOH, 11H), 1.53–1.44 (m, 3H), 1.20 (dd, J = 9.7, 7.5 Hz, 5H), 0.91 (d, J = 6.9 Hz, 3H), 0.80 (d, J = 6.9 Hz, 3H).

[0623] Example 2: Experiment on the efficacy of polypeptide compound in alleviating colitis

[0624] Experimental animals: Wild-type AB strain zebrafish, reproduced by natural paired mating. Zebrafish at 3 days post-fertilization (3 dpf). All zebrafish were raised in fish culture water at 28 °C (water quality: 200 mg of instant sea salt was added to every 1 L of reverse osmosis water, with a conductivity of 450-550 μS / cm; pH 6.5-8.5; hardness 50-100 mg / L CaCO3). The license number for the use of experimental animals is: SYXK(Zhe)2012-0171, and the feeding management meets the requirements of international AAALAC certification (certification number: 001458).

[0625] Experimental method:

[0626] (1) Grouping: Polypeptide group: Prepared into a stock solution of 20.0 mg / mL with ultrapure water and stored at -20 °C.

[0627] Positive control group: Prednisone, white powder, batch number C10016501, Shanghai Macklin Biochemical Co., Ltd., stored at 4 °C; prepared into a stock solution of 15.0 mg / mL with DMSO and stored in aliquots at -20 °C.

[0628] Normal control group and model control group.

[0629] (2) Experimental method: Wild-type AB strain zebrafish at 3 dpf were randomly selected and placed in 6-well plates, with 30 zebrafish in each well (experimental group). Except for the normal control group, the other experimental groups were given TNBS in aqueous solution to establish a zebrafish intestinal mucosal injury model. After treatment at 28 °C for 2 days, TNBS was removed, and polypeptide compounds (concentrations are shown in Table 4) were given in aqueous solution. The positive control was prednisone at 15.0 μg / mL. At the same time, a normal control group (healthy group) and a model control group (intestinal mucosal injury group) were set up, and the volume of each well (experimental group) was 3 mL. After continuing treatment at 28 °C for 2 days, 10 zebrafish were randomly selected from each experimental group and photographed under a dissection microscope. The NIS-Elements D 3.20 advanced image processing software was used to analyze and collect data, and the intestinal lumen area of zebrafish was analyzed. The statistical analysis results of this index were used to evaluate the efficacy of the samples in relieving colitis. The statistical processing results were expressed as mean ± SE. SPSS 26.0 software was used for statistical analysis, and p < 0.05 indicated that the difference was statistically significant.

[0630] Experimental results: The results of the efficacy of polypeptide compounds in relieving colitis are shown in Table 4:

[0631] Table 4 Experimental results of the efficacy evaluation of polypeptide compounds in relieving colitis (n = 10)

[0632]

[0633] Compared with the model control group, *p < 0.05, **p < 0.01, ***p < 0.001

[0634] According to the data in Table 4, polypeptide compound groups such as Compound 1, 4, 5, 6, 12, and 15 showed significant statistical differences (p < 0.05; p < 0.01; p < 0.001) compared with the model control group, and the effect was better than the prednisone group. The experimental results show that the polypeptide compounds provided in this application have the efficacy of relieving colitis, specifically manifested as significantly relieving intestinal lumen dilation.

[0635] In this experimental system, the set concentration gradient of the test substances was 250 μg / mL, 500 μg / mL, and 1000 μg / mL. By statistically analyzing the intestinal lumen area of zebrafish after intervention in each group, it can be seen that most of the test substances with the efficacy of relieving colitis had a more obvious effect at a concentration of 1000 μg / mL (p < 0.05; p < 0.01; p < 0.001). However, when the concentration of the test substance was continuously increased for intervention, it was found that zebrafish in the group died; therefore, in subsequent multiple rounds of activity evaluations, each test substance polypeptide compound was uniformly administered at 1000 μg / mL, and the results were summarized in Table 5.

[0636] Table 5 Summary of the activity of polypeptide compounds in relieving intestinal lumen dilation of zebrafish colitis

[0637]

[0638] Note: The anti-lumen dilation activity of each compound against zebrafish colitis was completed through multiple batches of experiments. For ease of comparison, its anti-lumen dilation activity was compared with the control group of the experimental model of the corresponding batch: *p < 0.05, **p < 0.01, ***p < 0.001; ND indicates not tested, “—” indicates no activity, “+” indicates certain anti-lumen dilation effect, “#” indicates all zebrafish died in the experiment, and “&” indicates 13 zebrafish died in the experiment.

[0639] According to the data in Table 4 and Table 5, significant statistical differences (p < 0.05, p < 0.01 or p < 0.001) were found between the polypeptide group and the model control group, and the effect was better than that of the prednisone group. Under the experimental conditions, Compounds 1, 4 - 6, 9, 10, 12, 15, 25, 26, 29, 31, 34, 38, 48 - 51, 53 - 55, 57, 62, 63, 65 - 68, 70, 72, 75, 83, 85, 86, 88 - 90, 92 - 100, 103 - 106 all had significant effects in alleviating colitis, specifically manifested as alleviating lumen dilation (p < 0.05); Compounds 7, 8, 11, 14, 16, 17, 19, 21 - 24, 27, 28, 30, 32, 33, 36, 37, 39 - 42, 46, 47, 52, 58, 59, 64, 69, 71, 74, 76, 78 - 82, 84, 87, 91 and 102 had certain anti-lumen dilation effects.

[0640] Example 3: Evaluation of the Therapeutic Efficacy of Polypeptide Compounds on TNBS-Induced Acute Inflammatory Bowel Disease (UC) Model in SD Rats

[0641] Objective: To evaluate the therapeutic effect of polypeptide compounds on TNBS-induced acute inflammatory bowel disease model in SD rats.

[0642] Materials and Methods:

[0643] In this experiment, male Sprague-Dawley (SD) rats were used as experimental animals, and a single enema intervention with trinitrobenzenesulfonic acid (TNBS) was adopted to establish a rat ulcerative colitis model. The acute colitis in rats induced by TNBS is an immune response induced by cytokines secreted by Th1 cells. In the model control group, the colon of the animals showed obvious atrophy and thickening of the intestinal wall. The ratio of colon weight to length increased significantly. Fissure-like ulcer lesions were visible on the mucosal surface of the intestinal wall. Typical granulomas were observed in the submucosa and muscular layer, accompanied by infiltration of inflammatory cells mainly composed of lymphocytes and plasma cells. At the same time, small blood vessels and connective tissue (fibroblasts) proliferated significantly. Crypt structure damage and bleeding were visible around the ulcer lesions. This model is simple to make and has good repeatability. It is an experimental animal model widely used to evaluate drugs for the treatment of inflammatory bowel disease. The experimental animals (male SD rats) were randomly grouped on the first day of the experiment according to their body weight parameters. There were a total of 6 groups, namely the normal control group, the model control group, the positive drug mesalazine treatment group, the low-dose compound 1 treatment group, the high-dose compound 1 treatment group, the low-dose compound 6 treatment group, the high-dose compound 6 treatment group, and the compound 12 treatment group, with 10 animals in each group. On the day of grouping (D0), except for the normal control group which was given the solvent, the animals in the other experimental groups were all given TNBS ethanol solution by enema for model induction. Starting from the day after model induction, the test articles and the positive control drug were administered. The treatment doses of compound 1 were 3.0 mg / kg and 6.0 mg / kg respectively, the treatment doses of compound 6 were 1.4 mg / kg and 2.8 mg / kg respectively, the treatment dose of compound 12 was 0.8 mg / kg, and the treatment dose of the positive control drug mesalazine was 30.0 mg / kg. The administration method was enema, and the administration frequency was once a day for 14 consecutive days. During the experimental treatment period (D1 - D14), the body weights and general clinical observation indicators (including but not limited to food intake, water intake, activity level, and defecation, etc.) of the animals in each experimental group were dynamically collected. At the same time, based on the scoring criteria related to the disease activity of ulcerative colitis, the degree of weight loss, fecal morphological characteristics, and blood in the stool of the animals in each experimental group after TNBS induction were scored, and the disease activity index (DAI) of ulcerative colitis was calculated once a day for 14 consecutive days. At the end of the experiment, the colon tissues of the animals in each experimental group were collected. After measuring the colon length and weighing, unsectioned images were collected. Subsequently, the colon was longitudinally dissected along the intestinal wall, and sectioned images were collected. Based on the "Scoring Criteria for Gross Morphological Findings of the Colon", the gross damage of colon adhesion, colon ulcer, and inflammation in the animals in each experimental group was observed and scored. Ulcer images were collected under a stereomicroscope, and the area of colon ulcer lesions was calculated. Subsequently, routine fixation was performed. According to the statistical analysis results of various pharmacodynamic detection indicators, the therapeutic effect of the test polypeptide compound on the ulcerative colitis disease model under the set treatment plan was evaluated.

[0644] Results and Conclusions:

[0645] Under this experimental research system, the animals in the model control group showed obvious disease characteristics of ulcerative colitis, including inhibited body weight gain, soft stools and loose stools, significantly increased disease activity index (DAI) scores of ulcerative colitis, and macroscopic observations showed colon atrophy, typical ulcer lesions and confluent ulcer lesions in the colon; Test compound 1 had an obvious improvement effect on the inhibited body weight gain state of the model animals under the set treatment plan, and the degree of improvement was statistically different compared with the body weight change degree of the model control group animals in the same period (P<0.05), while test compounds 6 and 12 did not show obvious improvement treatment effects on the inhibited body weight gain of the model animals.

[0646] Table 6 Effects of test polypeptide compounds on body weight changes of model animals

[0647]

[0648]

[0649] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 indicates the statistical analysis results between the model control group and the normal control group. # P<0.05, ## P<0.01, indicates the statistical analysis results between the test polypeptide compound treatment group animals and the model control group.

[0650] The DAI score results during the experimental period showed that test compounds 1, 6 and 12 had obvious improvement effects on the disease process of ulcerative colitis in model animals under the set treatment plan. The lesion characteristics of fecal traits and the body weight loss responses of the corresponding treatment group animals were significantly alleviated, and the mean DAI scores all showed a downward response, with obvious statistical differences compared with the model control group in the same period (P<0.05). The improvement treatment effect of compound 1 was the most obvious, and at the same time, the treatment effects of compounds 1 and 6 had obvious dose dependence.

[0651] Table 7 Effects of test polypeptide compounds on DAI scores of model animals

[0652]

[0653] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, ****P < 0.0001 indicates the statistical analysis results between the model control group and the normal control group. # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 indicates the statistical analysis results between the test polypeptide compound treatment group animals and the model control group. + P < 0.05, ++ P < 0.01, +++ P < 0.001, ++++ P < 0.0001 indicates the statistical analysis results between dose groups of Compound 1 or 6.

[0654] The results of gross anatomy at the experimental endpoint and the colon tissue injury score showed that the test compounds Compound 1, 6, and 12 had obvious therapeutic effects on the gross injury state of the colon induced by TNBS (colon adhesions, ulcers, and inflammation), the area of colon ulcer lesions, and the abnormal increase in the colon weight / length ratio. The degree of improvement was statistically different compared with the model control group during the same period (P < 0.05). The therapeutic effect of Compound 1 was the most obvious, and its therapeutic effect had an obvious dose-dependence.

[0655] Table 8 Effects of the test polypeptide compounds on the gross colon injury and ulcer area in model animals

[0656]

[0657]

[0658] Note: All data were statistically analyzed using the mean (Mean) ± standard deviation (SD). * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 indicates the statistical analysis results between the model control group and the normal control group. # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 indicates the statistical analysis results between the test polypeptide compound treatment group animals and the model control group. + P < 0.05, ++ P < 0.01, +++ P < 0.001, ++++ P < 0.0001 indicates the statistical analysis results between dose groups of Compound 1 or 6.

[0659] Table 9 Effects of the test polypeptide compounds on the colon weight / length ratio in model animals

[0660]

[0661] Note: All data were statistically analyzed using the mean ± standard deviation (SD). * P < 0.05, ** P < 0.01, *** P < 0.001, **** P < 0.0001 indicates the statistical analysis results between the model control group and the normal control group. # P < 0.05, ## P < 0.01, ### P < 0.001, #### P < 0.0001 indicates the statistical analysis results between the test polypeptide compound treatment group and the model control group. + P < 0.05, ++ P < 0.01, +++ P < 0.001, ++++ P < 0.0001 indicates the statistical analysis results between dose groups of Compound 1 or 6.

[0662] In this experiment, TNBS was used to perform enema intervention on male SD rats to induce colonic lesions and establish a rat ulcerative colitis model that conforms to clinical disease characteristics. Treatment with test compounds 1, 6, and 12 and the positive control drug mesalazine started on the day after model induction; during the treatment period (D1 - D14), by monitoring changes in the body weight of experimental animals, the disease activity index (DAI) score of ulcerative colitis, the score of gross colonic lesions (colon adhesions, ulcers, and inflammatory responses), the ulcer area of the colon tissue, and the ratio of colon weight / length, etc., the therapeutic effect of the test article on the TNBS-induced SD rat ulcerative colitis model was evaluated. The results showed that:

[0663] 1) After induction with TNBS, the experimental animals showed obvious manifestations of ulcerative colitis, mainly including a significant decrease in body weight, a significant increase in the disease activity index (DAI) score of ulcerative colitis, a significant increase in the score of colon adhesions and ulcers, an increase in the ulcer area of the colon tissue, and a significant increase in the ratio of colon weight / length, indicating that the rat ulcerative colitis model was successfully established and was suitable for the pharmacodynamic study of this experiment.

[0664] 2) Test compound 1 had an obvious improvement effect on the body weight loss response of model animals under the set treatment plan, and the degree of improvement was statistically different compared with the model control group during the same period (P < 0.05), while test compounds 6, 12, and the positive control drug mesalazine did not show an obvious body weight improvement effect.

[0665] 3) Test compounds 1, 6, and 12 had significant improvement effects on the disease process of ulcerative colitis in model animals under the set treatment regimen. Their DAI scores all showed a significant downward response compared with the model control group in the same period. The treatment effect of test compound 1 was the most obvious. At the same time, the improvement treatment effects of test compounds 1 and 6 had obvious dose-dependence, while the positive control drug mesalazine had no obvious effect on the symptoms of ulcerative colitis in model animals.

[0666] 4) Test compounds 1, 6, and 12 had obvious treatment effects on the gross damage performance of the colon in model animals under the set treatment regimen. Compared with the model control group in the same period, their colon adhesion scores, colon ulcer and inflammation scores, and the area of colon tissue ulcer lesions all showed a significant decrease, and the degree of improvement was statistically significant (P<0.05). The treatment effect of test compound 1 was the most obvious, and its improvement treatment effect had obvious dose-dependence.

[0667] 5) Test compounds 1, 6, and 12 had significant improvement effects on the colon atrophy process in model animals under the set treatment regimen. Compared with the model control group in the same period, the ratio of colon weight / length decreased significantly (P<0.05).

[0668] It can be seen that this experiment established a rat ulcerative colitis model that conforms to the clinical pathogenesis characteristics. The results of the pharmacodynamic evaluation on this model showed that test compounds 1, 6, and 12 all had significant therapeutic effects.

[0669] Example 4: Study on the effect of polypeptide compounds on the in vitro proliferation of cells CaCo-2

[0670] The following cell lines were used to study the in vitro proliferation of polypeptide compounds:

[0671] Table 10 Cell line information

[0672] Serial Number Cell Line Cancer Type Growth Characteristics Culture Medium 1 CaCo-2 Colorectal Cancer Adherent (MEM + 0.01 mM NEAA) + 20% FBS

[0673] Experimental method:

[0674] The cells were resuscitated and maintained according to the culture conditions shown in Table 10.

[0675] On the first day (cell seeding): Cells in the logarithmic growth phase were collected, resuspended, counted using a cell counter, and their viability was detected. The cell suspension was diluted according to the seeding density requirements, and 90 μL of the cell suspension was added to each well of a 96-well plate (the cell seeding density will be adjusted according to historical data or density optimization experiments). At the same time as seeding, three replicates of each cell were seeded as the T0 plate. All 96-well plates were placed in a constant temperature incubator at 37°C and 5% CO2 overnight.

[0676] Day 2 (medium change): Replace the medium with the corresponding serum concentration according to the plate map, 90 μL per well. Day 2: Read the T0 plate and treat the test compounds. Add 10 μL of medium to each well of the T0 plate to make the total volume up to 100 μL. Add 50 μL reagent. Mix and shake for 5 minutes to fully lyse the cells. Incubate at room temperature for 10 minutes to stabilize the luminescence signal (Note: Temperature, cell density, and edge effects can all cause uneven luminescence signals). Detect the fluorescence signal using an EnVision Multi LabelReader. The test compounds are configured according to the corresponding molecular weights as C1 = 91.08 μM, diluted C2 = 9.108 μM, C3 = 0.9108 μM. Cisplatin is diluted as shown in Table 11 to prepare a 10X compound working solution. Add 10 μL of the working solution (10X) to each well, and the final volume in each well of all plates is 100 μL. The cells are cultured in an incubator at 37 °C and 5% CO2.

[0677] Day 5, treat the test compounds for 72 hours (read the plate): Observe the status of the drug-treated group and the control group under the microscope to see if it is normal. Add 50 μL of CTG reagent to each well. Mix on a shaker for 5 minutes to fully lyse the cells. Incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the fluorescence signal using an EnVision Multi Label Reader.

[0678] Table 11 Concentrations after diluting Cisplatin

[0679] C1-1 C2-1 C3-1 C4-1 C5-1 C6-1 C7-1 C8-1 C9-1 C10-1 Concentration (μM) 1000 333.33 111.11 37.04 12.35 4.12 1.37 0.46 0.15 0 Solution Volume (μL) 90 90 90 90 90 90 90 90 90 90 Culture Medium Volume (μL) 209.7 209.7 209.7 209.7 209.7 209.7 209.7 209.7 209.7 209.7

[0680] Cell viability (%) = Lum 待测化合物 / Lum 溶剂对照 × 100%.

[0681] Experimental results: The statistical results of the proliferative activity promotion of the selected polypeptide compounds are shown in Table 12:

[0682] Compound Number Proliferation-Promoting Activity 1 Cell Viability > 110% 20 / 44 / 45 /

[0683] In this experimental system, the set concentration gradient of the test substances is C1 = 91.08 μM, diluted C2 = 9.108 μM, C3 = 0.9108 μM, with 0.88% FBS as the reference. The experimental results show that the polypeptide compound 1 of this application has the activity of promoting the proliferation of Caco-2 cells, specifically manifested as an increase in cell viability after intervention.

[0684] In summary, the above-mentioned polypeptide compound of the present invention has a short peptide chain and is absorbed faster and better. The experimental results show that the polypeptide compound provided by the present application has the activity of alleviating intestinal lumen dilation in zebrafish colitis; in the rat acute inflammatory bowel disease model test, it has a significant therapeutic effect. The above-mentioned polypeptide compound of the present invention has a significant effect of alleviating colitis and can be used to prepare drugs for treating enteritis, especially drugs for ulcerative colitis.

[0685] Although the present invention discloses the above-mentioned embodiments, the implementation manners of the present invention are not limited to the above-mentioned embodiments. Any other changes, modifications, substitutions, combinations, and simplifications that do not depart from the present invention shall be equivalent replacement manners and are all included in the protection scope of the present invention.

Claims

1. A compound or a physiologically compatible salt thereof, wherein the compound is selected from: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 2); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 3); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4); Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6); Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 19); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (Compound 26); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln (Compound 27); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln (Compound 28); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (Compound 29); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala (Compound 30); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (Compound 33); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 38); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val (Compound 56); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 58); D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 61); Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 62); Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 63); Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 64); Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 65); Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 66); Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 67); Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 68); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 69); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (Compound 70); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (Compound 71); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (Compound 72); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (Compound 73); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (Compound 74);Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (Compound 75); D-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 78); Glu-D-Pro-Val-Pro-Gln-Ala-Lys (Compound 79); Glu-Pro-D-Val-Pro-Gln-Ala-Lys (Compound 80); Glu-Pro-Val-D-Pro-Gln-Ala-Lys (Compound 81); Glu-Pro-Val-Pro-D-Gln-Ala-Lys (Compound 82); Glu-Pro-Val-Pro-Gln-D-Ala-Lys (Compound 83); Glu-Pro-Val-Pro-Gln-Ala-D-Lys (Compound 84); Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 88); Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 89); Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 90); Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 91); Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 92); Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93); Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 95); Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96); Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 97); Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 98); Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 100); Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (Compound 101); Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (Compound 102); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (Compound 103); or Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (Compound 104).

2. The compound of claim 1 or a physiologically compatible salt thereof, wherein the compound is selected from: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1); Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 63); Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96); Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 100); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (Compound 104); Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57); Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 68); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (Compound 72); Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 89); Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 92); Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 95); Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 97); Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 98); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (Compound 26); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (Compound 29); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 38); Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51); Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 62); Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 65); Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 66); Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 67); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (Compound 70); Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (Compound 75); Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 88); Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 90); Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93); or Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (Compound 103).

3. Use of a compound according to any one of claims 1-2 or a physiologically compatible salt thereof in the preparation of a medicament for the treatment of enteritis.

4. Use according to claim 3, wherein the enteritis is specific enteritis or non-specific enteritis.

5. Use according to claim 4, wherein the specific enteritis is inflammatory bowel disease, necrotizing enteropathy or dysbacteriosis enteritis.

6. Use according to claim 5, wherein the inflammatory bowel disease is ulcerative colitis.

7. A pharmaceutical composition, said pharmaceutical composition comprising a compound according to any one of claims 1-2 or a physiologically compatible salt thereof, and a pharmaceutically acceptable excipient.

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