Polypeptide compounds and their use in treating enteritis - Patent Application 20070122997

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 by the present application has a clear alleviating effect on intestinal lumen expansion in efficacy tests of zebrafish inflammatory bowel disease model and rat inflammatory bowel disease model. The polypeptide provided by the present invention has a significant alleviating effect on colitis and can be used to manufacture drugs for treating colitis, especially ulcerative colitis.

Description

[Technical Field]

[0001] The present invention relates to a novel polypeptide and its application. The polypeptide of the present invention has a significant effect in treating inflammatory bowel diseases, particularly ulcerative colitis. [Background technology]

[0002] Enteritis is an intestinal inflammatory reaction caused by various factors, such as infection or immune damage caused by intestinal bacteria, viruses, and other pathogenic bacteria, radiation damage, dietary irritation, drug irritation, etc. Clinical symptoms mainly include fever, nausea, vomiting, abdominal pain, diarrhea, watery stools or mucous purulent stools, and some patients may also experience tenesmus.

[0003] Enteritis can be divided into specific enteritis and nonspecific enteritis based on the inflammatory symptoms. Specific enteritis includes inflammatory bowel disease, necrotizing enteropathy, and intestinal dysbiosis. Among these, the more common inflammatory bowel disease is idiopathic, non-infectious, chronic, persistent, recurrent inflammatory bowel disease affecting the intestinal tract. Clinical symptoms include abdominal pain, diarrhea, and purulent bloody stool, as well as fever, abdominal pain, weight loss, malnutrition, and other symptoms. Inflammatory bowel disease is a chronic, long-term disease that requires long-term, aggressive treatment.

[0004] Generally, specific enteritis has a clear cause, such as bacterial enteritis, pseudomembranous enteritis, viral enteritis, and radiation enteritis. Nonspecific enteritis has an unclear cause and is thought to be caused by immune system disorders such as ulcerative colitis and Crohn's disease. Inflammatory bowel disease includes ulcerative colitis and Crohn's disease. Ulcerative colitis is a chronic, nonspecific intestinal inflammatory disease of unknown cause, most commonly occurring in young adults. Clinical symptoms include persistent or recurrent diarrhea, mucous and purulent stools accompanied by abdominal pain, tenesmus, and varying degrees of systemic symptoms. Extraintestinal symptoms may also occur in the skin, mucous membranes, joints, eyes, liver, and gallbladder. Complications include toxic megacolon, intestinal perforation, massive lower gastrointestinal bleeding, intraepithelial neoplasia, and cancer. Accurate data on the incidence of UC in China is lacking. Regional epidemiological surveys have estimated the incidence of UC in China to be 0.42–2.22 per 100,000. Although the prevalence remains low compared to Western countries, there has been a clear increase compared to 20 years ago. Ulcerative colitis primarily affects the colonic mucosa and submucosa, beginning in the distal rectum and progressing retrogradely toward the proximal end. In some cases, the entire colon may be affected, with 5% of cases affecting the terminal ileum, resulting in a continuous distribution. The main clinical symptoms of ulcerative colitis are diarrhea, abdominal pain, and mucous-purulent stools. Its cause remains unknown, but is currently thought to be related to infection, immune abnormalities, genetics, and psychological factors. Furthermore, patients with ulcerative colitis commonly experience symptoms such as intestinal luminal dilatation (also known as intestinal tract dilatation or bowel distention). Inflammation disrupts the nerve and muscle regulatory mechanisms that control the normal intestinal tract, resulting in intraluminal pressure that causes the intestinal wall to expand beyond its normal mobility. It can also be caused by excessive microbial growth and the resulting toxins and mucus exudation. Relieving or inhibiting intestinal luminal dilatation is helpful in treating ulcerative colitis. Summary of the Invention [Problem to be solved by the invention]

[0005] Currently, drugs commonly used to treat ulcerative colitis have certain preventive and therapeutic effects, but still have drawbacks such as relatively slow absorption, relatively long treatment cycles, and unclear therapeutic effects. [Means for solving the problem]

[0006] In order to overcome the shortcomings and defects of the prior art, the object of the present invention is to provide a new polypeptide compound and its application. The inventors of the present invention have found that the polypeptide compound of the present invention can effectively or significantly alleviate or inhibit the expansion of the intestinal lumen, thereby playing a role in treating enteritis.

[0007] According to a first aspect, the present invention relates to a compound according to formula (I) or a physiologically acceptable salt thereof, wherein said compound of formula (I) is HX a -Z1-Z2-Z3-Z4-X b -OH(I), where: Z1 is Pro, Ala, Gly, D-Pro or is deleted; Z2 is Val, Ala, D-Val, Ile or is deleted, Z3 is Pro, Ala, Gly, D-Pro or is deleted; Z4 is Gln, Ala, Glu, Ile, D-Gln or is deleted; The condition is that no more than two of Z1, Z2, Z3 and Z4 are deleted. X a is a sequence containing 0 to 10 amino acid residues, X b is a sequence containing 0 to 9 amino acid residues.

[0008] In one embodiment, two of Z1, Z2, Z3 and Z4 are deleted. In one embodiment, Z1 and Z2 are deleted. In one embodiment, Z3 and Z4 are deleted. In one embodiment, one of Z1, Z2, Z3 and Z4 is deleted. In one embodiment, Z1 is deleted. In one embodiment, Z4 is deleted. In one embodiment, zero of Z1, Z2, Z3 and Z4 are deleted.

[0009] 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 deleted. 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.

[0010] 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 linkage to Z1-Z2-Z3-Z4, X a10 is Gly or is deleted, X a9 is Gly, Pro, Ser or is deleted, X a8 is Pro, Glu, Ser or is deleted, X a7 is Arg, Glu, Thr, Ser or is deleted, X a6 is Lys, Thr, Ala, Asp, Glu, Arg, Ser or is deleted, X a5 is Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or is deleted, X a4 is Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or is deleted, X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or is deleted, X a2 is D-Lys, Lys, Ala, Arg, Val, Glu, Tyr or is deleted, and X a1 is Glu, Ala, D-Glu, Tyr, Gln, Asp, Asn or is deleted.

[0011] In one embodiment, X a is X aa -X a2 -X a1 -*, where * represents the position of linkage to Z1-Z2-Z3-Z4, and 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 -Xa3 - where X a10 is Gly or deleted, and X a9 is Gly, Pro, Ser or is deleted, and X a8 is Pro, Glu, Ser or is deleted, and X a7 is Arg, Glu, Thr, Ser or is deleted, and X a6 is Lys, Thr, Ala, Asp, Glu, Arg, Ser or is deleted, and X a5 is Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or is deleted, and X a4 is Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or is deleted, and X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or is deleted. 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 deleted, wherein the rightmost hyphen - is -X a2 -X a1 In one embodiment, X a is X aa -X a2 -X a1 -*, where * represents the position of linkage to Z1-Z2-Z3-Z4, where X a2 -X a1 is Lys-Glu-*, and X aa is as defined above.

[0012] In one embodiment, X a is X a1-*, where * represents the position of linkage to Z1-Z2-Z3-Z4, where X a1 is Glu, Ala, D-Glu, Asp, Asn or is deleted. In one embodiment, X a is X a2 -X a1 -*, where * represents the position of linkage to Z1-Z2-Z3-Z4, where X a2 is Lys, and X a1 is Glu, D-Glu or Gln.

[0013] In one embodiment, X a 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-G lu-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 deleted, wherein * represents the position of linkage to Z1-Z2-Z3-Z4.

[0014] In one embodiment, X b **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9where ** represents the position of linkage to Z1-Z2-Z3-Z4, X b1 is Ala, D-Ala or deleted, X b2 is Lys, Ala, D-Lys, Arg or is deleted, X b3 is Pro, Gly, D-Pro, Ser, Val, Ala or is deleted, X b4 is Arg, Ala, Ser, Pro, D-Arg or is deleted, X b5 is Lys, Ala, D-Lys, Glu, Tyr or is deleted, X b6 is Val, Asp, D-Val, Ala or is deleted, X b7 is Ala, D-Ala, Ile or is deleted, X b8 is Ala, D-Ala, Lys or is deleted, and X b9 is Gln, Ala, Glu, Asn, D-Gln or is deleted.

[0015] In one embodiment, X b **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 where ** represents the position of linkage to Z1-Z2-Z3-Z4, X b1 is Ala or D-Ala, X b2 is Lys, Ala or D-Lys, X b3 is Pro, Gly, or Ala, X b4 is Arg or D-Arg, X b5 is Lys or is deleted, X b6 is Val, D-Val, Ala or is deleted, X b7 is Ala or deleted, X b8 is Ala or deleted, and X b9 is Gln, Asn, D-Gln or is deleted.

[0016] In one embodiment, X b **-X b1 -X b2 -X bb where ** represents the position of linkage to Z1-Z2-Z3-Z4, and X b1 -X b2 - is **-Ala-Lys-, **-Ala-Lys-, **-Ala-D-Lys-, **-Ala-Ala- or **-D-Ala-Lys-, 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 is deleted, and X b4 is Arg, Ala, Ser, Pro, D-Arg or is deleted, and X b5 is Lys, Ala, D-Lys, Glu, Tyr or is deleted, and X b6 is Val, Asp, D-Val, Ala or is deleted, and X b7 is Ala, D-Ala, Ile or deleted, and X b8 is Ala, D-Ala, Lys or is deleted, and X b9 is Gln, Ala, Glu, Asn, D-Gln or is deleted, or X b3 is Pro, Gly, or Ala, and X b4 is Arg or D-Arg, and X b5 is Lys or deleted, and X b6 is Val, D-Val, Ala or deleted, and Xb7 is Ala or deleted, and X b8 is Ala or deleted, and X b9 is Gln, Asn, D-Gln or is deleted. bb is Pro-Arg-Lys-Val, -Pro-Arg-Lys, -Pro-Arg, -Ala-Gln, -Ala-Ala, -Pro, -Lys-Val, -Val-Pro-Tyr, -Arg-Ly s, -Val-Ala, -Pro-Arg-Lys-Val-Ala, -Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-L ys-Val-Ala-Ala-Gln, -Pro-Ala-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Ala-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Va l-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, -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-Al -Ala-Gln, -Ala-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Ala-Ala-Ala-Gln, -Pro-Arg-Lys-Val-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 deleted, wherein the leftmost hyphen - is X b1 -X b2 In one embodiment, X b **-X b1 -X b2 -X bb where ** represents the position of linkage to Z1-Z2-Z3-Z4, and Xb1 -X b2 - is **-Ala-Lys-, and X bb is as defined above. In one embodiment, X b is **-Ala-.

[0017] 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, **-Val-Ala-Ala-Gln, **-Lys-Val-Ala-Ala, **-Ala-Lys-Pro, **-Pro-Arg-Lys-Val, **-Ala-Lys-Val-Pro-Tyr, **-Lys-P ro-Arg-Lys、**-Arg-Lys-Val-Ala、**-Ala-Lys-Pro-Arg-Lys-Val-Ala、**-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala -Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala、**-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-G ln、**-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala -Gln、**-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn、**-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-G ln、**-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln、**-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln、**-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln, **-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln, **-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln or deleted, where ** represents the position of linkage to Z1-Z2-Z3-Z4.

[0018] In one embodiment, Z1 is Pro, Z2 is Val, Z3 is Pro, and Z4 is Gln; a is X aa -X a2 -X a1 -*, where * represents the position of linkage to Z1-Z2-Z3-Z4, where X a2 -X a1 Lys-Glu-* and X b **-X b1 -X b2 -X bb where ** represents the position of linkage to Z1-Z2-Z3-Z4, and X b1 -X b2 - is **-Ala-Lys-, where X aa and X bb is as defined above.

[0019] In one embodiment, the compound is 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), Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 5), Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 6), Lys-Glu-Pro-Val (compound 7) Val-Ala-Ala-Gln (compound 8) Glu-Pro-Val-Pro (Compound 9) Lys-Pro-Arg-Lys (compound 10) Ala-Lys-Pro-Arg (compound 11) Pro-Val-Pro-Gln (compound 12) Val-Pro-Gln-Ala (compound 13) Pro-Gln-Ala-Lys (compound 14) Arg-Lys-Val-Ala (compound 15)

[0020] Lys-Val-Ala-Ala (compound 16) Gln-Ala-Lys-Pro (Compound 17) Pro-Arg-Lys-Val (compound 18) Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 19), Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 20), Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 21), Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 22), Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 23), Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 24), Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 25), 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),

[0021] Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 31), Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 32), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 33), Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 34), Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 35), Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 36), Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 37), Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (compound 38) Pro-Val-Pro-Gln-Ala (compound 39) Pro-Val-Pro-Glu-Ala (compound 40) Pro-Val-Pro-Ile-Ala (compound 41) Pro-Val-Pro-Ala (compound 42) Glu-Pro-Val-Pro-Gln-Ala (compound 43) Pro-Val-Pro-Gln-Ala-Lys (compound 44) Glu-Pro-Val-Pro-Gln-Ala-Arg (compound 45)

[0022] Ala-Pro-Val-Pro-Gln-Ala-Lys (compound 46) Glu-Pro-Val-Pro-Ala-Ala-Lys (compound 47) Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48) Asp-Pro-Val-Pro-Gln-Ala-Lys (compound 49) Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50) Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51) Glu-Pro-Ala-Pro-Gln-Ala-Lys (compound 52) Glu-Ala-Val-Pro-Gln-Ala-Lys (compound 53) Glu-Pro-Val-Ala-Gln-Ala-Lys (compound 54) Glu-Pro-Val-Pro-Glu-Ala-Lys (compound 55) 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) Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (compound 59) Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 60)

[0023] 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),

[0024] Glu-Gly-Val-Pro-Gln-Ala-Lys (compound 76) Glu-Pro-Val-Gly-Gln-Ala-Lys (compound 77) 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) Lys-Glu-Pro-Val-Pro (Compound 85) Glu-Pro-Val-Pro-Gln (compound 86) Lys-Glu-Pro-Val-Pro-Gln (compound 87) 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),

[0025] 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) Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (compound 94) 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), Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (compound 99), 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), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (compound 104), Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 105), Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 106), Val-Pro-Gln-Ala (compound 107), or It is selected from Val-Pro-Gln-Ala-Lys (compound 108).

[0026] In one embodiment, the compound is 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) Pro-Val-Pro-Gln (compound 12) Glu-Pro-Val-Ala-Gln-Ala-Lys (compound 54) 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),

[0027] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 92), Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (compound 94) 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-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 105), Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 106), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 4) Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 5) Glu-Pro-Val-Pro (Compound 9) Lys-Pro-Arg-Lys (compound 10) Arg-Lys-Val-Ala (compound 15) Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 25),

[0028] 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), Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 31), Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 34), Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (compound 38) Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48) Asp-Pro-Val-Pro-Gln-Ala-Lys (compound 49) Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50) Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51) Glu-Ala-Val-Pro-Gln-Ala-Lys (compound 53) Glu-Pro-Val-Pro-Glu-Ala-Lys (compound 55) 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),

[0029] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (compound 75), Glu-Pro-Val-Pro-Gln-D-Ala-Lys (compound 83), Lys-Glu-Pro-Val-Pro (compound 85), Glu-Pro-Val-Pro-Gln (compound 86), 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), Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (compound 99), or Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (compound 103).

[0030] According to a second aspect, the present invention provides use of the polypeptide compound or a physiologically acceptable salt thereof in the manufacture of a medicament for treating enteritis, or a method for treating enteritis comprising administering a therapeutically effective amount of the polypeptide compound or a physiologically acceptable salt thereof to a subject, or the polypeptide compound or a physiologically acceptable salt thereof for treating enteritis. Furthermore, enteritis includes specific enteritis and non-specific enteritis, and specific enteritis further includes inflammatory bowel disease, necrotizing enteropathy, and intestinal dysbiosis. Additionally, inflammatory bowel disease includes ulcerative colitis.

[0031] The present invention further provides a pharmaceutical composition comprising a polypeptide compound or a physiologically acceptable salt of the present invention and a pharmaceutically acceptable excipient. Additionally, drug dosage forms include tablets, capsules, solutions, powders, and pills. The beneficial effects of the novel polypeptides provided by the present invention and their applications are as follows:

[0032] The polypeptides described in the present invention have a short peptide chain, which allows for faster and better absorption. Experimental results show that the polypeptides provided by the present invention have a significant alleviating effect on intestinal lumen dilation in a rat acute inflammatory bowel disease model test, demonstrating a significant therapeutic effect in the rat acute inflammatory bowel disease model test. The polypeptides described in the present invention have a significant alleviating effect on colitis and can be used to prepare drugs for treating enteritis, especially ulcerative colitis. [Brief explanation of the drawings]

[0033] [Figure 1] 1 shows a schematic diagram of the steps of solid phase synthesis of a polypeptide. [Figure 2] The mass spectrum of the polypeptide is shown. DETAILED DESCRIPTION OF THE INVENTION

[0034] The following is an explanation of the present invention in conjunction with specific tests, but is not intended to limit the scope of the claimed invention.

[0035] As used in this application (including the appended claims), singular words such as "a," "an," and "the" include their corresponding plural referents unless the context dictates otherwise.

[0036] Unless the context clearly indicates otherwise, the term "or" means, and is used interchangeably with, the term "and / or."

[0037] The term "effective amount" or "therapeutically effective amount" refers to the amount of an active ingredient (e.g., a compound) that, when administered to a subject for treating a disease or at least one clinical symptom of a disease or disorder, is sufficient to affect treatment of the disease, disorder, or condition. A "therapeutically effective amount" will vary with the compound, the disease, disorder, and / or symptoms of the disease or disorder, the severity of the disease, disorder, and / or symptoms of the disease or disorder, the age of the subject being treated, and / or the weight of the subject being treated. The appropriate amount for any given situation will be apparent to one of ordinary skill in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an effective amount of at least one compound disclosed herein and / or at least one stereoisomer thereof, and / or at least one pharmaceutically acceptable salt thereof, in the "treatment" (as defined above) of a disease or disorder in a subject. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combined components to effectively treat the disease, disorder, or condition.

[0038] The term "physiologically compatible salts" refers to salt forms that are physiologically compatible (i.e., pharmacologically acceptable) and essentially non-toxic to individuals to whom the compounds of the present invention are administered. Physiologically compatible salts of the compounds of the present invention include conventional stoichiometric acid or base addition salts formed from appropriate non-toxic organic or inorganic acids or inorganic bases.

[0039] The term "intestinal dilatation" refers to intestinal dilatation or intestinal tract dilation. In patients with enteritis, the intestinal tract with intestinal dilatation caused by various factors such as intestinal damage, mucus exudation, accumulation of gas or fluid in the intestinal tract, and microbial overgrowth is thicker than the normal intestine, and intestinal dilatation due to inflammatory bowel disease, or recurrent enteritis such as intestinal dilatation or intestinal obstruction due to tumors is commonly seen clinically.

[0040] As used herein, the abbreviations for each amino acid sequence are as follows: JPEG0007811806000001.jpg117121

[0041] JPEG0007811806000002.jpg89163

[0042] Example 1: Chemical synthesis of polypeptides The polypeptide compounds were synthesized by conventional solid-phase synthesis using a fully automated polypeptide synthesizer, and chemical synthesis of the polypeptides was carried out through resin swelling, deprotection, washing, amino acid activation, and condensation processes. A schematic diagram of the solid-phase polypeptide synthesis steps is shown in Figure 1, using Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1) as an example.

[0043] Step 1: Preparation of fully protected peptide resin (1) Swelling of resin: 7.71 g (SD=0.73 mmol / g) of 2-chlorotrityl chloride resin was weighed and added to a synthesis tube equipped with a sieve plate, and swelled with 100 ml of dichloromethane (DCM). (2) Preparation of Fmoc-Gln(Trt)-resin: Fmoc-Gln(Trt)-OH and DIPEA were weighed and added to a synthesis tube in a molar ratio of 1:1.78:4.31. The mixture was shaken and bubbled with nitrogen gas (N) at room temperature for 1-3 hours, then dried by suction. After washing with dimethylformamide (DMF) five times at 100 ml each time, the resin was dried by suction. (3) Removal of Fmoc protecting group: 100 ml of 20% piperidine-DMF (v / v) solution was added to the reactor, and the reaction was carried out by bubbling nitrogen gas for 20 minutes. The reaction mixture was then dried by suction, and the mixture was washed five times with DMF, 100 ml per wash for 3 minutes per wash. The mixture was then dried by suction, and the removal of Fmoc was detected by the ninhydrin method.

[0044] (4) Preactivation of amino acid: 15 mmol of Fmoc-protected amino acid, 15 mmol of HOBt, and 15 mmol of DIC were added to a 250 ml beaker, dissolved in 100 ml of DMF, and stirred at room temperature for use. (5) Amino acid coupling: The activated protected amino acid solution was poured into the reactor, and the reactor was replenished with an appropriate amount of DCM to rinse. The reaction was carried out at room temperature by bubbling nitrogen gas for 1-3 hours. The ninhydrin method was used to check whether the amino acid coupling was complete. If complete, the resin was dried by suction. The resin was washed five times with DMF, 100 ml per wash, for 3 min each, and then dried by suction. The amounts of each amino acid and condensation agent are shown in Table 2. (6) After the first amino acid condensation was completed, steps (4) and (5) were repeated to extend the peptide chain in the order of amino acids until the final amino acid coupling was completed. (7) The resin peptide was washed four times with DMF at 150 ml / time for 3 minutes, and then five times with DCM at 150 ml / time for 3 minutes, and then dried by suction.

[0045] JPEG0007811806000003.jpg100170

[0046] Step 2, cutting (1) 100 ml of a cleavage agent (TFA:TIPS:H2O = 95:2.5:2.5, v / v) was added to a synthesis tube, and the reaction was carried out by bubbling nitrogen gas through the tube for 1.5 to 3 hours. (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-quarter of the original volume of the cleavage agent, 10 times the existing volume of methyl tert-butyl ether was added and allowed to settle, yielding a white solid. The resulting mixture was filtered and washed three times with 50 ml of methyl tert-butyl ether. The resulting crude peptide was then placed in a sand funnel and dried using nitrogen gas in a fume hood. The solvent was evaporated until the crude peptide was powdered. 9.04 g of crude peptide was obtained, for a crude yield of 74.7%.

[0047] Step 3: Purification, salt exchange and lyophilization Direct salt exchange (acetate) by polypeptide HPLC A. Chromatographic Parameters Chromatography column: Dynamic axial compression column 80 x 250 mm, packing: Daisogel C18 (SP-100-8-ODS-P) Eluent A1: 0.1M acetic acid Eluent A2: 0.025M acetic acid - 0.1M ammonium acetate Eluent B: Acetonitrile Flow rate: 180ml / min UV detection wavelength: 220 nm

[0048] B. Operation steps a) Dissolve crude peptide in water and / or acetonitrile and filter through a 0.45 μm filter membrane. b) Equilibration of a chromatographic column with 95% A1 + 5% B c) injection d) Equilibration of a chromatographic column with 95% A2 + 5% B e) Gradient elution of A1 and B f) Collection of target peptide eluate g) Rotary evaporation and concentration h) Freeze drying 8.26 g of crude peptide was purified to give 4.92 g of pure peptide, for a purification yield of 59.5%. Other compounds were synthesized in a manner similar to that of compound 1. The results are shown in Table 3 and elsewhere in the specification.

[0049] JPEG0007811806000004.jpg238170

[0050] JPEG0007811806000005.jpg246170

[0051] JPEG0007811806000006.jpg240170

[0052] JPEG0007811806000007.jpg251170

[0053] JPEG0007811806000008.jpg250170

[0054] NOTE: A doubly charged peak indicates that the target molecule is bound to two protons, a triple charged peak indicates that the target molecule is bound to three protons, and N / A indicates that the actual weight is not included due to the difficulty of weighing.

[0055] Compound 1: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate) 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] + ). 1 H NMR(600MHz,D2O+CD3CN)δ4.48(dd,J=9.5,4.1Hz,1H)4.42(dd,J=9.2,4.5Hz,1H)4.32-4.27(m,1H) 4.27-4.21(m,3H)4.20-4.07(m,6H)4.00(dd,J=8.3,4.8Hz,1H)3.95(d,J=7.5Hz,1H)3.86(t,J=6.7H z,1H)3.77-3.62(m,3H)3.59-3.43(m,3H)3.04(t,J=6.7Hz,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).

[0056] Compound 2: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (acetate) 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] + ). 1H NMR(600MHz,DMSO-d6)δ4.57(dd,J=8.7,4.9Hz,1H)4.41-4.11(m,10H)3.83(s,1H)3.78(t,J=6.5Hz,1H)3.54(d,J=73.5Hz,7H)3.08(d,J=7.0Hz,2H)2 .74-2.68(m,7H)2.32(d,J=9.1Hz,2H)2.23-2.17(m,2H)2.05-1.46(m,AcOH ,56H)1.43-1.22(m,7H)1.17(d,J=7.0Hz,3H)0.82(dd,J=19.6,6.7Hz,6H).

[0057] Compound 3: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (hydrogen hydroxide) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,DMSO-d6)δ4.58-4.55(m,1H)4.44-4.37(m,2H)4.33(dd,J=8.4,4.2Hz,1 H)4.30-4.22(m,3H)4.16-4.12(m,2H)3.79(d,J=6.1Hz,1H)3.64-3.48(m,6H)3.08(t ,J=7.0Hz,2H)2.71(d,J=8.2Hz,5H)2.36-2.30(m,2H)2.15(t,J=7.6Hz,2H)2.09-1.4 1(m,AcOH,46H)1.37-1.29(m,4H)1.16(d,J=7.1Hz,3H)0.85(dd,J=20.7,6.7Hz,6H).

[0058] Compound 4: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 40 H 69 N 11 O 12 ;m / z:448.76653([M+2H] 2+ ), 896.52058([M+H] + ). 1 H NMR(600MHz,DMSO-d6)δ4.56(dd,J=9.0,4.9Hz,1H)4.39(dd,J=8.3,4.4Hz,1H)4 .31-4.24(m,3H)4.13(dd,J=9.1,5.1Hz,2H)3.78(dd,J=7.9,4.3Hz,1H)3.67-3. 51(m,4H)2.75-2.70(m,4H)2.38-2.29(m,2H)2.14(t,J=7.8Hz,2H)2.04-1.47(m ,AcOH,33H)1.35-1.28(m,4H)1.19(d,J=7.2Hz,3H)0.85(dd,J=22.1,6.8Hz,6H).

[0059] Compound 5: Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 33 H 60 N 12 O9;m / z:385.24021([M+2H] 2+ ), 769.46971([M+H) + ). 1 H NMR(600MHz,D2O)δ4.23-4.17(m,1H)4.15-4.07(m,4H)3.95(dd,J=8.5,4.8H z,1H)3.89(d,J=7.7Hz,1H)3.25-3.15(m,2H)3.00(t,J=7.0Hz,2H)2.78(t,J =7.7Hz,2H)2.30-2.22(m,1H)2.12-2.05(m,2H)1.93-1.80(m,5H)1.75(s,Ac OH,10H)1.62-1.40(m,8H)1.19(d,J=7.2Hz,8H)0.73(dd,J=6.7,4.0Hz,6H).

[0060] Compound 6:Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 34 H 57 N9O 11 ;m / z:768.42641([M+H] + ). 1 H NMR(600MHz,D2O)δ4.46(dd,J=8.4,6.4Hz,1H)4.35-4.27(m,3H)4.26-4.18(m,2H)4.0 9(dd,J=8.2,5.1Hz,1H)3.84-3.77(m,1H)3.68-3.52(m,3H)2.91(t,J=7.5Hz,2H)2.39( t,J=7.2Hz,2H)2.33(t,J=7.6Hz,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=11.8,7.5Hz,5H)0.92(dd,J=12.6,6.7Hz,6H).

[0061] Compound 7: Lys-Glu-Pro-Val (hydrogen acid) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 21 H 37 N5O7; m / z: 472.27768 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.43(dd,J=10.2,4.0Hz,1H)4.27(dd,J=8.3,5.3Hz,1H)3.85-3.80(m,2H)3.68-3.60(m,1H)3.59-3.46(m,1H)2.80(t,J =7.6Hz,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=15.3,6.9Hz,6H).

[0062] Compound 8: Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 16 H 29 N5O6; m / z: 388.2187 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.25(q,J=7.2Hz,1H)4.17(q,J=7.2Hz,1H)4.05(dd,J=8.5,4.8Hz,1H)3.67(d,J=6.0Hz,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=7.2,5.0Hz,6H)0.90(dd,J=10.3,6.9Hz,6H).

[0063] Compound 9: Glu-Pro-Val-Pro (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 20 H 32 N4O7;441.23562([M+H] + ). 1 H NMR(600MHz,DMSO-d6)δ4.42(dd,J=8.4,4.6Hz,1H)4.28(t,J=8.3Hz,1H)4.17(dd,J=8.5,4.7Hz,1H)3.78(dd ,J=8.3,4.2Hz,1H)3.64-3.45(m,4H)2.37-2.27(m,2H)2.08-1.58(m,AcOH,16H)0.87(dd,J=25.7,6.7Hz,6H).

[0064] Compound 10: Lys-Pro-Arg-Lys (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 23 H 45 N9O5; 264.68527([M+2H] 2+ ), 528.36210([M+H] + ). 1H NMR(600MHz,DMSO-d6)δ4.42(dd,J=8.2,5.2Hz,1H)4.23(t,J=6.7Hz,1H)4.14(dd,J=8.9,5.2Hz,1H)4.09(d,J=7.9Hz,1H)3.64(dd,J=9.9,6.6Hz,1H) 3.45-3.40(m,1H)3.07(s,2H)2.72(t,J=6.3Hz,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).

[0065] Compound 11: Ala-Lys-Pro-Arg (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 20 H 38 N8O5; 236.15638([M+2H] 2+ ), 471.30462([M+H] + ). 1 H NMR(600MHz,D2O))δ4.55(dd,J=8.3,5.6Hz,1H)4.34(dd,J=8.4,5.9Hz,1H)4.09-3.96(m,2H)3.82-3.74(m,1H)3.64-3.55(m,1H)3.12(t,J=6. 9Hz,2H)2.93(t,J=7.6Hz,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=7.1Hz,5H).

[0066] Compound 12: Pro-Val-Pro-Gln (hydrogen acid) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 20 H 33 N5O6; m / z: 440.25122([M+H] + ). 1H NMR(600MHz,D2O)δ4.33-4.18(m,3H)3.97(dd,J=8.9,4.8Hz,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=6.8Hz,3H)0.76(d,J=6.7Hz,3H).

[0067] Compound 13: Val-Pro-Gln-Ala (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.23575 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.37(t,J=7.5Hz,1H)4.15(dd,J=8.6,6.0Hz,1H)4.07(d,J=5.5Hz,1H)4.03(t,J=7.2Hz,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=7.2Hz,3H)0.98(d,J=7.0Hz,3H)0.87(d,J=6.8Hz,3H).

[0068] Compound 14: Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 19 H 34 N6O6; m / z: 222.13480 ([M+2H]) 2+ ), 443.26183([M+H] + ). 1H NMR(600MHz,D2O)δ4.28(dd,J=8.7,6.1Hz,1H)4.25-4.15(m,2H)4.01(dd,J=8.1,5.2Hz,1H)3.34-3.22(m,2H)2.86(t,J=7 .5Hz,2H)2.37-2.29(m,1H)2.26(t,J=7.6Hz,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).

[0069] Compound 15: Arg-Lys-Val-Ala (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 20 H 40 N8O5; m / z: 237.16465 ([M+2H]) 2+ ), 473.32087([M+H] + ). 1 H NMR(600MHz,D2O)δ4.28(t,J=7.3Hz,1H)4.00-3.94(m,2H)3.90(t,J=6.4Hz,1H)3.07(t,J=7.0Hz,2H)2.85(t,J=7.6Hz,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=7.2Hz,3H)0.81(t,J=6.9Hz,6H).

[0070] Compound 16: Lys-Val-Ala-Ala (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 17 H 33 N5O5; m / z: 388.25660 ([M+H] + ). 1H NMR(600MHz,D2O)δ4.18(q,J=7.1Hz,1H)4.03-3.91(m,3H)2.87(t,J=7.7Hz,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=7.2Hz,3H)1.19(d,J=7.2Hz,3H)0.83(d,J=6.8Hz,6H).

[0071] Compound 17: Gln-Ala-Lys-Pro (hydrogen acid) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 19 H 34 N6O6;m / z:443.26161([M+H] + ). 1 H NMR(600MHz,D2O)δ4.48(dd,J=8.2,5.6Hz,1H)4.26-4.20(m,1H)4.10(dd,J=8.5,5.4Hz,1H)3.91(t,J=6.6Hz,1H)3.68-3.61(m,1H)3.55-3. 43(m,1H)2.88(t,J=7.5Hz,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).

[0072] Compound 18: Pro-Arg-Lys-Val (hydrogen hydroxide) High energy dissolution mass analysis (TOF-HRMS), molecular formula: C 22 H 42 N8O5; m / z: 250.17158 ([M+2H]) 2+ ), 499.33464([M+H) + ). 1H NMR(600MHz,D2O)δ4.27(dd,J=8.7,6.0Hz,1H)4.24-4.17(m,2H)3.88(d,J=6.2Hz,1H)3.33-3.20(m,2H)3.09-3.02(m,2H)2.85(t,J =7.5Hz,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=11.2,6.8Hz,6H).

[0073] Compound 19: Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,D2O)δ4.53-4.43(m,2H)4.33(dd,J=8.3,6.0Hz,1H)4.27(t,J=7.7Hz,3H)4.24-4.1 2(m,6H)4.06-3.94(m,3H)3.77(q,J=7.6Hz,1H)3.73-3.67(m,2H)3.63-3.53(m,2H)3.51(q,J=7 .6Hz,1H)3.08(t,J=6.9Hz,2H)2.91-2.83(m,4H)2.29(t,J=7.6Hz,2H)2.26-2.12(m,7H)2.03-1 .46(m,AcOH,38H)1.39(d,J=7.1Hz,4H)1.36-1.30(m,2H)1.30-1.22(m,10H)0.92-0.77(m,12H).

[0074] Compound 20: Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,D2O)δ4.51(q,J=7.1Hz,1H)4.48-4.43(m,1H)4.31-4.25(m,3H)4.24-4.11(m,6H) 4.03(dd,J=8.4,4.9Hz,1H)3.98(d,J=7.6Hz,1H)3.87(t,J=6.7Hz,1H)3.79-3.67(m,3H)3.60-3 .47(m,3H)3.08(t,J=6.9Hz,2H)2.91-2.83(m,6H)2.28(t,J=7.6Hz,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).

[0075] Compound 21: Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1H NMR(600MHz,D2O)δ4.45(dd,J=9.4,4.9Hz,1H)4.30-4.24(m,3H)4.24-4.11(m,8H)4.02 (dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,1H)3.89(t,J=6.7Hz,1H)3.79-3.66(m,2H)3.6 0-3.47(m,2H)3.08(t,J=6.9Hz,2H)2.91-2.83(m,6H)2.28(t,J=7.6Hz,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).

[0076] Compound 22: Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.46(dd,J=9.4,4.8Hz,1H)4.35(dd,J=8.4,5.8Hz,1H)4.28(dd, J=8.3,6.1Hz,1H)4.25-4.13(m,7H)4.03(dd,J=8.3,4.9Hz,1H)3.98(d,J=7.6Hz,1H)3.94-3.88(m,2H)3.75-3.6 7(m,2H)3.63-3.56(m,1H)3.51(q,J=7.3Hz,1H)3.09(t,J=6.9Hz,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).

[0077] Compound 23: Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen hydroxide) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.44(dd,J=9.4,4.9Hz,1H)4.33(dd,J=8.4,5.8Hz,1H)4.31-4 .08(m,9H)4.03(dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,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=6.9Hz,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).

[0078] Compound 24: Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.7,4.4Hz,1H)4.45(q,J=7.1Hz,1H)4.33(dd,J=8.4,5.8Hz,1H)4.31-4.24 (m,3H)4.23-4.12(m,6H)4.03(dd,J=8.4,4.8Hz,1H)3.97(d,J=7.6Hz,1H)3.92-3.87(m,1H)3.79-3.73(m,1 H)3.73-3.64(m,2H)3.62-3.48(m,3H)3.08(t,J=6.9Hz,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).

[0079] Compound 25: Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.51(dd,J=9.5,4.4Hz,1H)4.48-4.41(m,2H)4.32-4.25(m,3H)4.21(dd,J=8.1, 6.7Hz,1H)4.19-4.12(m,5H)4.02(dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,1H)3.92-3.85(m,1H)3.7 4-3.64(m,3H)3.60-3.46(m,3H)3.07(t,J=6.9Hz,2H)2.90-2.83(m,6H)2.30-2.20(m,4H)2.20-2.1 2(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=6.8,4.4Hz,6H).

[0080] Compound 26: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.33(dd,J=8.4,5.8Hz,1H)4.31-4.23(m, 2H)4.23-4.09(m,8H)4.03(dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,1H)3.93-3.86(m,1H)3 .81-3.66(m,2H)3.62-3.52(m,2H)3.07(t,J=6.9Hz,2H)2.86(m,6H)2.31-2.11(m,8H)2.0 3-1.41(m,AcOH,48H)1.40-1.27(m,6H)1.25(dd,J=13.7,7.3Hz,12H)0.90-0.76(m,12H).

[0081] Compound 27: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 70 H 120 N 20 O 20 ;m / z:391.23177([M+4H] 4+ ), 781.45496([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.52-4.43(m,2H)4.33(dd,J=8.4,5.8Hz,1H)4.31-4.22(m,3H)4.21-4.10 (m,6H)4.02(dd,J=8.5,4.8Hz,1H)3.96(d,J=7.7Hz,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).

[0082] Compound 28: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.52-4.42(m,2H)4.33(dd,J=8.4,5.8Hz,1H)4.30-4.24(m,3H)4.23-4.09(m,6H )4.02(dd,J=8.5,4.8Hz,1H)3.95(d,J=7.5Hz,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=6.9Hz,2H)2.87(t,J=7.6Hz,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).

[0083] Compound 29: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.49(dd,J=9.6,4.3Hz,1H)4.45(dd,J=9.3,4.9Hz,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=8.4,4.8Hz,1H)3.89(t,J=6.8Hz,1H)3. 79-3.66(m,3H)3.61-3.47(m,3H)3.08(t,J=6.9Hz,2H)2.86(q,J=8.0Hz,6H)2.28(t,J=7.6Hz, 2H)2.23-2.13(m,7H)2.02-1.46(m,AcOH,47H)1.42-1.18(m,20H)0.85(dd,J=14.2,6.7Hz,6H).

[0084] Compound 30: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala (hydrogen hydroxide) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.46(dd,J=9.4,4.9Hz,1H)4.34(dd,J=8.4,5.8Hz,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,1 H)3.74-3.67(m,2H)3.63-3.43(m,3H)3.08(t,J=6.9Hz,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=16.0,8.1Hz,6H)1.27-1.20(m,12H)0.92-0.77(m,12H).

[0085] Compound 31: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1 H NMR(600MHz,D2O)δ4.45(dd,J=9.4,4.9Hz,1H)4.32(d,J=8.1Hz,1H)4.30-4.25(m,2H)4.24-4.19(m,2H)4.19-4 .11(m,5H)4.02(dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,1H)3.91-3.84(m,2H)3.82-3.73(m,2H)3.69(q,J=7.7,7 .0Hz,1H)3.59-3.52(m,1H)3.52-3.46(m,1H)3.07(t,J=6.9Hz,2H)2.90-2.82(m,6H)2.28(t,J=7.6Hz,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).

[0086] Compound 32: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1H NMR(600MHz,D2O)δ4.51(dd,J=9.7,4.4Hz,1H)4.46(dd,J=9.4,4.9Hz,1H)4.36(dd,J=8.3,5.9Hz,1H)4.28(dd,J=8. 3,6.1Hz,1H)4.24-4.14(m,6H)4.03(dd,J=8.3,4.9Hz,1H)3.97(dd,J=10.0,7.5Hz,2H)3.90(t,J=6.8Hz,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=6.9Hz,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=18.4,7.2Hz,9H)0.89-0.79(m,12H).

[0087] Compound 33: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.34(dd,J=8.4,5.8Hz,1H)4.31-4.11(m ,9H)4.03(dd,J=8.4,4.9Hz,1H)3.97(d,J=7.6Hz,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=7.0Hz,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).

[0088] Compound 34: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.6,4.4Hz,1H)4.35(dd,J=8.3,5.9Hz,1H)4.25-4.12(m,7H)4.03( dd,J=8.4,4.8Hz,1H)3.96(dd,J=10.6,7.5Hz,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=7.0Hz,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=11.0,6.7Hz,6H)0.80(dd,J=6.8,5.1Hz,6H).

[0089] Compound 35: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.27-4.13(m,8H)4.05-4.00(m,2H)3.97(d,J=7.6Hz,1H)3.93-3.87(m,2H)3.85-3.76(m,5H)3.06(t,J=7. 0Hz,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).

[0090] Compound 36: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.32(d,J=8.0Hz,1H)4.28(dd,J=8.2,6.7Hz,1H)4.25-4.12(m,8H)4 .03(dd,J=8.4,4.8Hz,1H)3.97(d,J=7.6Hz,1H)3.92-3.83(m,2H)3.83-3.73(m,4H)3.6 0-3.53(m,1H)3.06(t,J=7.0Hz,2H)2.91-2.83(m,6H)2.28(t,J=7.5Hz,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).

[0091] Compound 37: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.44(dd,J=9.4,4.9Hz,1H)4.29-4.12(m,8H)4.04-3.99( m,2H)3.96(d,J=7.6Hz,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=6.9Hz,2H)2.89-2.81(m,6H)2.23-2.12(m,7H)2.0 1-1.45(m,AcOH,43H)1.42-1.26(m,6H)1.26-1.20(m,9H)0.83-0.77(m,12H).

[0092] Compound 38: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 51 H 88 N 16 O 14 ;m / z:383.89569([M+3H] 3+ ), 575.33978([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.45(dd,J=9.2,5.0Hz,1H)4.39(dd,J=8.3,6.4Hz,1H)4.29-4.21 (m,4H)4.19-4.12(m,3H)4.01(dd,J=7.8,5.5Hz,1H)3.78-3.73(m,1H)3.72-3.67(m, 1H)3.61-3.48(m,4H)3.08(t,J=6.8Hz,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=10.3,6.7Hz,6H).

[0093] Compound 39: Pro-Val-Pro-Gln-Ala (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 23 H 38 N6O7; m / z: 511.2871 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.41(d,J=7.3Hz,1H)4.38-4.32(m,2H)4.20(dd,J=8.7,5. 9Hz,1H)4.11-4.04(m,1H)3.85-3.77(m,1H)3.62(dt,J=10.3,7.2Hz,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=7.3Hz,3H)0.94(d,J=6.8Hz,3H)0.88(d,J=6.8Hz,3H).

[0094] Compound 40: Pro-Val-Pro-Glu-Ala (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 23 H 37 N5O8;m / z:512.27081([M+H] + ). 1 H NMR(600MHz,D2O)δ4.41(d,J=7.3Hz,1H)4.38-4.32(m,2H)4.23(dd,J=8.9,5.6Hz,1H)4.13-4.09(m,1H)3.86-3.76(m,1H)3.62(dt,J=10.2,7.2Hz, 1H)3.38-3.28(m,2H)2.43-2.35(m,3H)2.26-2.16(m,1H)2.12-1.72(m,Ac OH,12H)1.28(d,J=7.2Hz,3H)0.94(d,J=6.8Hz,3H)0.87(d,J=6.8Hz,3H).

[0095] Compound 41: Pro-Val-Pro-Ile-Ala (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 24 H 41 N5O6; m / z: 496.31158 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.36-4.27(m,3H)4.03(q,J=7.2Hz,1H)3.98(d,J=7.8Hz,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=7.2Hz,3H)1.13- 1.02(m,1H)0.88(d,J=6.8Hz,3H)0.85-0.80(m,6H)0.80-0.77(m,1H)0.74(t,J=7.4Hz,3H).

[0096] Compound 42: Pro-Val-Pro-Ala High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C18 H 30 N4O5; m / z: 383.22791 ([M+H] + ). 1 H NMR(600MHz,D2O)δ4.36(d,J=7.2Hz,1H)4.30(dd,J=8.5,6.3Hz,1H)4.24(dd,J=8.1,6.5Hz,1H)4.00(q,J=7.2Hz,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,A cOH,10H)1.21(d,J=7.3Hz,3H)0.88(d,J=6.9Hz,3H)0.81(d,J=6.8Hz,3H).

[0097] Compound 43: Glu-Pro-Val-Pro-Gln-Ala (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 28 H 45 N7O 10 ;m / z:640.32892([M+H] + ). 1 H NMR(600MHz,D2O)δ4.34(dd,J=8.3,6.5Hz,1H)4.25-4.15(m,3H)4.08(dd, J=8.8,5.9Hz,1H)4.04-4.00(m,1H)3.73-3.65(m,1H)3.57-3.41(m,3H)2. 35(t,J=7.3Hz,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=7.2Hz,3H)0.80(dd,J=12.9,6.8Hz,6H).

[0098] Compound 44: Pro-Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 29 H 50 N8O8;m / z:320.19421([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.29-4.19(m,3H)4.13-4.06(m,2H)3.95(dd,J=8.2,5. 1Hz,1H)3.73-3.68(m,1H)3.52-3.47(m,1H)3.24-3.16(m,2H)2.79(t,J=7. 5Hz,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=6.8Hz,3H)0.75(d,J=6.7Hz,3H).

[0099] Compound 45:Glu-Pro-Val-Pro-Gln-Ala-Arg (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N 11 O 11 ;m / z:398.71835([M+2H] 2+ ), 796.42944([M+H) + ). 1 H NMR(600MHz,D2O)δ4.38(dd,J=8.3,6.4Hz,1H)4.27-4.19(m,3H)4.19-4.10(m,2H)4.03( dd,J=8.3,4.9Hz,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=7.6Hz,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=7.1Hz,3H)0.85(dd,J=12.8,6.7Hz,6H)

[0100] Compound 46: Ala-Pro-Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 32 H 55N9O9;m / z:355.71259([M+2H] 2+ ), 710.41809([M+H] + ). 1 H NMR(600MHz,DMSO-d6)δ8.23(d,J=7.7Hz,1H)8.08(d,J=8.1Hz,1H)7.87(d,J=8.4Hz,1H)7.68(s,1H)7.38(d,J=6.4Hz,1H)6.75(s ,1H)4.40-4.37(m,1H)4.33-4.25(m,3H)4.15(t,J=7.2Hz,3H)3.78(d,J=6.4Hz,1H)3.66(dd,J=32.4,8.0Hz,2H)3.58-3.51(m,2H) 3.43(d,J=7.0Hz,1H)3.36-3.27(m,1H)2.67(t,J=7.7Hz,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=7.2Hz,6H)1.11(d,J=6.7Hz,3H)1.04(d,J=6.6Hz,1H)0.87(d,J=6.7Hz,3H)0.83(d,J=6.9Hz,3H).

[0101] Compound 47: Glu-Pro-Val-Pro-Ala-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 32 H 54 N8O 10 ;m / z:356.20514([M+2H] 2+ ), 711.40198([M+H] + ). 1H NMR(600MHz,D2O)δ4.45(dd,J=8.4,6.4Hz,1H)4.33-4.27(m,3H)4.21(dd,J= 15.1,7.2Hz,2H)4.07(dd,J=8.1,5.1Hz,1H)3.86-3.75(m,1H)3.67-3.54(m,3 H)2.91(t,J=7.5Hz,2H)2.37(t,J=6.9Hz,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=13.6,6.8Hz,6H).

[0102] Compound 48:Glu-Pro-Val-Pro-Gln-Ala-Ala (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 50 N8O 11 ;m / z:356.18692([M+2H] 2+ ), 711.36597([M+H] + ). 1 H NMR(600MHz,D2O)δ4.34(dd,J=8.3,6.5Hz,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= 7.3Hz,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=11.2,7.2Hz,6H)0.80(dd,J=13.0,6.8Hz,6H).

[0103] Compound 49: Asp-Pro-Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 33 H 55 N9O 11 ;m / z:377.70767([M+2H] 2+ ), 754.40814([M+H] + ). 1 H NMR(600MHz,D2O)δ4.36-4.29(m,2H)4.23-4.14(m,2H)4.13-4.06(m,2H)3.97(dd,J=8.3,5.0Hz,1 H)3.74-3.65(m,1H)3.56-3.46(m,2H)3.44-3.39(m,1H)2.79(t,J=7.5Hz,2H)2.65(dd,J=17.5,3. 3Hz,1H)2.38(dd,J=17.5,10.7Hz,1H)2.21(t,J=7.6Hz,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=13.1,7.5Hz,5H)0.80(dd,J=11.0,6.7Hz,6H).

[0104] Compound 50: Asn-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 33 H 56 N 10 O 10 ;m / z:377.21542([M+2H] 2+ ), 753.42365([M+H) + ). 1 H NMR(600MHz,D2O)δ4.55(dd,J=9.3,4.0Hz,1H)4.47(dd,J=8.4,6.1Hz,1H)4.34-4.29(m ,2H)4.26-4.19(m,2H)4.07(dd,J=8.1,5.1Hz,1H)3.83-3.77(m,1H)3.69-3.53(m,3H)2 .94-2.90(m,3H)2.72(dd,J=17.0,9.3Hz,1H)2.33(t,J=7.6Hz,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=13.4,6.7Hz,6H).

[0105] Compound 51:Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 59 H 102 N 18 O 16 ;m / z:440.59735([M+3H] 3+ ), 660.39252([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.38(dd,J=9.3,4.8Hz,1H)4.33(dd,J=8.3,6.5Hz,1H)4.22-4.12(m,5 H)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,4 H)3.00(t,J=6.9Hz,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=9.7,6.7Hz,6H)0.74(dd,J=11.0,6.8Hz,6H).

[0106] Compound 52:Glu-Pro-Ala-Pro-Gln-Ala-Lys (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 32 H 53 N9O 11 ;m / z:370.6998([M+2H] 2+ ), 740.39221([M+H] + ). 1H NMR(600MHz,D2O)δ4.43(q,J=7.1Hz,1H)4.33(dd,J=8.4,6.5Hz,1H)4.26(dd,J=8.4,5.8Hz,1H)4.22( dd,J=7.6,4.6Hz,1H)4.18-4.11(m,2H)4.01(dd,J=8.3,5.0Hz,1H)3.67(dt,J=10.0,6.7Hz,1H)3.61- 3.54(m,1H)3.53-3.44(m,2H)2.84(t,J=7.5Hz,2H)2.30(t,J=7.2Hz,2H)2.25(t,J=7.6Hz,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=10.4,7.1Hz,6H).

[0107] Compound 53:Glu-Ala-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O 11 ;m / z:371.7081([M+2H] 2+ ), 742.4089([M+H] + ). 1 H NMR(600MHz,D2O)δ4.23-4.18(m,3H)4.13-4.06(m,2H)3.95(dd,J=8.3,5.0Hz, 1H)3.85-3.82(m,1H)3.73-3.66(m,1H)3.53-3.47(m,1H)2.79(t,J=7.5Hz,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=6.7Hz,3H)0.76(d,J=6.7Hz,3H).

[0108] Compound 54:Glu-Pro-Val-Ala-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 32 H55 N9O 11 ;m / z:371.70767([M+2H] 2+ ), 742.40802([M+H] + ). 1 H NMR(600MHz, DMSO-d6+D2O)δ4.34(dd,J=8.3,6.0Hz,1H)4.15-4.05(m,4H)3.97-3.87(m,2H)3.51(d,J=9.8Hz,1H)3.46-3.38(m,1H)2.74(t,J=7.5H z,2H)2.23(t,J=7.1Hz,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=6.8Hz,6H).

[0109] Compound 55:Glu-Pro-Val-Pro-Glu-Ala-Lys (Hydrogen Hyalate) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 56 N8O 12 ;m / z:385.2083([M+2H] 2+ ), 769.4092([M+H] + ). 1 H NMR(600MHz,D2O)δ4.33(dd,J=8.3,6.5Hz,1H)4.21-4.16(m,3H)4.11(t,J=7.1Hz,1H)4. 07(dd,J=8.8,5.7Hz,1H)3.98(dd,J=8.5,4.8Hz,1H)3.71-3.66(m,1H)3.55-3.41(m,3H) 2.78(t,J=7.5Hz,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=15.4,7.5Hz,5H)0.80(dd,J=12.5,6.7Hz,6H).

[0110] Compound 56:Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 56 H 97 N 17 O 15 ;m / z:416.91827([M+3H] 3+ ), 624.87354([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.43(dd,J=9.3,4.9Hz,1H)4.38(dd,J=8.4,6.4Hz,1H)4.27-4.19(m,5H) 4.16-4.10(m,3H)3.88(d,J=6.2Hz,1H)3.74(dt,J=10.1,6.9Hz,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=10.1,6.8Hz,6H)0.74(dd,J=11.8,6.9Hz,6H).

[0111] Compound 57:Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 45 H 76 N 14 O 13 ;m / z:511.29254([M+2H] 2+ ). 1H NMR(600MHz,D2O)δ4.39(dd,J=8.6,5.5Hz,1H)4.32(dd,J=8.3,6.5Hz,1H)4.22-4.13(m,4H)4.10-4 .03(m,2H)3.93(dd,J=7.9,5.2Hz,1H)3.72-3.60(m,2H)3.54-3.40(m,4H)3.00(t,J=6.9Hz,2H)2.80 (t,J=7.5Hz,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=7.1Hz,3H)0.80(dd,J=10.4,6.7Hz,6H).

[0112] Compound 58:Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 39 H 64 N 10 O 12 ;m / z:433.24188([M+2H] 2+ ), 865.47662([M+H] + ). 1 H NMR(600MHz,D2O)δ4.41(dd,J=8.5,5.5Hz,1H)4.33(dd,J=8.3,6.5Hz,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=7.4Hz,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=7.0Hz,3H)0.80(dd,J=11.5,6.7Hz,6H).

[0113] Compound 59: Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 40 H69 N 13 O 10 ;m / z:298.18314([M+3H] 3+ ), 446.77118([M+2H] 2+ ), 892.53497([M+H] + ). 1 H NMR(600MHz,D2O)δ4.40(dd,J=8.6,5.5Hz,1H)4.30-4.19(m,4H)4.11-4.05(m,2H)3.93(dd, J=7.9,5.2Hz,1H)3.73-3.63(m,2H)3.52-3.45(m,2H)3.26-3.17(m,2H)3.01(t,J=6.9Hz,2H )2.81(t,J=7.5Hz,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=7.3Hz,3H)0.82(d,J=6.8Hz,3H)0.76(d,J=6.7Hz,3H).

[0114] Compound 60: Pro-Val-Pro-Gln-Ala-Lys-Pro (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O9;m / z:368.7207([M+2H] 2+ ), 736.4343([M+H] + ). 1H NMR(600MHz,D2O)δ4.46(dd,J=8.4,5.6Hz,1H)4.34(d,J=7.4Hz,1H)4.29(dd,J=8.5,6.2Hz,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,2 H)2.86(t,J=7.5Hz,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,19 H)1.61-1.52(m,3H)1.42-1.27(m,2H)1.23-1.20(m,3H)0.87(d,J=6.8Hz,3H)0.81(d,J=6.7Hz,3H).

[0115] Compound 61: D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.46-4.35(m,2H)4.27(dd,J=8.3,6.1Hz,1H)4.22-4.04(m,9 H)3.96(dd,J=8.4,4.8Hz,1H)3.90(d,J=7.7Hz,1H)3.84(t,J=6.6Hz,1H)3.74-3 .59(m,3H)3.56-3.38(m,3H)3.01(t,J=6.9Hz,2H)2.83-2.76(m,6H)2.23-2.06( m,9H)1.96-1.39(m,AcOH,48H)1.18(dd,J=22.0,7.2Hz,15H)0.83-0.67(m,12H).

[0116] Compound 62: Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ;m / z:412.4976([M+4H] 4+ ), 549.6608([M+3H] 3+ ). 1 H NMR(600MHz,D2O)δ4.50(dd,J=9.8,4.4Hz,1H)4.37(dd,J=9.4,4.9Hz,1H)4.25-4.03(m,10H)3.95( dd,J=8.5,4.8Hz,1H)3.89(d,J=7.7Hz,1H)3.83(t,J=6.6Hz,1H)3.74-3.68(m,1H)3.64-3.55(m,2H )3.52-3.38(m,2H)3.00(t,J=6.9Hz,2H)2.83-2.75(m,6H)2.20(t,J=7.6Hz,2H)2.12-2.06(m,6H)1 .92-1.41(m,AcOH,47H)1.32-1.13(m,15H)0.78(dd,J=9.7,6.7Hz,6H)0.73(dd,J=6.8,4.1Hz,6H).

[0117] Compound 63: Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.45(dd,J=9.4,4.4Hz,1H)4.37(dd,J=9.4,4.9Hz,1H)4.29-4.25(m, 1H)4.21-4.04(m,8H)3.96-3.94(m,1H)3.89(d,J=7.7Hz,1H)3.79(d,J=6.9Hz,1H)3.68-3 .59(m,2H)3.54-3.35(m,3H)3.00(t,J=6.9Hz,2H)2.82-2.74(m,6H)2.23-2.19(m,2H)2.1 5-2.02(m,6H)1.95-1.41(m,AcOH,48H)1.17(dd,J=21.6,7.2Hz,15H)0.83-0.64(m,12H).

[0118] Compound 64: Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.46(dd,J=10.2,3.9Hz,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=7.7Hz,1H)3.83(t,J=6.6Hz,1H)3.6 7-3.50(m,5H)3.47-3.25(m,2H)3.00(t,J=6.9Hz,2H)2.81-2.76(m,6H)2.23-2.06 (m,10H)1.94-1.41(m,AcOH,50H)1.17(dd,J=19.9,7.1Hz,17H)0.76-0.68(m,12H).

[0119] Compound 65: Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.42(dd,J=9.9,4.2Hz,1H)4.34(dd,J=9.2,5.2Hz,1H)4.31-4.23(m,2 H)4.22-4.18(m,2H)4.15-4.05(m,6H)3.94(dd,J=8.4,4.8Hz,1H)3.89(d,J=7.7Hz,1H)3. 82(t,J=6.7Hz,1H)3.65(d,J=6.8Hz,3H)3.57-3.36(m,3H)3.00(t,J=6.9Hz,2H)2.82-2.7 5(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).

[0120] Compound 66: Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.44-4.35(m,2H)4.26-4.04(m,10H)3.94(dd,J=8.5,4.8Hz,1H)3 .89(d,J=7.7Hz,1H)3.82(t,J=6.8Hz,1H)3.76-3.68(m,1H)3.64(d,J=8.7Hz,2H)3.55 -3.37(m,3H)3.00(t,J=6.9Hz,2H)2.83-2.75(m,6H)2.19-2.05(m,9H)2.02-1.38(m,A cOH,47H)1.34-1.15(m,15H)0.78(dd,J=11.2,6.7Hz,6H)0.73(dd,J=6.7,3.9Hz,6H).

[0121] Compound 67: Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.47-4.38(m,2H)4.26(dd,J=8.4,5.8Hz,1H)4.22-4.04(m,9H)3.9 5(dd,J=8.5,4.8Hz,1H)3.89(d,J=7.7Hz,1H)3.82(t,J=6.8Hz,1H)3.74-3.56(m,3H)3. 54-3.35(m,3H)3.00(t,J=6.9Hz,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=10.5,6.7Hz,6H)0.73(dd,J=6.8,3.9Hz,6H).

[0122] Compound 68: Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.47-4.40(m,2H)4.26(dd,J=8.4,5.9Hz,1H)4.23-4.15(m,3H)4.1 4-4.01(m,6H)3.95(dd,J=8.5,4.8Hz,1H)3.89(d,J=7.7Hz,1H)3.82(t,J=6.8Hz,1H)3. 71-3.44(m,5H)3.01(t,J=6.9Hz,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=12.5,6.7Hz,6H)0.73(dd,J=6.8,4.6Hz,6H).

[0123] Compound 69: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ;m / z:412.4976([M+4H] 4+ ), 549.6608([M+3H] 3+ ). 1H NMR(600MHz,D2O)δ4.42(dt,J=8.2,4.3Hz,2H)4.26(dd,J=8.4,5.9Hz,1H)4.23-4.14(m,3 H)4.14-4.05(m,6H)3.94(dd,J=8.5,4.8Hz,1H)3.89(d,J=7.7Hz,1H)3.81(q,J=7.7,7.2Hz ,1H)3.74-3.58(m,3H)3.55-3.38(m,3H)2.98(t,J=7.0Hz,2H)2.82-2.75(m,6H)2.23-2.0 5(m,9H)1.93-1.13(m,AcOH,62H)0.79(dd,J=13.2,6.7Hz,6H)0.73(dd,J=6.8,4.7Hz,6H).

[0124] Compound 70: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.45-4.36(m,2H)4.27-4.14(m,6H)4.12-4.05(m,4H)3.95(dd, J=8.4,4.8Hz,1H)3.90(d,J=7.7Hz,1H)3.82(t,J=6.8Hz,1H)3.66(dd,J=35.9,8.3 Hz,3H)3.55-3.39(m,3H)2.99(t,J=7.0Hz,2H)2.82-2.75(m,6H)2.23-2.07(m,9H) 1.93-1.15(m,AcOH,63H)0.79(dd,J=13.9,6.7Hz,6H)0.74(dd,J=6.8,2.0Hz,6H).

[0125] Compound 71: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.45-4.36(m,2H)4.26(dd,J=8.4,5.8Hz,1H)4.22-4.16(m,3H)4.12 -4.05(m,6H)3.96-3.91(m,2H)3.82(t,J=6.8Hz,1H)3.73-3.58(m,3H)3.54-3.36(m,3H )3.00(t,J=7.0Hz,2H)2.82-2.75(m,6H)2.22-2.06(m,9H)1.93-1.41(m,AcOH,45H)1.3 2-1.14(m,15H)0.79(dd,J=13.8,6.7Hz,6H)0.74(d,J=6.8Hz,3H)0.70(d,J=6.8Hz,3H).

[0126] Compound 72: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR (600MHz, D2O) δ4.45-4.35(m,2H)4.26(dd,J=8.4,5.9Hz,1H)4.21-4.05(m,9H)3.94-3. 88(m,2H)3.82(t,J=6.8Hz,1H)3.73-3.57(m,3H)3.55-3.37(m,3H)2.99( t,J=6.8Hz,2H)2.82-2.75(m,6H)2.23-2.06(m,9H)1.96-1.36(m,AcOH,5 0H)1.32-1.14(m,15H)0.78(dd,J=13.9,6.7Hz,6H)0.73(d,J=6.7Hz,6H).

[0127] Compound 73: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.48(dd,J=9.7,4.3Hz,1H)4.43(dd,J=9.3,4.9Hz,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=9.2,4.6Hz,1H)3.89-3 .85(m,2H)3.76-3.66(m,3H)3.59-3.45(m,3H)3.05(t,J=6.9Hz,2H)2.87-2.81(m,6H)2.26(t, J=7.7Hz,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).

[0128] Compound 74: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.48(dd,J=9.6,4.3Hz,1H)4.44(dd,J=9.3,4.9Hz,1H)4.32(dd,J=8.4,5.8Hz,1H )4.28-4.17(m,5H)4.17-4.09(m,4H)4.05(dd,J=9.1,4.7Hz,1H)3.95(d,J=7.7Hz,1H)3.88(t,J=6.8H z,1H)3.78-3.63(m,3H)3.60-3.37(m,3H)3.06(t,J=6.9Hz,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=14.0,6.7Hz,6H)0.78(dd,J=14.3,6.8Hz,6H).

[0129] Compound 75: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.49-4.42(m,2H)4.32(dd,J=8.4,5.8Hz,1H)4.27-4.10(m,9H)4.04(dd ,J=8.4,4.6Hz,1H)3.96(d,J=7.4Hz,1H)3.90-3.84(m,1H)3.73(d,J=7.7Hz,1H)3.71-3.64( m,2H)3.60-3.32(m,3H)3.06(t,J=6.9Hz,2H)2.89-2.79(m,6H)2.28-2.06(m,9H)1.99-1.4 7(m,AcOH,44H)1.39-1.18(m,15H)0.84(dd,J=13.9,6.7Hz,6H)0.78(dd,J=6.8,3.3Hz,6H).

[0130] Compound 76:Glu-Gly-Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ;m / z:364.7022([M+2H] 2+ ), 728.3929([M+H] + ). 1 H NMR(600MHz,D2O)δ4.30(d,J=7.8Hz,1H)4.26(dd,J=8.2,6.7Hz,1H)4.19-4.11(m,2H)4.02(dd ,J=8.3,5.0Hz,1H)3.95(t,J=6.5Hz,1H)3.91-3.82(m,2H)3.78-3.72(m,1H)3.58-3.51(m,1H) 2.84(t,J=7.5Hz,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=7.5,4.7Hz,5H)0.84(d,J=6.8Hz,3H)0.80(d,J=6.7Hz,3H).

[0131] Compound 77:Glu-Pro-Val-Gly-Gln-Ala-Lys (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C31 H 53 N9O 11 ;m / z:364.7004([M+2H] 2+ ), 728.3932([M+H] + ). 1 H NMR(600MHz,D2O)δ4.40(dd,J=8.3,6.5Hz,1H)4.23(dd,J=7.7,4.4Hz,1H)4.20-4.15(m, 2H)4.01(dd,J=8.3,5.1Hz,1H)3.95(d,J=7.4Hz,1H)3.83-3.76(m,2H)3.63-3.55(m,1H)3 .50-3.45(m,1H)2.85(t,J=7.5Hz,2H)2.32(t,J=7.2Hz,2H)2.23-2.15(m,3H)2.05-1.67 (m,AcOH,12H)1.59-1.50(m,3H)1.26(dd,J=9.7,7.5Hz,5H)0.84(dd,J=14.3,6.8Hz,6H).

[0132] Compound 78: D-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ;m / z:384.716([M+2H] 2+ ), 768.4245([M+H] + ). 1 H NMR(600MHz,D2O)δ4.36(dd,J=8.8,4.3Hz,1H)4.29-4.21(m,3H)4.18-4.11 (m,2H)4.01(dd,J=8.2,5.1Hz,1H)3.78-3.72(m,1H)3.63-3.49(m,3H)2.84( t,J=7.5Hz,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=11.6,7.4Hz,5H)0.85(dd,J=15.5,6.8Hz,6H).

[0133] Compound 79:Glu-D-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ;m / z:384.7159([M+2H] 2+ ), 768.4244([M+H] + ). 1 H NMR(600MHz,D2O)δ4.36(dd,J=8.8,3.9Hz,1H)4.33(d,J=8.1Hz,1H)4.28(dd,J=8.3 ,6.6Hz,1H)4.23(dd,J=7.1,5.1Hz,1H)4.19-4.13(m,2H)4.02(dd,J=8.2,5.1Hz,1H )3.76-3.68(m,1H)3.61-3.51(m,3H)2.84(t,J=7.5Hz,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=22.8,6.7Hz,6H).

[0134] Compound 80:Glu-Pro-D-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ;m / z:384.7158([M+2H] 2+ ), 768.4241([M+H] + ). 1H NMR(600MHz,D2O)δ4.46(d,J=7.3Hz,1H)4.36(dd,J=8.3,6.6Hz,1H)4.30-4.20(m,3H)4 .17(dd,J=8.1,6.1Hz,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=7.5Hz,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=15.0,6.7Hz,6H).

[0135] Compound 81:Glu-Pro-Val-D-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ;m / z:384.7157([M+2H] 2+ ), 768.4240([M+H] + ). 1 H NMR(600MHz,D2O)δ4.43-4.30(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=7.5Hz,2H) 2.33(t,J=7.2Hz,2H)2.23-2.11(m,4H)2.07-1.74(m,AcOH,14H)1.73-1.6 4(m,2H)1.58-1.50(m,3H)1.29-1.23(m,5H)0.81(dd,J=15.1,6.7Hz,6H).

[0136] Compound 82:Glu-Pro-Val-Pro-D-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ;m / z:384.7158([M+2H] 2+), 768.4242([M+H] + ). 1 H NMR(600MHz,D2O)δ4.38(dd,J=8.3,6.4Hz,1H)4.27-4.14(m,5H)4.03(dd,J=8.4,5.0Hz,1H)3.80-3.75(m,1H)3.62-3.45(m,3H)2.85(t, J=7.5Hz,2H)2.32(t,J=7.3Hz,2H)2.24-2.12(m,4H)2.09-1.67(m,AcOH,15H)1.60-1.50(m,3H)1.28(d,J=7.3Hz,5H)0.88-0.80(m,6H).

[0137] Compound 83:Glu-Pro-Val-Pro-Gln-D-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ;m / z:384.7159([M+2H] 2+ ), 768.4243([M+H] + ). 1 H NMR(600MHz,D2O)δ4.38(dd,J=8.3,6.4Hz,1H)4.28-4.20(m,3H)4.19-4.12(m,2H) 4.05(dd,J=8.6,5.0Hz,1H)3.77-3.72(m,1H)3.60-3.45(m,3H)2.85-2.80(m,2H)2. 32(t,J=7.2Hz,2H)2.26(t,J=8.0Hz,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=13.0,6.7Hz,6H).

[0138] Compound 84:Glu-Pro-Val-Pro-Gln-Ala-D-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11;m / z:384.7160([M+2H] 2+ ), 768.4246([M+H] + ). 1 H NMR(600MHz,D2O)δ4.39(dd,J=8.3,6.4Hz,1H)4.30-4.20(m,3H)4.19-4.11(m,2H) 4.05(dd,J=8.3,4.8Hz,1H)3.79-3.71(m,1H)3.61-3.47(m,3H)2.86-2.81(m,2H)2. 32(t,J=7.2Hz,2H)2.27(t,J=7.5Hz,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=12.5,6.7Hz,6H).

[0139] Compound 85: Lys-Glu-Pro-Val-Pro (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 26 H 44 N6O8; m / z: 454.2655 ([M+2H] 2+ ), 569.3287([M+H] + ). 1 H NMR(600MHz,D2O)δ4.50(dd,J=9.9,4.2Hz,1H)4.36-4.22(m,3H)4.09(dd,J=8 .5,5.8Hz,1H)3.89(t,J=6.7Hz,1H)3.70-3.65(m,2H)3.60-3.53(m,2H)3.51- 3.26(m,1H)2.87(d,J=7.5Hz,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=6.8Hz,3H)0.82(d,J=6.7Hz,3H).

[0140] Compound 86: Glu-Pro-Val-Pro-Gln (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 25 H40 N6O9;m / z:569.2919([M+H] + ). 1 H NMR(600MHz,D2O)δ4.40(dd,J=8.3,6.4Hz,1H)4.31-4.23(m,3H)4.09(dd,J=9.0,4.8Hz,1H)3.78-3.72(m,1H)3 .61-3.48(m,3H)2.41(t,J=7.3Hz,2H)2.25-2.14(m,4H)2.09-1.70(m,AcOH,13H)0.86(dd,J=15.3,6.7Hz,6H).

[0141] Compound 87: Lys-Glu-Pro-Val-Pro-Gln (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 31 H 52 N8O 10 ;m / z:349.1971([M+2H] 2+ ), 697.3868([M+H] + ). 1 H NMR(600MHz,D2O)δ4.51(dd,J=9.8,4.3Hz,1H)4.34-4.25(m,3H)4.03(dd,J=8.8,4.7Hz,1H)3.89(t,J=6.7Hz,1H)3.79-3.65(m,2H)3.63-3.52(m,2 H)2.86(t,J=7.5Hz,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=6.8Hz,3H)0.83(d,J=6.6Hz,3H).

[0142] Compound 88: Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 92 H 152 N 26 O 24 ;m / z:502.2934([M+4H]4+ ), 669.3699([M+3H] 3+ ). 1 H NMR(600MHz,D2O)δ6.97-6.94(m,2H)6.70-6.66(m,2H)4.44(dd,J=9.4,4.8Hz,1H)4.35-4.08(m,17H)4.05-4.00 (m,2H)3.96(d,J=7.6Hz,1H)3.76-3.67(m,3H)3.64-3.53(m,3H)3.48(dd,J=10.2,6.3Hz,3H)3.07(t,J=6.9Hz,2 H)2.94(dd,J=13.6,6.6Hz,1H)2.88-2.79(m,7H)2.76(dd,J=13.6,9.2Hz,1H)2.27(t,J=7.6Hz,2H)2.21(t,J=7. 6Hz,2H)2.18-2.08(m,8H)2.01-1.45(m,AcOH,59H)1.30-1.10(m,16H)0.95(d,J=6.9Hz,3H)0.87-0.77(m,18H).

[0143] Compound 89: pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen hydroxide) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.47-4.42(m,2H)4.32-4.10(m,13H)4.02(dd,J=8.4,4.8Hz,1H)3. 96(d,J=7.6Hz,1H)3.82-3.60(m,3H)3.58-3.45(m,3H)3.07(t,J=6.9Hz,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=12.5,6.8Hz,6H)0.81-0.77(m,9H)0.75(d,J=6.0Hz,3H).

[0144] Compound 90: Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ6.99-6.92(m,2H)6.71-6.64(m,2H)4.47-4.42(m,1H)4.36(t,J =7.8Hz,1H)4.32-4.06(m,15H)4.04-3.99(m,1H)3.96(d,J=7.6Hz,1H)3.79-3.65( m,3H)3.60-3.46(m,3H)3.30-3.22(m,2H)3.07(t,J=6.9Hz,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).

[0145] Compound 91: Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen hydroxide) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ6.96(d,J=8.5Hz,2H)6.70-6.64(m,2H)4.50-4.43(m,2H)4.38(t,J=8.0Hz,1H)4.30-4.11 (m,13H)4.02(dd,J=8.4,4.9Hz,1H)3.96(d,J=7.6Hz,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=15.9,5.3Hz,1H)2.42(dd,J=16.0,8.5Hz,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=6.7Hz,6H).

[0146] Compound 92: Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ6.96(d,J=8.6Hz,2H)6.67(d,J=8.5Hz,2H)4.49(dd,J=8.4,5.3Hz,1H)4.38(t,J=8.0Hz,1H)4.31-4.2 3(m,5H)4.19-4.10(m,3H)4.01(dd,J=8.2,5.1Hz,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=16.0,5.3Hz,1H)2.42(dd,J=15.9,8.5Hz,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=11.1,7.4Hz,10H)0.83(dd,J=19.0,6.7Hz,6H)0.72(d,J=5.6Hz,6H).

[0147] Compound 93: Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 64 H 104 N 18 O 19 ;m / z:715.3917([M+2H] 2+ ). 1H NMR(600MHz,D2O)δ6.96(d,J=8.6Hz,2H)6.66(d,J=8.5Hz,2H)4.48-4.42(m,3H)4.26-4.12(m,6H)4.02(dd,J=8.2, 5.0Hz,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=16.0,5.1Hz,1H)2.45(dd,J=16.0,8.4Hz,1H)2.27(t,J=7.6Hz,2H)2.17-2.08(m,4H)1.98-1.66(m, AcOH,27H)1.65-1.45(m,9H)1.26(dd,J=11.3,7.4Hz,7H)0.84(dd,J=13.0,6.7Hz,6H)0.70(dd,J=6.8,2.8Hz,6H).

[0148] Compound 94: Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (hydrogen acid) High energy dissolution mass analysis (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] + ). 1H NMR(600MHz,D2O)δ4.45(dd,J=8.9,4.8Hz,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=10.1,6.4Hz,1H)3.69-3.63(m,1H)3.60-3.43(m,2H)3.09-3.05(m,2H)2.95(dd,J=1 4.3,5.2Hz,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,A cOH,29H)1.32-1.23(m,2H)0.90-0.81(m,6H)0.75(dd,J=10.3,6.8Hz,2H)0.67(dd,J=17.1,6.7Hz,4H).

[0149] Compound 95: Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ7.22(t,J=7.4Hz,2H)7.16(t,J=7.3Hz,1H)7.12-7.07(m,2H)4.47-4.41(m,3H)4.35-4. 03(m,19H)4.02(dd,J=8.4,4.8Hz,1H)3.95(d,J=3.6Hz,1H)3.86(s,1H)3.75(s,1H)3.68(t,J=8.5Hz,2H)3 .58-3.42(m,5H)3.06(t,J=6.9Hz,4H)2.91-2.81(m,7H)2.29-2.11(m,12H)2.00-1.19(m,AcOH,80H)1.14( d,J=7.1Hz,3H)1.06(d,J=6.3Hz,3H)0.84(dd,J=13.7,6.7Hz,6H)0.81-0.76(m,9H)0.72(d,J=5.6Hz,3H).

[0150] Compound 96: Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 74 H 118 N 20 O 22 ;m / z:547.2972([M+3H] 3+ ), 820.4424([M+2H] 2+ ). 1H NMR(600MHz,D2O)δ7.21(dd,J=8.2,6.6Hz,2H)7.16(t,J=7.3Hz,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=16.5Hz,1H)3.84(d,J=16.5Hz,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. 9,7.4Hz,5H)1.14(d,J=7.2Hz,3H)1.05(d,J=6.4Hz,3H)0.84(dd,J=15.5,6.7Hz,6H)0.77(d,J=5.9Hz,3H)0.72(d,J=5.7Hz,3H).

[0151] Compound 97:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen hydroxide) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.48-4.41(m,3H)4.34(t,J=5.4Hz,1H)4.31(dd,J=8.4,5.8Hz,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=6.9Hz,2H)2.90-2.80(m,8H)2.58(dd,J=16.0,6.3Hz,1H)2.48(dd,J=16.0,7.9Hz,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).

[0152] Compound 98:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ;m / z:519.5973([M+3H] 3+ ), 778.8925([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.54-4.47(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=7.6Hz,4H) 2.63(dd,J=16.2,6.2Hz,1H)2.51(dd,J=16.2,7.9Hz,1H)2.37-2.06(m,11H)1.99-1.49(m,A cOH,30H)1.34-1.24(m,8H)1.10-1.01(m,1H)0.84(dd,J=13.8,6.7Hz,6H)0.77-0.71(m,6H).

[0153] Compound 99:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 52 H 85 N 13 O 21 ;m / z:614.806([M+2H] 2+ ), 1228.605([M+H] + ). 1 H NMR(600MHz,D2O)δ4.54-4.48(m,2H)4.36(t,J=5.5Hz,1H)4.34-4.24(m,3H)4.23-4.18(m,2H)4.12 -4.05(m,2H)4.01(d,J=7.9Hz,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=7.6Hz,2H)2.65(dd,J=16.3,6.0Hz,1H)2.53(dd,J=16.4,8.0Hz,1H)2.40-2.03(m,9 H)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).

[0154] Compound 100: Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.49-4.42(m,2H)4.34-4.06(m,13H)4.05-4.00(m,2H)3.96(d ,J=7.6Hz,1H)3.80-3.73(m,1H)3.69(d,J=9.8Hz,4H)3.58-3.45(m,5H)3.07(t,J= 6.9Hz,2H)2.88-2.83(m,6H)2.27(t,J=7.7Hz,3H)2.20-2.11(m,9H)2.01-1.45(m, AcOH,55H)1.24(dd,J=21.5,7.2Hz,16H)0.97(d,J=6.9Hz,3H)0.88-0.78(m,15H).

[0155] Compound 101:Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (hydrogen chloride) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ;m / z:519.5978([M+3H] 3+ ), 778.8933([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ4.50(dd,J=8.0,6.0Hz,1H)4.40(dd,J=8.4,6.4Hz,1H)4.36-4.30(m,2H)4.27-4.19(m,6H) 4.18-4.11(m,2H)4.08(dd,J=8.8,4.9Hz,1H)4.01(d,J=8.1Hz,1H)3.82-3.71(m,5H)3.62-3.47(m,3H)2.86(t ,J=7.5Hz,4H)2.65(dd,J=16.4,6.0Hz,1H)2.51(dd,J=16.3,8.1Hz,1H)2.34(t,J=7.2Hz,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=11.5,6.7Hz,6H)0.76-0.70(m,6H).

[0156] Compound 102 Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (hyaluronate) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 53 H 82 N 12 O 15 ;m / z:564.3073([M+2H] 2+ ). 1 H NMR(600MHz,D2O)δ7.01-6.95(m,2H)6.69(d,J=8.5Hz,2H)4.40(dd,J=8.3,6.4H z,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=7.3Hz,2H)2.26(t,J=7.7Hz,2H)2.20-2.13(m,2H)2.06-1.52(m,AcOH,2 5H)1.33-1.21(m,5H)0.86(dd,J=11.3,6.7Hz,6H)0.77(dd,J=17.6,6.7Hz,6H).

[0157] Compound 103: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (hydrogen acid) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 73 H 126 N 22 O 21 ;m / z:824.4799([M+2H] 2+ ). 1H NMR(600MHz,D2O)δ4.49(dd,J=9.6,4.4Hz,1H)4.45(dd,J=9.4,4.9Hz,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=7.0Hz,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=14.2,6.7Hz,6H)0.80(dd,J=6.7,3.7Hz,6H).

[0158] Compound 104: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.49(dd,J=9.7,4.4Hz,1H)4.45(dd,J=9.4,4.8Hz,1H)4.34-4.10(m,11H)3. 96(d,J=7.6Hz,1H)3.92-3.84(m,1H)3.78-3.66(m,3H)3.62-3.43(m,3H)3.07(t,J=6.9Hz,2H)2. 90-2.82(m,6H)2.63(dd,J=15.1,4.9Hz,1H)2.53(dd,J=15.1,8.1Hz,1H)2.30-2.11(m,7H)2.03 -1.42(m,AcOH,44H)1.39-1.19(m,15H)0.85(dd,J=14.0,6.7Hz,6H)0.80(dd,J=6.8,3.0Hz,6H).

[0159] Compound 105: Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1 H NMR(600MHz,D2O)δ4.53(dd,J=9.0,5.0Hz,1H)4.44(dd,J=9.4,4.8Hz,1H)4.34(dd,J=8.4,6.0Hz,1H)4.3 0-4.23(m,3H)4.22-4.11(m,6H)4.02(dd,J=8.4,4.8Hz,1H)3.96(d,J=7.6Hz,1H)3.90(t,J=6.7Hz,1H)3. 80-3.63(m,3H)3.60-3.42(m,3H)3.07(t,J=6.9Hz,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=15.5,6.7Hz,6H)0.80(dd,J=6.8,4.3Hz,6H).

[0160] Compound 106: Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (hydrogen acid) High energy dissolution mass analysis (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+ ). 1H NMR(600MHz,D2O)δ4.50(dd,J=9.6,4.4Hz,1H)4.45(dd,J=9.3,4.9Hz,1H)4.36-4.22(m,4H)4.22-4. 10(m,6H)4.02(dd,J=8.4,4.9Hz,1H)3.96(d,J=7.6Hz,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=6.9Hz,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=6.8Hz,3H)0.80(dd,J=6.8,4.3Hz,6H)0.75(t,J=7.4Hz,3H).

[0161] Compound 107: Val-Pro-Gln-Ala (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.2341 ([M+1H]) + ). 1 H NMR(600MHz,D2O)δ4.29(t,J=7.6Hz,1H)4.07(dd,J=8.5,6.1Hz,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=7.3Hz,3H)0.91(d,J=7.0Hz,3H)0.80(d,J=6.8Hz,3H).

[0162] Compound 108: Val-Pro-Gln-Ala-Lys (hydrogen hydroxide) High energy dissolution mass analysis (Orbitrap-HRMS), molecular formula: C 24 H 43 N7O7;m / z:271.6681([M+2H]2+), 542.3289([M+1H] + ). 1H NMR(600MHz,D2O)δ4.28(t,J=7.6Hz,1H)4.13-4.06(m,2H)3.99(d,J=5.5Hz,1H )3.94(dd,J=8.2,5.1Hz,1H)3.60-3.54(m,1H)3.46-3.41(m,1H)2.78(t,J=7.5H z,2H)2.21(t,J=7.6Hz,2H)2.17-2.09(m,2H)1.93-1.58(m,AcOH,11H)1.53-1.4 4(m,3H)1.20(dd,J=9.7,7.5Hz,5H)0.91(d,J=6.9Hz,3H)0.80(d,J=6.9Hz,3H).

[0163] Example 2: Experiment showing that polypeptide compounds have a mitigating effect on colitis Experimental animals: Wild-type AB zebrafish, bred by natural pair mating, were 3 days post-fertilization (dpf). All zebrafish were maintained at 28°C in fish culture water (water quality: 1 L of reverse osmosis water supplemented with 200 mg of instant sea salt, conductivity 450-550 μS / cm, pH 6.5-8.5, hardness 50-100 mg / L CaCO3). Laboratory Animal Use Permit Number: SYXK (Zhejiang) 2012-0171. Animal husbandry practices met the requirements of the international AAALAC certification (certificate number: 001458).

[0164] Experimental Method: (1) Grouping: Polypeptide group: A 20.0 mg / mL mother solution was prepared with ultrapure water and stored at -20°C. Positive control group: prednisone, white powder, lot number C10016501, Shanghai McLean Biotechnology Co., Ltd., stored at 4°C, and a 15.0 mg / mL mother solution was prepared with DMSO and stored in aliquots at -20°C. Normal control group and model control group. (2) Experimental Method: Three-day-old wild-type AB zebrafish were randomly placed in six-well plates, with 30 zebrafish per well (experimental group). Except for the normal control group, all other experimental groups were treated with water-soluble TNBS to establish a zebrafish intestinal mucosal injury model. After two days of treatment at 28°C, TNBS was removed, and a water-soluble polypeptide compound (concentration: see Table 4) and a positive control, prednisone 15.0 μg / mL, were added. At the same time, a normal control group (healthy group) and a model control group (intestinal mucosal injury group) were established, with each well (experimental group) containing 3 mL of water. After two days of treatment at 28°C, 10 zebrafish were randomly selected from each experimental group and photographed under a dissecting microscope. Data were collected and analyzed using NIS-Elements D3.20 advanced image processing software. The intestinal lumen area of ​​the zebrafish was analyzed, and the statistical analysis of this index was used to evaluate the effect of the sample on alleviating colitis. Statistical analysis was performed using SPSS 26.0 software, and p<0.05 indicated a statistically significant difference. Experimental results: The results shown in Table 4 indicate that the polypeptide compound has an alleviating effect on colitis.

[0165] JPEG0007811806000009.jpg135142

[0166] Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001. As can be seen from the data in Table 4, the polypeptide compound group, including compounds 1, 4, 5, 6, 12, and 15, showed significant statistical differences (p<0.05, p<0.01, p<0.001) compared to the model control group, and their effects were superior to those of the prednisone group. The experimental results showed that the polypeptide compounds provided by the present application have an alleviating effect on colitis, specifically manifested as a significant alleviation of intestinal distension.

[0167] In this experimental system, the test compounds were administered at concentrations of 250 μg / mL, 500 μg / mL, and 1000 μg / mL. Analysis of the intestinal area of ​​each group revealed that the majority of test compounds exhibited a significant alleviating effect on colitis at 1000 μg / mL (p<0.05, p<0.01, p<0.001). However, increasing concentrations of test compounds resulted in the death of zebrafish within each group. Therefore, in subsequent activity evaluations, each test compound was administered at a uniform concentration of 1000 μg / mL. The results are summarized in Table 5.

[0168] JPEG0007811806000010.jpg198151

[0169] NOTE: The efficacy of each compound in alleviating the intestinal distension activity of zebrafish colitis was tested in multiple batches. For ease of comparison, the anti-intestinal distension activity was compared to the control group of the same batch of experimental model. *p<0.05, **p<0.01, ***p<0.001. ND indicates not tested, "-" indicates no activity, "+" indicates a certain intestinal distension alleviation effect, "#" indicates all zebrafish died during the experiment, and "&" indicates 13 zebrafish died during the experiment.

[0170] As can be seen from the data in Tables 4 and 5, the polypeptide group showed significant statistical differences (p<0.05, p<0.01 or p<0.001) compared with the model control group, and the effect was superior to that of the prednisone group. Under these 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, and 103-106 all had significant alleviating effects on colitis, specifically intestinal inflammation. This was manifested as a reduction in intestinal distension (p<0.05), and 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 a certain effect of reducing intestinal distension.

[0171] Example 3: Evaluation of the therapeutic effect of polypeptide compounds on TNBS-induced acute inflammatory bowel disease (UC) model in SD rats Objective: To evaluate the therapeutic effects of polypeptide compounds on TNBS-induced acute inflammatory bowel disease model in SD rats.

[0172] Materials and Methods: In this study, a rat ulcerative colitis model was established in male SD rats using a single enema of trinitrobenzene sulfonic acid (TNBS). TNBS-induced acute colitis in rats is a cytokine-driven immune response mediated by Th1 cells. The control animals showed significant colon atrophy and thickening of the intestinal wall, a marked increase in colon weight-to-length ratio, fissure-like ulcerative lesions on the surface of the intestinal wall mucosa, typical granulomas in the submucosa and muscularis, and an infiltration of inflammatory cells, primarily lymphocytes and plasma cells, along with the presence of small blood vessels and fibroblastic tissue proliferation. Crypt structural destruction and bleeding were observed around the ulcerative lesions. This model is easy to prepare, has good reproducibility, and is widely used in the evaluation of therapeutic agents for inflammatory bowel disease. On the first day of the experiment, experimental animals (male SD rats) were randomly divided into six groups, each with 10 animals per group, according to body weight parameters, including a normal control group, a model control group, a positive drug mesalazine treatment group, a low-dose compound 1 treatment group, a high-dose compound 1 treatment group, a low-dose compound 6 treatment group, a high-dose compound 6 treatment group, and a compound 12 treatment group. On the day of grouping (D0), except for the normal control group, which was administered with the vehicle, all animals in each experimental group were administered an enema of TNBS ethanol solution for model induction, and treatment with the test article and positive control drug began the day after model induction.The therapeutic doses of Compound 1 were 3.0 mg / kg and 6.0 mg / kg, Compound 6 1.4 mg / kg and 2.8 mg / kg, Compound 12 0.8 mg / kg, and the positive control drug mesalazine 30.0 mg / kg. All were administered by enema once daily for 14 consecutive days. During the experimental treatment period (D1 to D14), the body weight and general clinical observation indicators (eating, drinking, activity level, defecation, etc.) of the animals in each experimental group were recorded. The colonic adhesions, colonic ulcers, and macroscopic damage of inflammation in each experimental group were observed and scored according to the colonic morphology and morphology scoring criteria. Animals in each experimental group were simultaneously scored for weight loss, fecal morphology, and fecal bloodiness after TNBS induction, based on the ulcerative colitis disease activity scoring criteria. Ulcerative colitis disease activity (DAI) was calculated daily for 14 consecutive days. At the end of the experiment, colonic tissues were collected from animals in each experimental group, their length measured, and weighed. Non-necropsy images were then collected. The intestinal wall was then incised longitudinally, and necropsy images were collected. Macroscopic colonic adhesions, colonic ulcers, and inflammatory damage were observed and scored according to the colonic macroscopic morphological morphology scoring criteria. Images of the ulcers were collected under a stereomicroscope, and the area of ​​the colonic ulcer lesions was calculated. Following routine fixation, the therapeutic effects of the test polypeptide compounds in the ulcerative colitis model were evaluated based on the statistical analysis of various pharmacodynamic parameters.

[0173] Results and conclusions: In this experimental research system, animals in the model control group showed clear disease characteristics of ulcerative colitis, including inhibited weight gain, loose and diluted stools, a significant increase in the DAI score for ulcerative colitis disease activity, macroscopically observable colonic atrophy, and typical ulcer lesions and confluent colonic ulcer lesions. Test compound 1 had a clear improving effect on the inhibited weight gain of the model animals under the established treatment regimen, and the degree of improvement was statistically different (P<0.05) from the degree of change in animal weight of the model control group over the same period, while test compounds 6 and 12 showed no clear improvement in the therapeutic effect of inhibiting weight gain in the model animals.

[0174] JPEG0007811806000011.jpg107162

[0175] NOTE: All data were analyzed statistically using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 represents the statistical analysis results of the model control group and the normal control group; # P<0.05, ## P<0.01 represents the result of statistical analysis of the test polypeptide compound-treated animals and the model control group.

[0176] The DAI scoring results for the experimental period showed that test compounds 1, 6, and 12 had a significant ameliorative effect on the progression of ulcerative colitis disease in the model animals under the established treatment regimen. The fecal lesion characteristics and weight loss response of the animals in the corresponding treatment groups were all significantly alleviated, and the average DAI scores all decreased, with significant statistical differences (P<0.05) compared with the model control group over the same period. The improvement in the therapeutic effect of compound 1 was most obvious, and the therapeutic effects of compounds 1 and 6 were clearly dose-dependent.

[0177] JPEG0007811806000012.jpg71166

[0178] NOTE: All data were analyzed statistically using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 represents the statistical analysis results of the model control group and the normal control group; # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 represents the statistical analysis result of the test polypeptide compound-treated animals and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++P<0.0001 represents the statistical analysis result between compound 1 or 6 dose groups.

[0179] The results of gross dissection and scoring of colonic tissue damage at the end of the experiment showed that test compounds 1, 6 and 12 had obvious therapeutic effects on TNBS-induced colonic macroscopic damage (colonic adhesions, ulcers and inflammation), the abnormal increase in the area of ​​colonic ulcer lesions and the colonic weight / length ratio, and the degree of improvement was statistically different (P<0.05) compared with the model control group over the same period. Compound 1 had the most obvious therapeutic effect, and at the same time, the therapeutic effect was clearly dose-dependent.

[0180] JPEG0007811806000013.jpg65166

[0181] NOTE: All data were analyzed statistically using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 represents the statistical analysis results of the model control group and the normal control group; # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 represents the statistical analysis result of the test polypeptide compound-treated animals and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++ P<0.0001 represents the statistical analysis result between compound 1 or 6 dose groups.

[0182] JPEG0007811806000014.jpg68170

[0183] NOTE: All data were analyzed statistically using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, ****P<0.0001 represents the statistical analysis results of the model control group and the normal control group; # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 represents the statistical analysis result of the test polypeptide compound-treated animals and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++ P<0.0001 represents the statistical analysis result between compound 1 or 6 dose groups.

[0184] In this study, TNBS was administered via enema to male SD rats to induce colonic lesions and establish an ulcerative colitis model with clinical characteristics. Treatment with test compounds 1, 6, and 12 and the positive control drug mesalazine began the day after model induction. During the treatment cycle (D1-D14), changes in animal weight, ulcerative colitis disease activity (DAI), gross colonic damage (colonic adhesions, ulcers, and inflammatory responses), colonic tissue ulcer area, and colon weight / length ratio were monitored to evaluate the therapeutic effects of the test products on the TNBS-induced SD rat ulcerative colitis model. The following findings were obtained:

[0185] 1) After TNBS induction, the experimental animals showed obvious ulcerative colitis disease, including significant weight loss, significant increases in ulcerative colitis disease activity scores (DAI scores), significant increases in colonic adhesion and ulcer scores, increases in the ulcer area of ​​colonic tissue, and significant increases in the colon weight / length ratio. This suggests that the rat ulcerative colitis model was successfully established and is suitable for pharmacodynamic studies in this experiment. 2) Test compound 1 had a clear improvement effect on weight loss in model animals under the established treatment regimen, and the degree of improvement was statistically different (P<0.05) compared with the model control group over the same period, while test compounds 6, 12 and the positive control drug mesalazine did not show any clear improvement effect on weight loss. 3) Test compounds 1, 6, and 12 had obvious ameliorative effects on the ulcerative colitis disease process in model animals under the established treatment regimen, and the DAI scores all showed a significant decrease compared to the model control group over the same period. The therapeutic effect of test compound 1 was the most obvious. At the same time, the ameliorative and therapeutic effects of test compounds 1 and 6 were clearly dose-dependent, while the positive control drug mesalazine had no obvious effect on the ulcerative colitis disease symptoms in model animals.

[0186] 4) Test compounds 1, 6 and 12 had obvious therapeutic effects on the macroscopic damage manifestations of the colon of model animals under the established treatment regimen. Compared with the model control group over the same period, the colon adhesion scores, colon ulcer and inflammation scores, and the area of ​​ulcer lesions in the colon tissue were all significantly reduced, and the degree of improvement was statistically significant (P<0.05). Test compound 1 had the most obvious therapeutic effect, and the improvement and therapeutic effect were clearly dose-dependent. 5) Test compounds 1, 6 and 12 had obvious ameliorative effects on the colon atrophy process of model animals under the established treatment regimen, and the colon weight / length ratio was significantly reduced compared with the model control group during the same period (P<0.05). This study established a rat ulcerative colitis model that met the clinical onset characteristics, and the results of efficacy evaluation in this model showed that test compounds 1, 6 and 12 all had significant therapeutic effects.

[0187] Example 4: Study of the effect of polypeptide compounds on the in vitro proliferation of CaCo-2 cells The following cell lines were used to study the in vitro propagation of polypeptide compounds:

[0188] JPEG0007811806000015.jpg23145

[0189] Experimental Method: The cells were resuscitated and maintained according to the culture conditions shown in Table 10. Day 1 (cell seeding): Cells in the logarithmic growth phase were harvested and resuspended, then counted using a cell counter to detect activity. The cell suspension was diluted according to the seeding density requirements, and 90 μL of cell suspension was added to each well of a 96-well plate (cell seeding density was adjusted based on historical data or density optimization experiments). At the same time, each cell was seeded into three parallel wells as the TO plate. All 96-well plates were placed in a 37°C, 5% CO2 incubator overnight.

[0190] Day 2 (liquid exchange): According to the plate map, the medium was replaced with 90 μL per well according to the serum concentration. Day 2: The TO plate was read and treated with the compounds to be measured. 10 μL of medium was added to each well of the TO plate to bring the total volume to 100 μL. 50 μL of CellTiter-Glo® reagent was added to each well. The wells were mixed and shaken for 5 minutes to fully lyse the cells. The luminescence signal was then incubated at room temperature for 10 minutes to stabilize (Note: Temperature, cell density, and edge effects can all cause inconsistencies in the luminescence signal). Fluorescence signals were detected using an EnVision Multi Label Reader. The compounds to be measured were diluted according to their corresponding molecular weight settings: C1 = 91.08 μM, C2 = 9.108 μM, and C3 = 0.9108 μM. Cisplatin was diluted as shown in Table 11 to prepare a 10x compound working solution. 10 μL of the working solution (10x) was added to each well, and the final volume of each well of all plates was 100 μL. The cells were cultured in an incubator at 37°C and 5% CO2.

[0191] On the fifth day, the compound to be measured was treated for 72 hours (plate reading). The conditions of the treated and control groups were observed under a microscope to determine whether they were normal. 50 μL of CTG reagent was added to each well. The wells were mixed on a shaker for 5 minutes to thoroughly dissolve the cells. The wells were incubated at room temperature for 10 minutes to stabilize the luminescence signal. The fluorescent signal was read using an EnVision Multi Label Reader.

[0192] Table 11 Cisplatin concentration after dilution JPEG0007811806000016.jpg26164

[0193] Cell viability (%)=Lum 測定される化合物 / Lum 溶媒対照 ×100% Experimental Results: The statistical results of the growth-promoting activity of the selected polypeptide compounds are shown in Table 12.

[0194] JPEG0007811806000017.jpg3388

[0195] The test substance was administered in this experimental system at a concentration gradient of C1 = 91.08 μM, C2 = 9.108 μM, and C3 = 0.9108 μM, with 0.88% FBS as the reference. The experimental results showed that the polypeptide compound 1 of the present application had the activity of promoting Caco-2 cell proliferation, which was specifically manifested as an increase in cell viability after the intervention.

[0196] In summary, the polypeptide compounds of the present invention have a shorter peptide chain and are more rapidly and effectively absorbed. Experimental results show that the polypeptide compounds provided by the present application can alleviate the intestinal lumen dilation activity of zebrafish colitis and have significant therapeutic effects in rat acute inflammatory bowel disease model tests. The polypeptide compounds of the present invention have significant alleviating effects on colitis and can be used to prepare drugs for treating enteritis, especially ulcerative colitis.

[0197] Although the present invention discloses the above examples, the embodiments of the present invention are not limited to the above examples, and any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the present invention are equivalent substitutions and fall within the scope of protection of the present invention.

Claims

【Request Item 1】 Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1) Lys-Glu-Pro-Val-Pro-Glu-Al-Ala-Lys-Pro-Arg-Lys (Compound 2) Lys-Glu-Pro-Val-Pro-Glu-Al-Ala-Lys-Pro-Arg (compound 3) Lys-Glu-Pro-Val-Pro-Glu-Al-Lys (compound 4) Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6) Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-P ro-Arg-Lys-Val-Ala-Ala-Gln (compound 19), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-A la-Arg-Lys-Val-Ala-Ala-Gln (compound 26), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-P ro-Ala-Lys-Val-Ala-Ala-Gln (compound 27), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-P ro-Arg-Ala-Val-Ala-Ala-Gln (compound 28), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-P ro-Arg-Lys-Ala-Ala-Ala-Gln (compound 29), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-P ro-Arg-Lys-Val-Ala-Ala-Ala (compound 30), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-G ly-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-Al-Lys-Pro-Arg-Lys-Val (Compound 56) Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57) Glu-Pro-Val-Pro-Glun-Ala-Lys-Pro (Compound 58) D-Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Gln (Compound 61), Lys-D-Glu-Pro-Val-Pro-Glu-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Glu (Compound 62), Lysine-Glue-D-Pro-Valine-Pro-Glue-Al-Lysine-Pro-Argine-Lysine-Valine-Al-Al-Glue (Compound 63), Lysine-Glue-Pro-D-Valine-Pro-Glue-Al-Lysine-Pro-Arg-Lysine-Valine-Al-Al-Glue (Compound 64), Lys-Glu-Pro-Val-D-Pro-Glu-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Glu (Compound 65), Lysine-Glue-Pro-Val-Pro-D-Glue-Al-Lysine-Pro-Arg-Lysine-Val-Al-Al-Glue (Compound 66), Lysine-Glue-Pro-Val-Pro-Glue-D-Al-Lysine-Pro-Arg-Lysine-Val-Al-Al-Glue (Compound 67), Lys-Glu-Pro-Val-Pro-Gln-Al-D-Lys-Pro-Arg-Lys-Val-Al-Al-Gln (Compound 68), Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-D-Pro-Arg-Lys-Val-Al-Al-Gln (Compound 69), Lysine-Glue-Pro-Valine-Pro-Glue-Al-Lysine-Pro-D-Arg-Lysine-Valine-Al-Al-Glue (compound 70), Lysine-Glue-Pro-Valine-Pro-Glue-Al-Lysine-Pro-Arg-D-Lysine-Valine-Al-Al-Glue (Compound 71), Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-D-Val-Al-Al-Gln (Compound 72), Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-Val-D-Al-Al-Gln (Compound 73), Lysine-Glue-Pro-Valine-Pro-Glue-Al-Lysine-Pro-Argine-Lysine-Valine-Al-D-Al-Glue (Compound 74), Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pr o-Arg-Lys-Val-Ala-Ala-D-Gln (compound 75), D-Glu-Pro-Val-Pro-Glu-Al-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-P ro-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-P ro-Gln-Ala-Lys-Pro-Arg-Ly s-Val-Ala-Ala-Gln (compound 95), Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Glu-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), The compound or a physiologically acceptable salt thereof.

2. The compound is 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-Al-D-Lys-Pro-Arg-Lys-Val-Al-Al-Gln (Compound 68), Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-D-Val-Al-Al-Gln (Compound 72), Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Gln (Compound 89), Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Glu-Al-Lys (Compound 92), Gly-Pro-Glu-Thr-Al-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Al-Lys-Pro-Arg-Lys-Val-Al-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-Glu-Ala-Lys (Compound 98), The Lysine-Glue-Pro-Valine-Pro-Glue-Al-Lysine-Al-Argine-Lysine-Valine-Al-Al-Glue (Compound 26), Lysine-Glue-Pro-Valine-Pro-Glue-Al-Lysine-Pro-Arg-Lysine-Al-Al-Al-Glue (Compound 29), - - Lys-D-Glu-Pro-Val-Pro-Glu-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Glu (Compound 62), Lys-Glu-Pro-Val-D-Pro-Glu-Al-Lys-Pro-Arg-Lys-Val-Al-Al-Glu (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), 2. The compound of claim 1 or a physiologically acceptable salt thereof.

3. 10. Use of a compound according to any one of claims 1 to 2 or a physiologically acceptable salt thereof in the manufacture of a medicament for treating enterocolitis.

4. The use according to claim 3, wherein the enteritis includes specific enteritis and non-specific enteritis.

5. Use of claim 4, wherein the specific enteritis includes inflammatory bowel disease, necrotizing enteropathy and intestinal dysbiosis.

6. Use of claim 5, wherein the inflammatory bowel disease includes ulcerative colitis.

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

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