Polypeptide compound and application thereof in treating enteritis

Abstract

The invention relates to a novel polypeptide and application thereof. The polypeptide provided by the invention is short in peptide chain and faster and better in absorption. Experimental results show that the polypeptide provided by the invention shows an obvious enteric cavity dilatation relieving effect in pharmacodynamic tests of a zebra fish inflammatory bowel disease model and a rat inflammatory bowel disease model. The polypeptide provided by the invention has a remarkable colitis relieving effect, and can be used for preparing a medicine for treating enteritis, especially a medicine for treating 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 disease, especially has an effect in treating ulcerative colitis. Background Art

[0002] Enteritis is an inflammatory reaction to the intestines caused by various factors, including infection with pathogens such as bacteria and viruses, immune damage, radiation damage, dietary stimulation, and drug stimulation. Clinical manifestations include fever, nausea, vomiting, abdominal pain, diarrhea, loose watery stools or stools containing mucus, pus, and blood. Some patients may also experience a feeling of urgency and heaviness in the abdomen.

[0003] Enteritis can be divided into specific enteritis and nonspecific enteritis according to the manifestations of inflammation. Specific enteritis includes inflammatory bowel disease, necrotizing enteropathy and dysbacteriosis enteritis. Among them, inflammatory bowel disease, as the more common one, is an idiopathic, non-infectious, intestinal, chronic, persistent, recurrent, inflammatory disease involving the intestines. Clinical manifestations include abdominal pain and diarrhea, bloody stools, and even fever, abdominal mass, weight loss, malnutrition and other symptoms. Inflammatory bowel disease is a chronic, long-term disease that requires long-term and active treatment.

[0004] Generally, specific enteritis has a clear cause, such as bacterial enteritis, pseudomembranous enteritis, viral enteritis, and radiation enteritis. Nonspecific enteritis, on the other hand, lacks a clear cause and is often caused by immune disorders, such as ulcerative colitis and Crohn's disease. Inflammatory bowel disease also includes ulcerative colitis and Crohn's disease. Ulcerative colitis is a chronic, nonspecific inflammatory bowel disease with an unclear etiology, most commonly occurring in young adults. Clinical manifestations include persistent or recurrent diarrhea, bloody and mucous stools, accompanied by abdominal pain, tenesmus, and varying degrees of systemic symptoms. Extraintestinal manifestations may occur, including those affecting the skin, mucous membranes, joints, eyes, liver, and gallbladder. Complications include toxic megacolon, intestinal perforation, massive lower gastrointestinal bleeding, intraepithelial neoplasia, and cancer. While precise data on the incidence of ulcerative colitis in my country are lacking, regional epidemiological surveys suggest an incidence of 0.42-2.22 cases per 100,000 population. Although the incidence rate is still low compared with Western countries, it has shown a clear upward trend compared with 20 years ago. The lesions mainly involve the colonic mucosa and submucosa, starting from the distal rectal colon and developing retrogradely to the proximal end, even involving the entire colon. 5% may involve the terminal ileum, showing a continuous distribution. The main clinical manifestations of ulcerative colitis are diarrhea, abdominal pain, and mucus, pus and blood in the stool. The cause is not yet fully understood, but it is currently believed to be related to infection, immune abnormalities, genetics and mental factors. In addition, patients with enteritis usually have symptoms such as intestinal dilatation (also known as intestinal dilatation or intestinal tube dilatation). This may be because inflammation destroys the nerve and muscle regulatory mechanisms that control the normal intestine, and the pressure in the intestinal cavity causes the intestinal wall to expand beyond its normal activity. Or it may be caused by excessive growth of microorganisms and the toxins they produce, mucus exudation, etc. Relieving or inhibiting intestinal dilatation can help treat enteritis.

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

[0006] In order to overcome the deficiencies and defects of the prior art, the present invention aims to provide a novel 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 intestinal expansion, thereby playing a role in treating enteritis.

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

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

[0009] in

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

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

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

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

[0014] The condition is that at most 2 of Z1, Z2, Z3 and Z4 are missing.

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

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

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

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

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

[0020] X a10 Gly or missing,

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

[0022] X a8 Pro, Glu, Ser or missing,

[0023] X a7 Arg, Glu, Thr, Ser or missing,

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

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

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

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

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

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

[0030] In one embodiment, X a For X aa -X a2 -X a1 -*, where * indicates the position connected to Z1-Z2-Z3-Z4, X a2 -X a1 is Lys-Glu-*, Arg-Glu-*, Val-Tyr-*, Glu-Glu-*, Lys-Gln-*, Lys-D-Glu-* or Tyr-Glu-*, and X aa For X a10 -X a9 -X a8 -X a7 -X a6 -X a5 -X a4 -X a3 -, where X a10 Gly or missing, X a9 Gly, Pro, Ser or missing, X a8 Pro, Glu, Ser or missing, X a7 Arg, Glu, Thr, Ser or missing, X a6 Lys, Thr, Ala, Asp, Glu, Arg, Ser or missing, X a5 Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or missing, X a4Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or missing, and X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or is missing. In one embodiment, X aa 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 missing, wherein the rightmost connector - indicates the same as -X a2 -X a1 In one embodiment, X a For X aa -X a2 -X a1 -*, where * indicates the position connected to Z1-Z2-Z3-Z4, where X a2 -X a1 Lys-Glu-*, and X aa As defined above.

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

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

[0033] In one embodiment, X aFor 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-L ys-Glu-*, Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-*, Val-Pro-Pro-Lys-Glu-*, Pyro-Glu-Leu-Lys-Glu-*, Arg-Lys-Asp-Val-Tyr-*, Gly- Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-*, Val-Pro-Tys-Lys-Glu-*, Pro-Ala-Tys-Lys-Glu-*, Arg-Lys-Asp-Val-Tyr-Glu-*, Ser-Ser-Glu-Asp-Ile-Lys-Glu-* or are absent, where * indicates the position of attachment to Z1-Z2-Z3-Z4.

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

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

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

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

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

[0039] X b5Lys, Ala, D-Lys, Glu, Tyr or missing,

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

[0041] X b7 Ala, D-Ala, Ile or missing,

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

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

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

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

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

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

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

[0049] X b5 Lys or missing,

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

[0051] X b7 Ala or missing,

[0052] X b8 is Ala or missing, and

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

[0054] In one embodiment, Xb For **-X b1 -X b2 -X bb , where ** indicates the position connected to Z1-Z2-Z3-Z4, X b1 -X b2 - is **-Ala-Lys-, **-Ala-Lys-, **-Ala-D-Lys-, **-Ala-Ala- or **-D-Ala-Lys-, X bb -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 , where X b3 Pro, Gly, D-Pro, Ser, Val, Ala or missing, X b4 Arg, Ala, Ser, Pro, D-Arg or missing, X b5 Lys, Ala, D-Lys, Glu, Tyr or missing, X b6 Val, Asp, D-Val, Ala or missing, X b7 Ala, D-Ala, Ile or missing, X b8 Ala, D-Ala, Lys or missing, and X b9 is Gln, Ala, Glu, Asn, D-Gln or missing; or X b3 is Pro, Gly, or Ala, X b4 is Arg or D-Arg, X b5 Lys or missing, X b6 Val, D-Val, Ala or missing, X b7 Ala or missing, X b8 Ala or missing, and X b9 In one embodiment, X bb-Pro-Arg-Lys-Val, -Pro-Arg-Lys, -Pro-Arg, -Ala-Gln, -Ala-Ala, -Pro, -Lys-Val, -Val-Pro-Tyr, -Arg- Lys, -Val-Ala, -Pro-Arg-Lys-Val-Ala, -Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Ar g-Lys-Val-Ala-Ala-Gln, -Pro-Ala-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Ala-Val-Ala-Ala-Gln, -Pro-Arg-Ly s-Val-Ala-Ala-Ala, -Gly-Arg-Lys-Val-Ala-Ala-Gln, -D-Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-D-Ly s-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-D-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-D-Ala-Gln, -Ser-Ser-Gl u-Asp-Ile-Lys-Glu, -Pro-Arg-Lys-Val-Ala-Ala-Asn, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-D- Val-Ala-Ala-Gln, -Ala-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Ala-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-Gln, -Pro-D-Arg-Lys-Val-Ala-Ala-Gln, -Pro-Arg-Lys-Val-Ala-Ala-D-Gln, or missing, wherein the leftmost connector - indicates the same as X b1 -X b2 In one embodiment, X b For **-X b1 -X b2 -X bb , where ** indicates the position connected to Z1-Z2-Z3-Z4, X b1 -X b2 - is **-Ala-Lys-, X bb As defined above.

[0055] In one embodiment, X b It is **-Ala-.

[0056] 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-Al a-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-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 missing, wherein ** indicates the position of connection with Z1-Z2-Z3-Z4.

[0057] In one embodiment, Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is Gln; X a For X aa -X a2 -X a1 -

[0058] *, where * indicates the position connected to Z1-Z2-Z3-Z4, where X a2 -X a1 Lys-Glu-*, and X b For **-X b1 -X b2 -X bb , where ** indicates the position connected to Z1-Z2-Z3-Z4, X b1 -X b2 - is **-Ala-Lys-, where X aa and X bb As defined above.

[0059] In one embodiment, the compound is selected from:

[0060] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 1);

[0061] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 2);

[0062] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 3);

[0063] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4);

[0064] Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 5);

[0065] Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6);

[0066] Lys-Glu-Pro-Val (Compound 7);

[0067] Val-Ala-Ala-Gln (Compound 8);

[0068] Glu-Pro-Val-Pro (Compound 9);

[0069] Lys-Pro-Arg-Lys (Compound 10);

[0070] Ala-Lys-Pro-Arg (Compound 11);

[0071] Pro-Val-Pro-Gln (Compound 12);

[0072] Val-Pro-Gln-Ala (Compound 13);

[0073] Pro-Gln-Ala-Lys (Compound 14);

[0074] Arg-Lys-Val-Ala (Compound 15);

[0075] Lys-Val-Ala-Ala (Compound 16);

[0076] Gln-Ala-Lys-Pro (Compound 17);

[0077] Pro-Arg-Lys-Val (Compound 18);

[0078] Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 19);

[0079] 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-P ro-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-P ro-Arg-Lys-Val-Ala-Ala-Ala (compound 30); 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);

[0080] Pro-Val-Pro-Gln-Ala (Compound 39);

[0081] Pro-Val-Pro-Glu-Ala (Compound 40);

[0082] Pro-Val-Pro-Ile-Ala (Compound 41);

[0083] Pro-Val-Pro-Ala (Compound 42);

[0084] Glu-Pro-Val-Pro-Gln-Ala (Compound 43);

[0085] Pro-Val-Pro-Gln-Ala-Lys (Compound 44);

[0086] Glu-Pro-Val-Pro-Gln-Ala-Arg (Compound 45);

[0087] Ala-Pro-Val-Pro-Gln-Ala-Lys (Compound 46);

[0088] Glu-Pro-Val-Pro-Ala-Ala-Lys (Compound 47);

[0089] Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48);

[0090] Asp-Pro-Val-Pro-Gln-Ala-Lys (Compound 49);

[0091] Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50);

[0092] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51);

[0093] Glu-Pro-Ala-Pro-Gln-Ala-Lys (Compound 52);

[0094] Glu-Ala-Val-Pro-Gln-Ala-Lys (Compound 53);

[0095] Glu-Pro-Val-Ala-Gln-Ala-Lys (Compound 54);

[0096] Glu-Pro-Val-Pro-Glu-Ala-Lys (Compound 55);

[0097] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val (Compound 56);

[0098] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57);

[0099] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 58);

[0100] Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 59);

[0101] Pro-Val-Pro-Gln-Ala-Lys-Pro (Compound 60);

[0102] 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);

[0103] Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 66);

[0104] Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 67);

[0105] Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 68);

[0106] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 69);

[0107] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (compound 70);

[0108] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (compound 71);

[0109] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (compound 72);

[0110] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (compound 73);

[0111] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (compound 74);

[0112] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (compound 75);

[0113] Glu-Gly-Val-Pro-Gln-Ala-Lys (Compound 76);

[0114] Glu-Pro-Val-Gly-Gln-Ala-Lys (Compound 77);

[0115] D-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 78);

[0116] Glu-D-Pro-Val-Pro-Gln-Ala-Lys (Compound 79);

[0117] Glu-Pro-D-Val-Pro-Gln-Ala-Lys (Compound 80);

[0118] Glu-Pro-Val-D-Pro-Gln-Ala-Lys (Compound 81);

[0119] Glu-Pro-Val-Pro-D-Gln-Ala-Lys (Compound 82);

[0120] Glu-Pro-Val-Pro-Gln-D-Ala-Lys (Compound 83);

[0121] Glu-Pro-Val-Pro-Gln-Ala-D-Lys (Compound 84);

[0122] Lys-Glu-Pro-Val-Pro (Compound 85);

[0123] Glu-Pro-Val-Pro-Gln (Compound 86);

[0124] Lys-Glu-Pro-Val-Pro-Gln (Compound 87);

[0125] Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 88);

[0126] Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 89);

[0127] Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 90);

[0128] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 91);

[0129] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 92);

[0130] Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93);

[0131] Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (Compound 94);

[0132] 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);

[0133] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96);

[0134] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 97);

[0135] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 98);

[0136] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (Compound 99);

[0137] Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 100);

[0138] Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (compound 101);

[0139] Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (Compound 102);

[0140] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (compound 103);

[0141] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (compound 104);

[0142] Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 105);

[0143] Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 106);

[0144] Val-Pro-Gln-Ala (Compound 107); or

[0145] Val-Pro-Gln-Ala-Lys (Compound 108).

[0146] In one embodiment, the compound is selected from:

[0147] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 1);

[0148] Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 63);

[0149] Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 96);

[0150] Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 100);

[0151] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (compound 104);

[0152] Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 6);

[0153] Pro-Val-Pro-Gln (Compound 12);

[0154] Glu-Pro-Val-Ala-Gln-Ala-Lys (Compound 54);

[0155] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (Compound 57);

[0156] Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 68);

[0157] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (compound 72);

[0158] Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 89);

[0159] Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 92);

[0160] Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (Compound 94);

[0161] 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);

[0162] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 97);

[0163] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (compound 98);

[0164] Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 105);

[0165] Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 106);

[0166] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 4);

[0167] Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 5);

[0168] Glu-Pro-Val-Pro (Compound 9);

[0169] Lys-Pro-Arg-Lys (Compound 10);

[0170] Arg-Lys-Val-Ala (Compound 15);

[0171] Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 25);

[0172] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (compound 26);

[0173] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (compound 29);

[0174] Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 31);

[0175] Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 34);

[0176] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (Compound 38);

[0177] Glu-Pro-Val-Pro-Gln-Ala-Ala (Compound 48);

[0178] Asp-Pro-Val-Pro-Gln-Ala-Lys (Compound 49);

[0179] Asn-Pro-Val-Pro-Gln-Ala-Lys (Compound 50);

[0180] Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (Compound 51);

[0181] Glu-Ala-Val-Pro-Gln-Ala-Lys (Compound 53);

[0182] Glu-Pro-Val-Pro-Glu-Ala-Lys (Compound 55);

[0183] Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 62);

[0184] Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 65);

[0185] Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 66);

[0186] Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 67);

[0187] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (compound 70);

[0188] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (compound 75);

[0189] Glu-Pro-Val-Pro-Gln-D-Ala-Lys (Compound 83);

[0190] Lys-Glu-Pro-Val-Pro (Compound 85);

[0191] Glu-Pro-Val-Pro-Gln (Compound 86);

[0192] Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 88);

[0193] Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (compound 90);

[0194] Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (Compound 93);

[0195] Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (Compound 99); or

[0196] Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (Compound 103).

[0197] In a second aspect, the present invention provides the use of the polypeptide compound or a physiologically compatible salt thereof in the preparation of a medicament for treating enteritis; or a method for treating enteritis, the method comprising administering a therapeutically effective amount of the polypeptide compound or a physiologically compatible salt thereof to a subject; or the polypeptide compound or a physiologically compatible salt thereof, which is used to treat enteritis.

[0198] Furthermore, enteritis includes specific enteritis and nonspecific enteritis. Furthermore, specific enteritis includes inflammatory bowel disease, necrotizing enteropathy and dysbacteriosis enteritis.

[0199] Further, inflammatory bowel disease includes ulcerative colitis.

[0200] Furthermore, the present invention provides a pharmaceutical composition comprising the polypeptide compound of the present invention or a physiologically compatible salt thereof, and a pharmaceutically acceptable excipient.

[0201] Furthermore, the dosage forms of the drug include tablets, capsules, solutions, powders and pills.

[0202] The beneficial effects of the novel polypeptides provided by the present invention and their applications are as follows:

[0203] The polypeptides of the present invention have short peptide chains, resulting in faster and better absorption. Experimental results show that the polypeptides provided herein exhibited significant relief of intestinal distension in rat models of acute inflammatory bowel disease; in rat models of acute inflammatory bowel disease, they also exhibited significant therapeutic effects. The polypeptides of the present invention have significant efficacy in relieving colitis and can be used to prepare drugs for treating enteritis, particularly ulcerative colitis. BRIEF DESCRIPTION OF THE DRAWINGS

[0204] Figure 1 Shown is a schematic diagram of the steps of solid phase synthesis of polypeptides;

[0205] Figure 2 The mass spectrum of the polypeptide is shown. DETAILED DESCRIPTION

[0206] The following is an explanation of the present invention in combination with specific experiments, which is not intended to limit the scope of protection of the present invention.

[0207] As used in this application, including the appended claims, singular forms such as "a," "an," and "the" include their plural referents unless the context clearly dictates otherwise.

[0208] Unless the context clearly indicates otherwise, the term "or" is used to mean, and is used interchangeably with, the term "and / or."

[0209] The term "effective amount" or "therapeutically effective amount" refers to an amount of an active ingredient (such as a compound) that is sufficient to affect such treatment of the disease, disorder or symptom when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder. A "therapeutically effective amount" can vary with the compound, the disease, disorder and / or the symptoms of the disease or disorder, the severity of the disease, disorder and / or the symptoms of the disease or disorder, the age of the subject to be treated and / or the weight of the subject to be treated. In any given case, the appropriate amount will be clear to those skilled in the art or can be determined by routine experimentation. In some embodiments, a "therapeutically effective amount" is an amount that is effective for the disease or disorder of a subject of "treating" (as defined above) a compound disclosed herein and / or at least one of its stereoisomers and / or at least one of its pharmaceutically acceptable salts. In the case of combination therapy, a "therapeutically effective amount" refers to the total amount of the combination subject used to effectively treat a disease, disorder or condition.

[0210] The term "physiologically compatible salts" refers to salt forms that are physiologically compatible (i.e., pharmacologically acceptable) and substantially non-toxic to the individual to whom the compounds of the present invention are administered. Physiologically compatible salts of the compounds of the present invention include conventional and stoichiometric acid addition salts or base addition salts formed from suitable, non-toxic organic or inorganic acids or inorganic bases.

[0211] The term "intestinal dilatation" refers to intestinal distension or enlargement of the bowel. In patients with enteritis, dilatation can result in a thicker bowel than normal due to various factors, including intestinal damage, mucus exudation, intestinal gas or fluid accumulation, and microbial overgrowth. Clinically, recurrent enteritis, such as inflammatory bowel disease, can cause intestinal dilatation, or tumors can cause intestinal distension and obstruction.

[0212] The amino acid abbreviations used in this application are as follows

[0213] Chinese name English name abbreviation Alanine Alanine Ala Arginine Arginine Arg Asparagine Asparagine Asn Aspartic acid Aspartic acid Asp Cysteine Cysteine Cys glutamine Glutamine Gln glutamate Glutamic acid Glu Glycine Glycine Gly Histidine Histidine His Isoleucine Isoleucine Ile Leucine Leucine Leu Lysine Lysine Lys Methionine Methionine Met Phenylalanine Phenylalanine Phe Proline Proline Pro Serine Serine Ser Threonine Threonine Thr Tryptophan Tryptophan Trp Tyrosine Tyrosine Tyr Valine Valine Val

[0214] Table 1 Solvents, reagents, etc. English names and their abbreviations in Chinese

[0215]

[0216]

[0217] Example 1: Chemical synthesis of polypeptides

[0218] The synthesis of polypeptide compounds adopts the conventional solid-phase synthesis method of a fully automatic polypeptide synthesizer, and the chemical synthesis of polypeptides is carried out through the processes of resin swelling, deprotection, washing, amino acid activation, and condensation.

[0219] Taking Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 1) as an example, the schematic diagram of the peptide solid phase synthesis steps is shown in Figure 1 .

[0220] Step 1: Preparation of fully protected peptide resin

[0221] (1) Resin swelling: Weigh 7.71 g (SD = 0.73 mmol / g) of 2-Chlorotrityl Chloride Resin, add it to a synthesis tube with a sieve plate, and swell it with 100 ml of dichloromethane (DCM).

[0222] (2) Preparation of Fmoc-Gln(Trt)-resin: Weigh Fmoc-Gln(Trt)-OH and DIPEA at a molar ratio of 1:1.78:4.31 and add them to a synthesis tube. Bubble nitrogen (N2) at room temperature for 1-3 hours and drain. Then, wash the resin with dimethylformamide (DMF) five times, 100 ml each time, and drain.

[0223] (3) Removal of Fmoc protecting group: 100 ml of 20% piperidine-DMF (v / v) solution was added to the reactor, nitrogen was bubbled for 20 min, and the mixture was drained; then, the mixture was washed with DMF five times, 100 ml / time, 3 min / time, and the mixture was drained. The Fmoc removal result was detected by ninhydrin method.

[0224] (4) Amino acid preactivation: Add 15 mmol of Fmoc-protected amino acid, 15 mmol of HOBt, and 15 mmol of DIC into a 250 ml beaker, dissolve in 100 ml of DMF, stir at room temperature, and set aside.

[0225] (5) Amino acid ligation: Pour the activated protected amino acid solution into the reactor and add an appropriate amount of DCM to rinse the equipment. Incubate the reaction at room temperature with nitrogen bubbling for 1 to 3 hours. Check the complete amino acid ligation using the ninhydrin method. If complete, drain the mixture. Wash the resin with DMF five times, 100 ml / time, 3 min / time, and drain. The amount of each amino acid and condensing agent used is shown in Table 2.

[0226] (6) After the first amino acid is condensed, steps (4) and (5) are repeated to extend the peptide chain according to the amino acid sequence until the last amino acid is coupled.

[0227] (7) The resin peptide was washed with DMF 4 times, 150 ml / time, 3 min / time; then washed with DCM 5 times, 150 ml / time, 3 min / time, and dried.

[0228] Table 2 Amounts of amino acids and condensing agents

[0229]

[0230]

[0231] Step 2: Cutting

[0232] (1) Add 100 ml of a cutting agent (TFA:TIPS:H2O=95:2.5:2.5, v / v) to a synthesis tube and allow to react by nitrogen bubbling for 1.5 to 3 hours.

[0233] (2) After the cleavage reaction is completed, the cleavage agent is filtered into a 250 ml round-bottom flask. After vacuum concentration to one-fourth of the original volume of the cleavage agent, 10 times the existing volume of methyl tert-butyl ether is added to precipitate a white solid. The resulting mixture is filtered and washed three times with 50 ml of methyl tert-butyl ether. The resulting crude peptide product is placed in a sand core funnel and blown dry with nitrogen in a fume hood to evaporate the solvent until the crude peptide is powdery. 9.04 g of crude peptide is obtained, with a crude yield of 74.7%.

[0234] Step 3: Purification, salt exchange and freeze-drying

[0235] Direct salt exchange (acetate) for peptide HPLC

[0236] A. Chromatographic parameters

[0237] Chromatographic column: dynamic axial compression column 80*250mm, packing: Daisogel C18 (SP-100-8-ODS-P)

[0238] Eluent A1: 0.1 M acetic acid

[0239] Eluent A2: 0.025M acetic acid-0.1M ammonium acetate

[0240] Eluent B: acetonitrile

[0241] Flow rate: 180ml / min

[0242] UV detection wavelength: 220nm

[0243] B. Operation steps

[0244] a) Dissolve the crude peptide in water and / or acetonitrile and filter through a 0.45 μm filter membrane

[0245] b) 95% A1 + 5% B balanced column

[0246] c) Injection

[0247] d) 95% A2 + 5% B balanced column

[0248] e) Gradient elution of A1 and B

[0249] f) Collect the target peptide eluate

[0250] g) Rotary evaporation concentration

[0251] h) Freeze drying

[0252] 8.26 g of crude peptide was purified to obtain 4.92 g of pure peptide, with a purification yield of 59.5%.

[0253] Other compounds were synthesized in a similar manner to compound 1. The results are shown in Table 3 and other parts of the specification.

[0254] Table 3 Synthesized polypeptide compounds

[0255]

[0256]

[0257]

[0258]

[0259]

[0260]

[0261] Note: Doubly charged peaks indicate that the target molecule is bound to 2 protons, and triply charged peaks indicate that the target molecule is bound to 3 protons; N / A indicates that the actual weight is not included due to the difficulty in weighing.

[0262] Compound 1: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0263] 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] + ).

[0264] 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=6.7Hz ,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).

[0265] Compound 2: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (acetate)

[0266] 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] + ).

[0267] 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).

[0268] Compound 3: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0269] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 51 H 88 N 16 O 14 ; m / z: 383.89927 ([M+3H] 3+ ), 575.34276([M+2H] 2+ ), 1149.67551([M+H] + ).

[0270] 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,1H ),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. 41(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).

[0271] Compound 4: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0272] High resolution mass spectrometry (TOF-HRMS), molecular formula: C40 H 69 N 11 O 12 ; m / z: 448.76653 ([M+2H] 2+ ), 896.52058([M+H] + ).

[0273] 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),3.67–3.5 1(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).

[0274] Compound 5: Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0275] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 33 H 60 N 12 O9; m / z: 385.24021 ([M+2H] 2+ ), 769.46971([M+H] + ).

[0276] 1 H NMR(600MHz,D2O)δ4.23–4.17(m,1H),4.15–4.07(m,4H),3.95(dd,J=8.5,4.8Hz ,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,A cOH,10H),1.62–1.40(m,8H),1.19(d,J=7.2Hz,8H),0.73(dd,J=6.7,4.0Hz,6H).

[0277] Compound 6: Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0278] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z:768.42641([M+H] + ).

[0279] 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),4.09 (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).

[0280] Compound 7: Lys-Glu-Pro-Val (acetate)

[0281] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 21 H 37 N5O7; m / z: 472.27768 ([M+H] + ).

[0282] 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,1 1H),1.52–1.47(m,2H),1.29–1.22(m,2H),0.71(dd,J=15.3,6.9Hz,6H).

[0283] Compound 8: Val-Ala-Ala-Gln (acetate)

[0284] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 16 H 29 N5O6; m / z: 388.2187 ([M+H] + ).

[0285] 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),2.23–2.1 4(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).

[0286] Compound 9: Glu-Pro-Val-Pro (acetate)

[0287] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 32 N4O7;441.23562([M+H] + ).

[0288] 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).

[0289] Compound 10: Lys-Pro-Arg-Lys (acetate)

[0290] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 23 H 45 N9O5;264.68527([M+2H] 2+ ), 528.36210([M+H] + ).

[0291] 1 H 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).

[0292] Compound 11: Ala-Lys-Pro-Arg (acetate)

[0293] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 38 N8O5;236.15638([M+2H] 2+ ), 471.30462([M+H] + ).

[0294] 1 H NMR(600MHz,D2O))δ4.55(dd,J=8.3,5.6Hz,1H),4.34(dd,J=8.4,5.9Hz,1 H),4.09–3.96(m,2H),3.82–3.74(m,1H),3.64–3.55(m,1H),3.12(t,J=6.9 Hz,2H),2.93(t,J=7.6Hz,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).

[0295] Compound 12: Pro-Val-Pro-Gln (acetate)

[0296] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 33 N5O6; m / z: 440.25122 ([M+H] + ).

[0297] 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).

[0298] Compound 13: Val-Pro-Gln-Ala (acetate)

[0299] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.23575 ([M+H] + ).

[0300] 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).

[0301] Compound 14: Pro-Gln-Ala-Lys (acetate)

[0302] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 19 H 34 N6O6; m / z: 222.13480 ([M+2H] 2+ ), 443.26183([M+H] + ).

[0303] 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).

[0304] Compound 15: Arg-Lys-Val-Ala (acetate)

[0305] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 20 H 40 N8O5; m / z: 237.16465 ([M+2H] 2+ ), 473.32087([M+H] + ).

[0306] 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).

[0307] Compound 16: Lys-Val-Ala-Ala (acetate)

[0308] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 17 H 33 N5O5; m / z: 388.25660 ([M+H] + ).

[0309] 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).

[0310] Compound 17: Gln-Ala-Lys-Pro (acetate)

[0311] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 19 H 34 N6O6; m / z: 443.26161 ([M+H] + ).

[0312] 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),3.55–3.4 3(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).

[0313] Compound 18: Pro-Arg-Lys-Val (acetate)

[0314] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 22 H 42 N8O5; m / z: 250.17158 ([M+2H] 2+ ), 499.33464([M+H] + ).

[0315] 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).

[0316] Compound 19: Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0317] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 530.64499 ([M+3H] 3+ ), 795.46224([M+2H] 2+ ), 1589.91350([M+H] + ).

[0318] 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),4.24–4.12 (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).

[0319] Compound 20: Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0320] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 18 ; m / z: 530.32804 ([M+3H] 3+ ), 794.98683([M+2H] 2+ ), 1588.96546([M+H] + ).

[0321] 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).

[0322] Compound 21: Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0323] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 540.99125 ([M+3H] 3+ ), 810.98235([M+2H] 2+ ), 1620.94722([M+H] + ).

[0324] 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),3.60 –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).

[0325] Compound 22: Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0326] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 540.99088 ([M+3H] 3+ ), 810.98168([M+2H] 2+ ), 1620.95237([M+H] + ).

[0327] 1H 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),3.75–3.67( 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).

[0328] Compound 23: Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0329] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 124 N 22 O 19 ; m / z: 398.24191 ([M+4H] 4+ ), 530.65344([M+3H] 3+ ), 795.97791([M+2H] 2+ ).

[0330] 1H 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).

[0331] Compound 24: Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0332] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 398.23245 ([M+4H] 4+ ), 530.64075([M+3H] 3+ ), 795.45752([M+2H] 2+ ).

[0333] 1H 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,1H) ,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).

[0334] Compound 25: Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0335] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 123 N 23 O 20 ; m / z: 405.48935 ([M+4H] 4+ ), 540.31677([M+3H] 3+ ), 809.97144([M+2H] 2+ ).

[0336] 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. 12(m,5H),2.02–1.45(m,AcOH,48H),1.43–1.27(m,6H),1.27–1.21(m,12H),0.80(dd,J=6.8,4.4Hz,6H).

[0337] Compound 26: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0338] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 125 N 23 O 20 ; m / z: 405.99350 ([M+4H] 4+ ), 540.98883([M+3H] 3+ ), 810.97961([M+2H] 2+ ).

[0339] 1H 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. 03–1.41(m,AcOH,48H),1.40–1.27(m,6H),1.25(dd,J=13.7,7.3Hz,12H),0.90–0.76(m,12H).

[0340] Compound 27: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln (acetate)

[0341] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 20 O 20 ; m / z: 391.23177 ([M+4H] 4+ ), 781.45496([M+2H] 2+ ).

[0342] 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).

[0343] Compound 28: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln (acetate)

[0344] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 120 N 22 O 20 ; m / z: 398.23303 ([M+4H] 4+ ), 530.64142([M+3H] 3+ ), 795.45850([M+2H] 2+ ).

[0345] 1 H 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,2 H),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).

[0346] Compound 29: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln (acetate)

[0347] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 71 H 123 N 23 O 20 ; m / z: 405.48969 ([M+4H] 4+ ), 540.31714([M+3H] 3+ ), 809.97205([M+2H] 2+ ).

[0348] 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=8.4,5.8Hz ,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),3.7 9–3.66(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,2 H),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).

[0349] Compound 30: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala (acetate)

[0350] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 71 H 124 N 22 O 19 ; m / z: 398.24493 ([M+4H] 4+ ), 530.65551([M+3H] 3+ ), 795.47815([M+2H] 2+ ), 1589.94194([M+H] + ).

[0351] 1H 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),4.3 1–4.24(m,3H),4.24–4.20(m,1H),4.20–4.09(m,5H),4.02–3.96(m,2H),3.93–3.86(m,1H),3.80–3.74(m,1H ),3.74–3.67(m,2H),3.63–3.43(m,3H),3.08(t,J=6.9Hz,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).

[0352] Compound 31: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0353] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.49240 ([M+4H] 4+ ), 536.31955([M+3H] 3+ ), 803.97442([M+2H] 2+ ), 1606.91471([M+H] + ).

[0354] 1H 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).

[0355] Compound 32: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0356] High resolution mass spectrometry (TOF-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.49278 ([M+4H] 4+ ), 536.31975([M+3H] 3+ ), 803.97422([M+2H] 2+ ), 1606.92969([M+H] + ).

[0357] 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).

[0358] Compound 33: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0359] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 123 N 23 O 20 ; m / z: 402.48917 ([M+4H] 4+ ), 536.31647([M+3H] 3+ ), 803.97101([M+2H] 2+ ).

[0360] 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,9 H),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).

[0361] Compound 34: Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0362] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48178 ([M+4H] 4+ ), 522.97314([M+3H] 3+ ), 784.45752([M+2H] 2+ ).

[0363] 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(d d,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).

[0364] Compound 35: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0365] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 64 H 115 N 23 O 20 ; m / z: 382.47363 ([M+4H] 4+ ), 509.62903([M+3H] 3+ ), 763.93982([M+2H] 2+ ).

[0366] 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).

[0367] Compound 36: Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0368] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48172 ([M+4H] 4+ ), 522.97314([M+3H] 3+ ), 783.95605([M+2H] 2+ ).

[0369] 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).

[0370] Compound 37: Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0371] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 67 H 119 N 23 O 20 ; m / z: 392.48172 ([M+4H] 4+ ), 522.97314([M+3H] 3+ ), 783.95605([M+2H] 2+ ).

[0372] 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).

[0373] Compound 38: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys (acetate)

[0374] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 51 H 88 N 16 O 14 ; m / z: 383.89569 ([M+3H] 3+ ), 575.33978([M+2H] 2+ ).

[0375] 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,1 H),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).

[0376] Compound 39: Pro-Val-Pro-Gln-Ala (acetate)

[0377] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 23 H 38 N6O7; m / z: 511.2871 ([M+H] + ).

[0378] 1 H NMR(600MHz,D2O)δ4.41(d,J=7.3Hz,1H),4.38–4.32(m,2H),4.20(dd,J=8.7,5.9 Hz,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).

[0379] Compound 40: Pro-Val-Pro-Glu-Ala (acetate)

[0380] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 23 H 37 N5O8; m / z: 512.27081 ([M+H] + ).

[0381] 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,1 H),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).

[0382] Compound 41: Pro-Val-Pro-Ile-Ala (acetate)

[0383] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 24 H 41 N5O6; m / z: 496.31158 ([M+H] + ).

[0384] 1H 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).

[0385] Compound 42: Pro-Val-Pro-Ala

[0386] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 18 H 30 N4O5; m / z: 383.22791 ([M+H] + ).

[0387] 1 H NMR(600MHz,D2O)δ4.36(d,J=7.2Hz,1H),4.30(dd,J=8.5,6.3Hz,1H),4.24(d d,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).

[0388] Compound 43: Glu-Pro-Val-Pro-Gln-Ala (acetate)

[0389] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 28 H 45 N7O 10 ; m / z:640.32892([M+H] + ).

[0390] 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).

[0391] Compound 44: Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0392] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 29 H 50 N8O8; m / z: 320.19421 ([M+2H] 2+ ).

[0393] 1 H NMR(600MHz,D2O)δ4.29–4.19(m,3H),4.13–4.06(m,2H),3.95(dd,J=8.2,5.1 Hz,1H),3.73–3.68(m,1H),3.52–3.47(m,1H),3.24–3.16(m,2H),2.79(t,J=7. 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).

[0394] Compound 45: Glu-Pro-Val-Pro-Gln-Ala-Arg (acetate)

[0395] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N 11 O 11 m / z: 398.71835 ([M+2H] 2+ ), 796.42944([M+H]+ ).

[0396] 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(d d,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).

[0397] Compound 46: Ala-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0398] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O9; m / z: 355.71259 ([M+2H] 2+ ), 710.41809([M+H] + ).

[0399] 1H 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).

[0400] Compound 47: Glu-Pro-Val-Pro-Ala-Ala-Lys (acetate)

[0401] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 54 N8O 10 ; m / z: 356.20514 ([M+2H] 2+ ), 711.40198([M+H] + ).

[0402] 1 H NMR(600MHz,D2O)δ4.45(dd,J=8.4,6.4Hz,1H),4.33–4.27(m,3H),4.21(dd,J=1 5.1,7.2Hz,2H),4.07(dd,J=8.1,5.1Hz,1H),3.86–3.75(m,1H),3.67–3.54(m,3H ),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).

[0403] Compound 48: Glu-Pro-Val-Pro-Gln-Ala-Ala (acetate)

[0404] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 50 N8O 11 ; m / z: 356.18692 ([M+2H] 2+ ), 711.36597([M+H] + ).

[0405] 1 H NMR(600MHz,D2O)δ4.34(dd,J=8.3,6.5Hz,1H),4.24–4.16(m,3H),4.12–4.0 6(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).

[0406] Compound 49: Asp-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0407] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 33 H 55 N9O 11 ; m / z: 377.70767 ([M+2H] 2+ ), 754.40814([M+H] + ).

[0408] 1H 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,1H ),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).

[0409] Compound 50: Asn-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0410] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 33 H 56 N 10 O 10 ; m / z: 377.21542 ([M+2H] 2+ ), 753.42365([M+H] + ).

[0411] 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).

[0412] Compound 51: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala (acetate)

[0413] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 59 H 102 N 18 O 16 ; m / z: 440.59735 ([M+3H] 3+ ), 660.39252([M+2H] 2+ ).

[0414] 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,5H ),4.10–4.04(m,3H),3.93–3.88(m,2H),3.75–3.67(m,1H),3.66–3.58(m,1H),3.56–3.41(m,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).

[0415] Compound 52: Glu-Pro-Ala-Pro-Gln-Ala-Lys (acetate)

[0416] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 53 N9O 11 ; m / z: 370.6998 ([M+2H] 2+ ), 740.39221([M+H] + ).

[0417] 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(d d,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).

[0418] Compound 53: Glu-Ala-Val-Pro-Gln-Ala-Lys (acetate)

[0419] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O 11 ; m / z: 371.7081 ([M+2H] 2+ ), 742.4089([M+H] + ).

[0420] 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,1 H),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).

[0421] Compound 54: Glu-Pro-Val-Ala-Gln-Ala-Lys (acetate)

[0422] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 32 H 55 N9O 11 ; m / z: 371.70767 ([M+2H] 2+ ), 742.40802([M+H] + ).

[0423] 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=7.5Hz ,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).

[0424] Compound 55: Glu-Pro-Val-Pro-Glu-Ala-Lys (acetate)

[0425] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 56 N8O 12 ; m / z: 385.2083 ([M+2H] 2+ ), 769.4092([M+H] + ).

[0426] 1H 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).

[0427] Compound 56: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val (acetate)

[0428] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 56 H 97 N 17 O 15 ; m / z: 416.91827 ([M+3H] 3+ ), 624.87354([M+2H] 2+ ).

[0429] 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).

[0430] Compound 57: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0431] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 45 H 76 N 14 O 13 ; m / z: 511.29254 ([M+2H] 2+ ).

[0432] 1 H 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),4.10–4.0 3(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).

[0433] Compound 58: Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro (acetate)

[0434] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 39 H 64 N 10 O 12 ; m / z: 433.24188 ([M+2H] 2+ ), 865.47662([M+H] + ).

[0435] 1H 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).

[0436] Compound 59: Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg (acetate)

[0437] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 40 H 69 N 13 O 10 ; m / z: 298.18314 ([M+3H] 3+ ), 446.77118([M+2H] 2+ ), 892.53497([M+H] + ).

[0438] 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).

[0439] Compound 60: Pro-Val-Pro-Gln-Ala-Lys-Pro (acetate)

[0440] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O9; m / z: 368.7207 ([M+2H] 2+ ), 736.4343([M+H] + ).

[0441] 1 H 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,2H ),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).

[0442] Compound 61: D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0443] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6611([M+3H] 3+ ), 823.9882([M+2H] 2+ ).

[0444] 1H NMR(600MHz,D2O)δ4.46–4.35(m,2H),4.27(dd,J=8.3,6.1Hz,1H),4.22–4.04(m,9H ),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).

[0445] Compound 62: Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0446] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6608([M+3H] 3+ ).

[0447] 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(d d,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).

[0448] Compound 63: Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0449] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6609([M+3H] 3+ ), 823.9878([M+2H] 2+ ).

[0450] 1 H 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. 15–2.02(m,6H),1.95–1.41(m,AcOH,48H),1.17(dd,J=21.6,7.2Hz,15H),0.83–0.64(m,12H).

[0451] Compound 64: Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0452] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6609([M+3H] 3+ ), 823.9878([M+2H] 2+ ).

[0453] 1H 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).

[0454] Compound 65: Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0455] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4979 ([M+4H] 4+ ), 549.6612([M+3H] 3+ ), 823.9883([M+2H] 2+ ).

[0456] 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,2H) ,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),3.8 2(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),2.82–2.75 (m,6H),2.18–2.03(m,9H),1.95–1.40(m,AcOH,46H),1.37–1.08(m,16H),0.80–0.68(m,12H).

[0457] Compound 66: Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0458] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6611([M+3H] 3+ ), 823.9881([M+2H] 2+ ).

[0459] 1 H 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, AcOH,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).

[0460] Compound 67: Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0461] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4961([M+4H] 4+ ), 549.6615([M+3H] 3+ ), 823.9886([M+2H] 2+ ).

[0462] 1H NMR(600MHz,D2O)δ4.47–4.38(m,2H),4.26(dd,J=8.4,5.8Hz,1H),4.22–4.04(m,9H),3.95 (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).

[0463] Compound 68: Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0464] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M+4H] 4+ ), 549.6615([M+3H] 3+ ), 823.9879([M+2H] 2+ ).

[0465] 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),4.14 –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).

[0466] Compound 69: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0467] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6608([M+3H] 3+ ).

[0468] 1 H 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,3H) ,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).

[0469] Compound 70: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0470] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6611([M+3H] 3+ ), 823.9883([M+2H] 2+ ).

[0471] 1H 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).

[0472] Compound 71: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln (acetate)

[0473] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6609([M+3H] 3+ ), 823.9878([M+2H] 2+ ).

[0474] 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).

[0475] Compound 72: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln (acetate)

[0476] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4976 ([M+4H] 4+ ), 549.6609([M+3H] 3+ ), 823.9876([M+2H] 2+ ).

[0477] 1 H NMR(600MHz,D2Oδ4.45–4.35(m,2H),4.26(dd,J=8.4,5.9Hz,1H),4.21–4.05(m,9 H),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,AcO H,50H),1.32–1.14(m,15H),0.78(dd,J=13.9,6.7Hz,6H),0.73(d,J=6.7Hz,6H).

[0478] Compound 73: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln (acetate)

[0479] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M+4H] 4+ ), 549.6609([M+3H] 3+ ), 823.9879([M+2H] 2+ ).

[0480] 1H 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=8.4,5.8Hz ,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).

[0481] Compound 74: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln (acetate)

[0482] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4977 ([M+4H] 4+ ), 549.6610([M+3H] 3+ ), 823.9879([M+2H] 2+ ).

[0483] 1H 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=6.8Hz ,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).

[0484] Compound 75: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln (acetate)

[0485] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 127 N 23 O 20 ; m / z: 412.4978 ([M+4H] 4+ ), 549.6611([M+3H] 3+ )823.9881([M+2H] 2+ ).

[0486] 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. 47(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).

[0487] Compound 76: Glu-Gly-Val-Pro-Gln-Ala-Lys (acetate)

[0488] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 364.7022 ([M+2H] 2+ ), 728.3929([M+H] + ).

[0489] 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).

[0490] Compound 77: Glu-Pro-Val-Gly-Gln-Ala-Lys (acetate)

[0491] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 364.7004 ([M+2H] 2+ ), 728.3932([M+H] + ).

[0492] 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).

[0493] Compound 78: D-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0494] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 384.716 ([M+2H] 2+ ), 768.4245([M+H] + ).

[0495] 1H 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).

[0496] Compound 79: Glu-D-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0497] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 ; m / z: 384.7159 ([M+2H] 2+ ), 768.4244([M+H] + ).

[0498] 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).

[0499] Compound 80: Glu-Pro-D-Val-Pro-Gln-Ala-Lys (acetate)

[0500] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11m / z: 384.7158 ([M+2H] 2+ ), 768.4241([M+H] + ).

[0501] 1 H 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).

[0502] Compound 81: Glu-Pro-Val-D-Pro-Gln-Ala-Lys (acetate)

[0503] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 34 H 57 N9O 11 m / z: 384.7157 ([M+2H] 2+ ), 768.4240([M+H] + ).

[0504] 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. 64(m,2H),1.58–1.50(m,3H),1.29–1.23(m,5H),0.81(dd,J=15.1,6.7Hz,6H).

[0505] Compound 82: Glu-Pro-Val-Pro-D-Gln-Ala-Lys (acetate)

[0506] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 m / z: 384.7158 ([M+2H] 2+ ), 768.4242([M+H] + ).

[0507] 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).

[0508] Compound 83: Glu-Pro-Val-Pro-Gln-D-Ala-Lys (acetate)

[0509] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 384.7159 ([M+2H] 2+ ), 768.4243([M+H] + ).

[0510] 1H 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).

[0511] Compound 84: Glu-Pro-Val-Pro-Gln-Ala-D-Lys (acetate)

[0512] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 53 N9O 11 ; m / z: 384.7160 ([M+2H] 2+ ), 768.4246([M+H] + ).

[0513] 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).

[0514] Compound 85: Lys-Glu-Pro-Val-Pro (acetate)

[0515] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 26 H 44N6O8; m / z: 454.2655 ([M+2H] 2+ ), 569.3287([M+H] + ).

[0516] 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).

[0517] Compound 86: Glu-Pro-Val-Pro-Gln (acetate)

[0518] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 25 H 40 N6O9; m / z: 569.2919 ([M+H] + ).

[0519] 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).

[0520] Compound 87: Lys-Glu-Pro-Val-Pro-Gln (acetate)

[0521] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 31 H 52 N8O 10 ; m / z: 349.1971 ([M+2H] 2+ ), 697.3868([M+H]+ ).

[0522] 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,2H ),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).

[0523] Compound 88: Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0524] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 92 H 152 N 26 O 24 ; m / z: 502.2934 ([M+4H] 4+ ), 669.3699([M+3H] 3+ ).

[0525] 1H 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).

[0526] Compound 89: pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0527] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 84 H 145 N 25 O 24 ; m / z: 468.7766 ([M+4H] 4+ ), 624.6998([M+3H] 3+ ), 936.5460([M+2H] 2+ ).

[0528] 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),3.9 6(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).

[0529] Compound 90: Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0530] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 90 H 148 N 26 O 24 ; m / z: 495.2855 ([M+4H] 4+ ), 660.0449([M+3H] 3+ ), 989.5637([M+2H] 2+ ).

[0531] 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).

[0532] Compound 91: Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0533] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 103 H 174 N 32 O 28 ; m / z: 578.0856 ([M+4H] 4+ ), 770.4463([M+3H] 3+ ), 1155.1642([M+2H] 2+ ).

[0534] 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).

[0535] Compound 92: Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0536] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 70 H 116 N 20 O 20 ; m / z: 390.2233 ([M+4H] 4+ ), 519.9619([M+3H] 3+ ), 779.4393([M+2H]2+ ).

[0537] 1 H 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),4.31–4.23 (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),1.9 7–1.65(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).

[0538] Compound 93: Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0539] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 64 H 104 N 18 O 19 m / z: 715.3917 ([M+2H] 2+ ).

[0540] 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).

[0541] Compound 94: Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln (acetate)

[0542] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 50 H 80 N 14 O 14 ; m / z: 367.8727 ([M+3H] 3+ ), 551.3051([M+2H] 2+ ), 1101.6030([M+H] + ).

[0543] 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=7.0,5.8H z,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=14 .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).

[0544] 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 (acetate)

[0545] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 113 H 188 N 34 O 31 ; m / z: 504.6906 ([M+5H] 5+ ), 630.6115([M+4H] 4+ ), 840.4796([M+3H] 3+ ).

[0546] 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).

[0547] Compound 96: Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0548] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 74 H 118 N 20 O 22 ; m / z: 547.2972 ([M+3H] 3+ ), 820.4424([M+2H] 2+ ).

[0549] 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).

[0550] Compound 97: Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0551] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 105 H 179 N 31 O 35 ; m / z: 488.0708 ([M+5H] 5+ ), 609.8367([M+4H] 4+ ), 812.7799([M+3H] 3+ ).

[0552] 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).

[0553] Compound 98: Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys (acetate)

[0554] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ; m / z: 519.5973 ([M+3H] 3+ ), 778.8925([M+2H] 2+ ).

[0555] 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).

[0556] Compound 99: Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln (acetate)

[0557] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 52 H 85 N 13 O 21 m / z: 614.806 ([M+2H] 2+ ), 1228.605([M+H] + ).

[0558] 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).

[0559] Compound 100: Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0560] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 88 H 150 N 26 O 23 ; m / z: 389.0348 ([M+5H] 5+ ), 480.0415([M+4H] 4+ ), 647.7197([M+3H] 3+ ).

[0561] 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).

[0562] Compound 101: Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu (acetate)

[0563] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 66 H 109 N 17 O 26 ; m / z: 519.5978 ([M+3H] 3+ ), 778.8933([M+2H] 2+ ).

[0564] 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).

[0565] Compound 102Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr (acetate)

[0566] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 53 H 82 N 12 O 15 ; m / z: 564.3073 ([M+2H] 2+ ).

[0567] 1 H NMR(600MHz,D2O)δ7.01–6.95(m,2H),6.69(d,J=8.5Hz,2H),4.40(dd,J=8.3,6.4Hz ,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, 25H),1.33–1.21(m,5H),0.86(dd,J=11.3,6.7Hz,6H),0.77(dd,J=17.6,6.7Hz,6H).

[0568] Compound 103: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu (acetate)

[0569] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 126 N 22 O 21 ; m / z: 824.4799 ([M+2H] 2+ ).

[0570] 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,3 H),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).

[0571] Compound 104: Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn (acetate)

[0572] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 72 H 125 N 23 O 20 ; m / z: 408.9938 ([M+4H] 4+ ), 544.9891([M+3H] 3+ ), 816.9801([M+2H] 2+ ).

[0573] 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),3.9 6(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),2.0 3–1.42(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).

[0574] Compound 105: Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0575] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 73 H 128 N 24 O 19 ; m / z: 412.2515 ([M+4H] 4+ ), 549.3327([M+3H] 3+ ), 823.4955([M+2H] 2+ ).

[0576] 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),4.30 –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).

[0577] Compound 106: Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln (acetate)

[0578] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 74 H 129 N 23 O 20 ; m / z: 416.0015 ([M+4H] 4+ ), 554.3328([M+3H] 3+ ), 830.9956([M+2H] 2+ ).

[0579] 1 H 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),4.22–4.1 0(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).

[0580] Compound 107: Val-Pro-Gln-Ala (acetate)

[0581] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 18 H 31 N5O6; m / z: 414.2341 ([M+1H] + ).

[0582] 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).

[0583] Compound 108: Val-Pro-Gln-Ala-Lys (acetate)

[0584] High resolution mass spectrometry (Orbitrap-HRMS), molecular formula: C 24 H 43 N7O7; m / z: 271.6681([M+2H]2+), 542.3289([M+1H] + ).

[0585] 1 H 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=7.5Hz ,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).

[0586] Example 2: Experiment on the efficacy of polypeptide compounds in alleviating colitis

[0587] Experimental Animals: Wild-type AB strain zebrafish, bred by natural pair mating, were used. Zebrafish were 3 days post-fertilization (dpf). Zebrafish were maintained at 28°C in aquaculture water (water quality: 200 mg of instant sea salt per liter of reverse osmosis water, conductivity 450-550 μS / cm; pH 6.5-8.5; hardness 50-100 mg / L CaCO3). The experimental animal use license number is SYXK (Zhejiang) 2012-0171. The animal husbandry and management system complies with AAALAC accreditation (certification number: 001458).

[0588] Experimental methods:

[0589] (1) Grouping: Peptide group: Prepare into 20.0 mg / mL stock solution with ultrapure water and store at -20°C.

[0590] Positive control group: prednisone, white powder, batch number C10016501, Shanghai MacLean Biochemical Technology Co., Ltd., stored at 4°C; prepared with DMSO to a 15.0 mg / mL stock solution, stored in aliquots at -20°C.

[0591] Normal control group and model control group.

[0592] (2) Experimental method: 3dpf wild-type AB strain zebrafish were randomly selected and placed in a 6-well plate. 30 zebrafish were treated in each well (experimental group). Except for the normal control group, all other experimental groups were given TNBS in water to establish a zebrafish intestinal mucosal injury model. After 2 days of treatment at 28℃, TNBS was removed and the peptide compounds (concentrations shown in Table 4) and the positive control prednisone 15.0μg / mL were given in water. At the same time, a normal control group (healthy group) and a model control group (intestinal mucosal injury group) were set up. The volume of each well (experimental group) was 3mL. After 2 days of treatment at 28℃, 10 zebrafish were randomly selected from each experimental group and photographed under a dissecting microscope. The data were analyzed and collected using NIS-Elements D 3.20 advanced image processing software. The zebrafish intestinal lumen area was analyzed and the statistical analysis results of this indicator were used to evaluate the efficacy of the sample in alleviating colitis. The statistical analysis results were expressed as mean±SE. Statistical analysis was performed using SPSS26.0 software. P<0.05 indicated that the difference was statistically significant.

[0593] Experimental results: The results of the efficacy of the polypeptide compound in relieving colitis are shown in Table 4:

[0594] Table 4 Results of the experimental evaluation of the efficacy of polypeptide compounds in relieving colitis (n=10)

[0595]

[0596] Compared with the model control group, *p<0.05, **p<0.01, ***p<0.001

[0597] According to the data in Table 4, the peptide compound groups of compounds 1, 4, 5, 6, 12, and 15 showed significant statistical differences compared to the model control group (p < 0.05; p < 0.01; p < 0.001), and the effects were superior to those of the prednisone group. The experimental results show that the peptide compounds provided herein have the effect of alleviating colitis, specifically manifested by significantly reducing intestinal dilatation.

[0598] The experimental system was designed with a dose gradient of 250 μg / mL, 500 μg / mL, and 1000 μg / mL for the test compounds. By analyzing the intestinal area of ​​zebrafish after intervention in each group, it was found that the vast majority of test compounds with colitis-relieving effects were more pronounced at a concentration of 1000 μg / mL (p<0.05; p<0.01; p<0.001). Further increasing the test compound concentration resulted in zebrafish mortality within the group. Therefore, in subsequent rounds of activity evaluation, each test compound was uniformly administered at 1000 μg / mL. The results are summarized in Table 5.

[0599] Table 5 Summary of the intestinal expansion activity of peptide compounds in alleviating zebrafish colitis

[0600]

[0601] Note: The activity of each compound in alleviating intestinal dilation of zebrafish colitis was completed after multiple batches of experiments. For the convenience of comparison, its anti-intestinal dilation activity was compared relative to the control group of the experimental model of the same batch: *p<0.05, **p<0.01, ***p<0.001; ND means not tested, "—" means no activity, "+" means a certain effect of alleviating intestinal dilation, "#" means all zebrafish died in the experiment, and "&" means 13 zebrafish died in the experiment.

[0602] According to the data in Tables 4 and 5, the polypeptide group showed significant statistical differences compared with the model control group (p<0.05, p<0.01 or p<0.001), and the effect was better than that of the prednisone group. Under the experimental conditions of this study, 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 efficacy in alleviating colitis, specifically by relieving intestinal dilatation (p<0.05); compounds 7, 8, 11, 14, 16, 17, 19, 21-24, 27, 28, 30, 32, 33, 36, 37, 39-42, 46, 47, 52, 58, 59, 64, 69, 71, 74, 76, 78-82, 84, 87, 91, and 102 had a certain effect in alleviating intestinal dilatation.

[0603] Example 3: Evaluation of the therapeutic efficacy of polypeptide compounds on TNBS-induced acute inflammatory bowel disease (UC) model in SD rats

[0604] Objective: To evaluate the therapeutic effect of peptide compounds on TNBS-induced acute inflammatory bowel disease model in SD rats.

[0605] Materials and methods

[0606] In this study, a rat ulcerative colitis model was established by administering a single enema of trinitrobenzenesulfonic acid (TNBS) to male SD rats. TNBS-induced acute colitis in rats is an immune response induced by cytokines secreted by Th1 cells. Animals in the control group exhibited significant colon atrophy and intestinal wall thickening, with a significantly increased ratio of colon weight to length. Fissure-like ulcers formed on the intestinal mucosal surface, and typical granulomas were seen in the submucosa and muscularis, accompanied by inflammatory cell infiltration, primarily of lymphocytes and plasma cells. There was also significant proliferation of small blood vessels and connective tissue (fibroblasts), and crypt structural destruction and hemorrhage were observed around the ulcers. This model is simple to prepare and has good reproducibility, making it a widely used experimental animal model for evaluating drugs for the treatment of inflammatory bowel disease. Experimental animals (male SD rats) were randomly divided into 6 groups according to body weight parameters on the first day of the experiment, namely normal control group, model control group, positive drug mesalazine treatment group, low-dose compound 1 treatment group, high-dose compound 1 treatment group, low-dose compound 6 treatment group, high-dose compound 6 treatment group and compound 12 treatment group, each with 10 rats / group. On the day of grouping (D0), except for the normal control group which was given vehicle, the animals in the other experimental groups were given TNBS ethanol solution by enema to induce the model. The test article and positive control drug treatment began on the day after model induction. The treatment doses of compound 1 were 3.0 mg / kg and 6.0 mg / kg, respectively, the treatment doses of compound 6 were 1.4 mg / kg and 2.8 mg / kg, respectively, the treatment dose of compound 12 was 0.8 mg / kg, and the treatment dose of positive control drug mesalazine was 30.0 mg / kg. The administration method was enema, and the administration frequency was once a day for 14 consecutive days. The experimental treatment cycle ( During the period (D1-D14) between the experimental groups, the body weight and general clinical observation indicators (including but not limited to food intake, water intake, activity level and defecation, etc.) of the animals in each experimental group were dynamically collected. At the same time, the weight loss, stool morphology and bloody stool reactions of the animals in each experimental group after TNBS induction were scored based on the ulcerative colitis disease activity scoring criteria, and the ulcerative colitis disease activity (DAI) was calculated once a day for 14 consecutive days. At the end of the experiment, the colon tissue of the animals in each experimental group was collected, the colon length was measured and weighed, and then the non-autopsy images were collected. The colon was then dissected longitudinally along the intestinal wall and autopsy images were collected. Based on the "Colon Gross Morphological Manifestation Scoring Criteria", the gross damage of the colon adhesions, colon ulcers and inflammation of the animals in each experimental group were observed and scored. Ulcer images were collected under a stereomicroscope and the area of ​​the colon ulcer lesions was calculated. The animals were then routinely fixed. Based on the statistical analysis results of various pharmacodynamic test indicators, the therapeutic effect of the test polypeptide compound on the ulcerative colitis disease model under the set treatment regimen was evaluated.

[0607] Results and Conclusions:

[0608] In this experimental research system, the animals in the model control group showed obvious disease characteristics of ulcerative colitis, including suppressed weight gain, soft and loose stools, significantly increased ulcerative colitis disease activity index (DAI) score, and gross observation of colon atrophy, typical ulcer foci, and colonic confluent ulcer foci. Test compound 1 had a significant improvement effect on the suppressed weight gain of the model animals under the set treatment regimen, and the degree of improvement was statistically significant compared with the degree of weight change of the model control group animals during the same period (P<0.05). However, test compounds 6 and 12 did not show a significant improvement therapeutic effect on the suppressed weight gain of the model animals.

[0609] Table 6 Effects of the tested polypeptide compounds on body weight changes in model animals

[0610]

[0611]

[0612] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 indicates the statistical analysis results of the model control group and the normal control group. # P<0.05, ## P<0.01, indicates the statistical analysis results of the animals in the test polypeptide compound treatment group and the model control group.

[0613] The DAI score results of the experimental period showed that the test compounds 1, 6 and 12 had a significant improvement effect on the disease progression of ulcerative colitis in model animals under the set treatment regimen. The fecal pathological characteristics and weight loss responses of the corresponding treatment groups were significantly alleviated, and the mean DAI scores showed a decrease, which was significantly statistically different from the model control group in the same period (P<0.05). The improvement therapeutic effect of compound 1 was the most obvious, and the therapeutic effects of compounds 1 and 6 were obviously dose-dependent.

[0614] Table 7 Effects of the tested polypeptide compounds on the DAI scores of model animals

[0615]

[0616] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, ****P<0.0001 indicates the statistical analysis results of the model control group and the normal control group. # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 indicates the statistical analysis results of the test polypeptide compound treatment group and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++ P<0.0001 indicates the statistical analysis results between the compound 1 or 6 dose groups.

[0617] The results of gross anatomy and colon tissue injury scores at the experimental endpoint showed that the test compounds 1, 6 and 12 had significant therapeutic effects on TNBS-induced gross colon injury (colonic adhesions, ulcers and inflammation), colon ulcer area and abnormal increase in colon weight / length ratio. The degree of improvement was statistically different from that of the model control group during the same period (P<0.05). The therapeutic effect of compound 1 was the most significant, and its therapeutic effect was significantly dose-dependent.

[0618] Table 8 Effects of the tested polypeptide compounds on the gross damage and ulcer area of ​​the colon in model animals

[0619]

[0620]

[0621] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 indicates the statistical analysis results of the model control group and the normal control group. # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 indicates the statistical analysis results of the test polypeptide compound treatment group and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++ P<0.0001 indicates the statistical analysis results between the compound 1 or 6 dose groups.

[0622] Table 9 Effects of the tested polypeptide compounds on the colon weight / length ratio of model animals

[0623]

[0624] Note: All data were statistically analyzed using mean ± standard deviation (SD). * P<0.05, ** P<0.01, *** P<0.001, **** P<0.0001 indicates the statistical analysis results of the model control group and the normal control group. # P<0.05, ## P<0.01, ### P<0.001, #### P<0.0001 indicates the statistical analysis results of the test polypeptide compound treatment group and the model control group. + P<0.05, ++ P<0.01, +++ P<0.001, ++++ P<0.0001 indicates the statistical analysis results between the compound 1 or 6 dose groups.

[0625] This study used TNBS enema intervention in male SD rats to induce colonic lesions and establish a rat ulcerative colitis model consistent 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 period (D1-D14), the therapeutic effects of the test compounds on the TNBS-induced SD rat ulcerative colitis model were evaluated by monitoring changes in the experimental animals' body weight, ulcerative colitis disease activity index (DAI) score, gross colon damage (colonic adhesions, ulcers, and inflammatory response) score, colon tissue ulcer area, and colon weight / length ratio. The results showed that:

[0626] 1) After TNBS induction, the experimental animals showed obvious symptoms of ulcerative colitis, including significant weight loss, a significant increase in the ulcerative colitis disease activity score (DAI score), a significant increase in the colonic adhesion and ulcer score, an increase in the ulcer area of ​​colonic tissue, and a significant increase in the colon weight / length ratio. This indicates that the rat ulcerative colitis model was successfully established and is suitable for this experimental pharmacodynamic study.

[0627] 2) Test compound 1 significantly improved the weight loss response of the model animals under the established treatment regimen, with the degree of improvement being statistically significant compared with the model control group during the same period (P<0.05). However, test compounds 6 and 12, as well as the positive control drug mesalazine, did not show a significant effect on weight loss.

[0628] 3) Test compounds 1, 6, and 12 significantly improved the disease progression of ulcerative colitis in the model animals under the established treatment regimen, with DAI scores showing a significant decrease compared to the control group during the same period. The therapeutic effect of test compound 1 was the most pronounced. The improvement effects of test compounds 1 and 6 were clearly dose-dependent. The positive control drug, mesalazine, had no significant effect on the symptoms of ulcerative colitis in the model animals.

[0629] 4) Test compounds 1, 6, and 12 had significant therapeutic effects on the gross damage to the colon in model animals under the established treatment regimen. Compared with the model control group during the same period, the colon adhesion scores, colon ulcer and inflammation scores, and colon tissue ulcer area all showed a significant decrease, and the degree of improvement was statistically significant (P<0.05). The therapeutic effect of test compound 1 was the most significant, and its improved therapeutic effect was clearly dose-dependent.

[0630] 5) Test compounds 1, 6 and 12 had a significant improvement effect on the colon atrophy process of model animals under the set treatment regimen. Compared with the model control group during the same period, the colon weight / length ratio was significantly decreased (P<0.05).

[0631] It can be seen that this study established a rat ulcerative colitis model that is consistent with the clinical pathogenesis characteristics. The efficacy evaluation results in this model showed that test compounds 1, 6 and 12 all had significant therapeutic effects.

[0632] Example 4: Study on the Effect of Polypeptide Compounds on the Proliferation of CaCo-2 Cells in Vitro

[0633] The following cell lines were used to study the in vitro proliferation of peptide compounds:

[0634] Table 10 Cell line information

[0635] Serial number cell lines Cancer type Growth characteristics culture medium 1 CaCo-2 Colorectal cancer Adherence (MEM+0.01mM NEAA)+20% FBS

[0636] Experimental methods:

[0637] Cells were recovered and maintained according to the culture conditions shown in Table 10.

[0638] Day 1 (Cell Plating): Collect cells in the logarithmic growth phase, resuspend, count using a cell counter, and test for viability. Dilute the cell suspension according to the plating density requirements and add 90 μL of cell suspension to each well of a 96-well plate (cell plating density will be adjusted based on historical data or density optimization experiments). While plating, plate three replicate wells for each cell as T0 plates. Place all 96-well plates in a 37°C, 5% CO2 incubator overnight.

[0639] Day 2 (Change medium): Change the medium to the corresponding serum concentration according to the plate map, 90 μL per well. Day 2: Read the T0 plate and treat with the test compound. Add 10 μL of medium to each well of the T0 plate to make the total volume up to 100 μL. Add 50 μL to each well. Reagents. Mix and shake for 5 minutes to allow cells to fully lyse. Incubate at room temperature for 10 minutes to stabilize the luminescent signal (Note: temperature, cell density, and edge effects can lead to uneven luminescent signals). Use EnVision Multi Label Reader to detect the fluorescent signal. The test compound is configured according to the corresponding molecular weight C1 = 91.08 μM, diluted C2 = 9.108 μM, and C3 = 0.9108 μM. Cisplatin is diluted as shown in Table 11 to prepare a 10X compound working solution. Add 10 μL of working solution (10X) to each well, and the final volume per well of all plates is 100 μL. Cells are cultured in a 37°C, 5% CO2 incubator.

[0640] On day 5, after 72 hours of treatment with test compound (plate reading): Observe the normal function of the treated and control groups under a microscope. Add 50 μL of CTG reagent to each well. Mix on a shaker for 5 minutes to allow for complete cell lysis. Incubate at room temperature for 10 minutes to stabilize the luminescence signal. Read the fluorescence signal using the EnVision Multi Label Reader.

[0641] Table 11Cisplatin concentration after dilution

[0642] C1-1 C2-1 C3-1 C4-1 C5-1 C6-1 C7-1 C8-1 C9-1 C10-1 Concentration (μM) 1000 333.33 111.11 7.04 12.35 .12 .37 .46 0.15 0 Solution volume (μL) 90 0 0 0 90 90 0 90 90 90 Culture medium volume (μL) 09.7 09.7 09.7 09.7 209.7 09.7 09.7 09.7 209.7 09.7

[0643] Cell viability (%) = Lum 待测化合物 / Lum 溶剂对照 ×100%.

[0644] Experimental results: The statistical results of the proliferation-promoting activity of the selected polypeptide compounds are shown in Table 12:

[0645] Compound number Proliferative activity 1 Cell viability>110% 20 / 44 / 45 /

[0646] The experimental system was set with a test substance administration concentration gradient of C1 = 91.08 μM, C2 = 9.108 μM, and C3 = 0.9108 μM, using 0.88% FBS as a reference. The experimental results showed that the polypeptide compound 1 of the present application has the activity of promoting Caco-2 cell proliferation, specifically manifested by an increase in cell viability after intervention.

[0647] In summary, the polypeptide compounds of the present invention have short peptide chains and are absorbed faster and better. Experimental results show that the polypeptide compounds provided by this application have the activity of alleviating intestinal dilation of zebrafish colitis; in rat acute inflammatory bowel disease model tests, they have significant therapeutic effects. The polypeptide compounds of the present invention have significant efficacy in alleviating colitis and can be used to prepare drugs for treating enteritis, especially ulcerative colitis.

[0648] Although the present invention discloses the above embodiments, the implementation of the present invention is not limited to the above embodiments, and any other changes, modifications, substitutions, combinations, and simplifications that do not deviate from the present invention should be considered as equivalent replacement methods and are included in the protection scope of the present invention.

Claims

1. A compound of formula (I) or a physiologically compatible salt thereof, wherein the compound of formula (I) is as follows: H-X a -Arg-Lys-Val-Ala-X b -OH(I) in X a is one of the following amino acid residues: Pro, Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro, Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro, Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro, Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro, Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro, Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro, Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro, Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly, Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly, Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro, Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro, Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro or is absent; X b It is Ala-Gln or missing.

2. The compound according to claim 1 or a physiologically compatible salt thereof, wherein the compound is selected from the group consisting of: Pro-Arg-Lys-Val-Ala-Ala-Gln (Compound 5) Arg-Lys-Val-Ala (Compound 15) 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-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-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln (compound 34); 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); 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).

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

4. The use according to claim 3, wherein enteritis includes specific enteritis and nonspecific enteritis; further, specific enteritis includes inflammatory bowel disease, necrotizing enteropathy and dysbacteriosis enteritis; further, inflammatory bowel disease includes ulcerative colitis.

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

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