WO2023138644A1 - 多肽化合物及其治疗肠炎的用途 - Google Patents

多肽化合物及其治疗肠炎的用途 Download PDF

Info

Publication number
WO2023138644A1
WO2023138644A1 PCT/CN2023/073068 CN2023073068W WO2023138644A1 WO 2023138644 A1 WO2023138644 A1 WO 2023138644A1 CN 2023073068 W CN2023073068 W CN 2023073068W WO 2023138644 A1 WO2023138644 A1 WO 2023138644A1
Authority
WO
WIPO (PCT)
Prior art keywords
ala
pro
lys
val
gln
Prior art date
Application number
PCT/CN2023/073068
Other languages
English (en)
French (fr)
Inventor
耿福能
Original Assignee
四川好医生攀西药业有限责任公司
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by 四川好医生攀西药业有限责任公司 filed Critical 四川好医生攀西药业有限责任公司
Priority to CN202380012589.4A priority Critical patent/CN117858890A/zh
Publication of WO2023138644A1 publication Critical patent/WO2023138644A1/zh

Links

Classifications

    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P1/00—Drugs for disorders of the alimentary tract or the digestive system
    • A61P1/04—Drugs for disorders of the alimentary tract or the digestive system for ulcers, gastritis or reflux esophagitis, e.g. antacids, inhibitors of acid secretion, mucosal protectants
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K11/00—Depsipeptides having up to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K5/00—Peptides containing up to four amino acids in a fully defined sequence; Derivatives thereof
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof

Definitions

  • the present invention relates to a novel polypeptide and its application.
  • the polypeptide of the present invention has remarkable effect on treating inflammatory bowel disease, especially ulcerative colitis.
  • Enteritis is an intestinal inflammatory response caused by various reasons, such as intestinal bacteria, viruses and other pathogenic vitamin infection or immune damage, radiation damage, diet stimulation, drug stimulation and other factors.
  • the clinical manifestations mainly include fever, nausea, vomiting, abdominal pain, diarrhea, watery stools or mucus, pus and blood in stools, and some patients may also have tenesmus.
  • Enteritis can be divided into specific enteritis and non-specific enteritis according to inflammatory manifestations.
  • Specific enteritis also includes inflammatory bowel disease, necrotizing enteropathy, and dysbacteriotic enteritis. Among them, as the more common inflammatory bowel disease, it is an idiopathic, non-infectious, chronic, persistent, recurrent, and inflammatory disease involving the intestinal tract. The clinical manifestations are abdominal pain and diarrhea, pus and blood in the stool, and even fever, abdominal mass, emaciation and malnutrition. Inflammatory bowel disease is a chronic, long-term disease that requires long-term active treatment.
  • enteritis has a clear cause, such as bacterial enteritis, pseudomembranous enteritis, viral enteritis, radiation enteritis, etc., which are all types of enteritis with a clear cause, while non-specific enteritis has no clear cause, and it is considered to be caused by immune system diseases, such as ulcerative colitis, Crohn's disease, etc.
  • Inflammatory bowel disease also includes ulcerative colitis and Crohn's disease.
  • Ulcerative colitis is a chronic nonspecific intestinal inflammatory disease of unknown etiology, which most commonly occurs in young adults. The clinical manifestations are persistent or recurrent diarrhea, mucus pus and blood stools accompanied by abdominal pain, tenesmus, and systemic symptoms of varying degrees.
  • the lesions mainly involve the colonic mucosa and submucosa, starting from the distal colon of the rectum, developing retrogradely to the proximal end, and even involving the entire colon, and 5% can 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 etiology is not completely clear, but it is currently believed to be related to infection, immune abnormalities, genetics, and mental factors.
  • patients with enteritis often have symptoms such as intestinal lumen dilatation (also known as intestinal dilatation or intestinal tube dilatation).
  • inflammation destroys the nerve and muscle regulation mechanisms that control the normal intestine, and the pressure in the intestinal lumen expands the intestinal lumen wall beyond its normal activity. Or the overgrowth of microorganisms and the toxins they produce, mucus exudation, etc. are caused. Alleviating or inhibiting the expansion of the intestinal lumen is helpful for the treatment of enteritis.
  • the object of the present invention is to provide a new polypeptide compound and its application.
  • the inventors of the present invention found that the polypeptide compound of the present invention can effectively or significantly alleviate or inhibit the expansion of the intestinal lumen, thereby playing a role in treating enteritis.
  • the present invention relates to a compound of formula (I) or a physiologically compatible salt thereof, wherein said compound of formula (I) is as follows:
  • Z 1 is Pro, Ala, Gly, D-Pro or missing;
  • Z 2 is Val, Ala, D-Val, Ile or missing
  • Z 3 is Pro, Ala, Gly, D-Pro or missing;
  • Z4 is Gln, Ala, Glu, Ile, D-Gln or deletion
  • the condition is that at most 2 of Z 1 , Z 2 , Z 3 and Z 4 are missing.
  • X a is a sequence containing 0-10 amino acid residues
  • Xb is a sequence containing 0-9 amino acid residues.
  • Z1 , Z2 , Z3 and Z4 are deleted.
  • Z1 and Z2 are deleted.
  • Z3 and Z4 are deleted.
  • 1 of Z1 , Z2 , Z3 and Z4 is deleted.
  • Z1 is deleted.
  • Z4 is deleted.
  • zero of Z 1 , Z 2 , Z 3 and Z 4 are deleted.
  • Z 1 is Pro; Z 2 is Val; Z 3 is Pro; and Z 4 is Gln.
  • Z 1 is D-Pro; Z 2 is Val; Z 3 is Pro; and Z 4 is Gln.
  • Z 1 is Pro; Z 2 is Val; Z 3 is Ala; and Z 4 is Gln.
  • Z 1 is Pro; Z 2 is Ile; Z 3 is Pro; and Z 4 is Gln.
  • Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is deletion.
  • Z 1 is Pro; Z 2 is Ala; Z 3 is Pro; and Z 4 is Gln.
  • Z 1 is Gly; Z 2 is Val; Z 3 is Pro; and Z 4 is Gln.
  • Z 1 is Pro; Z 2 is Val; Z 3 is Gly; and Z 4 is Gln.
  • Z 1 is Ala; Z 2 is Val; Z 3 is Pro; and Z 4 is Gln.
  • Z1 is Pro; Z2 is Val; Z3 is Pro; and Z4 is Glu.
  • Z 1 is Pro; Z 2 is Val; Z 3 is D-Pro; and Z 4 is Gln.
  • Z 1 is Pro; Z 2 is Val; Z 3 is Pro; and Z 4 is D-Gln.
  • X a is X a10 -X a9 -X a8 -X a7 -X a6 -X a5 -X a4 -X a3 -X a2 -X a1 -*, wherein * represents the position attached to Z 1 -Z 2 -Z 3 -Z 4 , wherein
  • X a10 is Gly or missing
  • X a9 is Gly, Pro, Ser or missing
  • X a8 is Pro, Glu, Ser or missing
  • X a7 is Arg, Glu, Thr, Ser or missing
  • X a6 is Lys, Thr, Ala, Asp, Glu, Arg, Ser or missing,
  • X a5 is Asp, Ala, Val, Arg, Phe, Ile, Pro, Lys, Glu or missing,
  • X a4 is Val, Phe, Pro, Pyro-Glu, Lys, Leu, Ile, Ala, Asp or missing,
  • X a3 is Tyr, Leu, Pro, Asp, Arg, Glu, Lys, Tys, Val, Ile or missing,
  • X a2 is D-Lys, Lys, Ala, Arg, Val, Glu, Tyr or deletion, and
  • Xal is Glu, Ala, D-Glu, Tyr, Gln, Asp, Asn or deletion.
  • Xa is Xaa - Xa2 - Xa1- *, wherein * indicates the position of attachment to Z1 - Z2 - Z3 - Z4 , wherein Xa2 - Xa1 is Lys-Glu-*, and Xaa is as defined above.
  • X a is X a1 -*, wherein * represents the position linked to Z 1 -Z 2 -Z 3 -Z 4 , wherein X a1 is Glu, Ala, D-Glu, Asp, Asn or deletion.
  • X a is X a2 -X a1 -*, wherein * represents the position connected to Z 1 -Z 2 -Z 3 -Z 4 , wherein X a2 is Lys, and X a1 is Glu, D-Glu or Gln.
  • X b is **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 , wherein ** represents the position attached to Z 1 -Z 2 -Z 3 -Z 4 , wherein
  • X b1 is Ala, D-Ala or missing
  • X b2 is Lys, Ala, D-Lys, Arg or missing,
  • X b3 is Pro, Gly, D-Pro, Ser, Val, Ala or missing,
  • X b4 is Arg, Ala, Ser, Pro, D-Arg or missing,
  • X b5 is Lys, Ala, D-Lys, Glu, Tyr or deletion
  • X b6 is Val, Asp, D-Val, Ala or missing
  • X b7 is Ala, D-Ala, Ile or missing
  • X b8 is Ala, D-Ala, Lys or deletion
  • Xb9 is Gln, Ala, Glu, Asn, D-Gln or deletion.
  • X b is **-X b1 -X b2 -X b3 -X b4 -X b5 -X b6 -X b7 -X b8 -X b9 , wherein ** represents the position attached to Z 1 -Z 2 -Z 3 -Z 4 , wherein
  • X b1 is Ala or D-Ala
  • X b2 is Lys, Ala or D-Lys
  • X b3 is Pro, Gly, or Ala
  • X b4 is Arg or D-Arg
  • X b5 is Lys or missing
  • X b6 is Val, D-Val, Ala or missing
  • X b7 is Ala or missing
  • X b8 is Ala or missing
  • X b9 is Gln, Asn, D-Gln or deletion.
  • X b is **-X b1 -X b2 -X bb , wherein ** represents the position connected to Z 1 -Z 2 -Z 3 -Z 4 , X b1 -X b2 - is **-Ala-Lys-, and X bb is as defined above.
  • Xb is **-Ala-.
  • X b For **-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-Pro-Arg-Lys, **-Arg-Lys-Val-Ala, **-Ala-Lys-Pro-Arg-Arg-Lys-Val-Ala, **-Ala-Lys-Pro-Arg-Arg-Lys-Val-Ala, **-Pro
  • Z 1 is Pro ;
  • Z 2 is Val ;
  • Z 3 is Pro ;
  • Z 4 is Gln;
  • the position of the 3 -Z 4 linkage , X b1 -X b2 - is ** - Ala - Lys-, wherein X aa and X bb are as defined above.
  • the compound is selected from:
  • the compound is selected from:
  • 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 for treating enteritis.
  • enteritis includes specific enteritis and non-specific enteritis. Further, specific enteritis includes inflammatory bowel disease, necrotizing enteropathy and dysbacteriosis enteritis.
  • inflammatory bowel disease includes ulcerative colitis.
  • the present invention provides a pharmaceutical composition
  • a pharmaceutical composition comprising the polypeptide compound of the present invention or a physiologically compatible salt thereof, and a pharmaceutically acceptable excipient.
  • the dosage forms of the medicine include tablets, capsules, solutions, powders and pills.
  • the peptide chain of the above-mentioned polypeptide of the present invention is short, so it can be absorbed faster and better.
  • the experimental results show that the polypeptide provided by the present application has obvious effect of alleviating intestinal lumen expansion in the model test of acute inflammatory bowel disease in rats, and has a significant therapeutic effect in the model test of acute inflammatory bowel disease in rats.
  • the above-mentioned polypeptide of the present invention has a remarkable effect of alleviating colitis, and can be used to prepare medicines for treating enteritis, especially medicines for ulcerative colitis.
  • Figure 1 shows a schematic diagram of the steps of polypeptide solid-phase synthesis
  • Figure 2 shows the mass spectrum of the polypeptide.
  • an effective amount refers to an amount of an active ingredient, such as a compound, which when administered to a subject to treat a disease or at least one clinical symptom of a disease or disorder is sufficient to effect such treatment of the disease, disorder or condition.
  • the “therapeutically effective amount” may vary with the compound, the disease, disorder and/or symptoms of the disease or disorder, the severity of the disease, disorder and/or symptoms of the disease or disorder, the age of the subject to be treated and/or the weight of the subject to be treated. The appropriate amount in any given case will be apparent to those skilled in the art, or can be determined by routine experimentation.
  • a “therapeutically effective amount” is an amount effective for “treating” (as defined above) a disease or disorder in a subject of at least one compound disclosed herein and/or at least one stereoisomer thereof, and/or at least one pharmaceutically acceptable salt thereof.
  • therapeutically effective amount refers to the total amount of the combination used to effectively treat the disease, disorder or condition.
  • physiologically compatible salt refers to salt forms that are physiologically compatible (ie, pharmacologically acceptable) and substantially nontoxic to the individual to whom the compound of the invention will be administered.
  • Physiologically compatible salts of the compounds of the invention include those made from suitable, The customary and stoichiometric acid or base addition salts formed from non-toxic organic or inorganic acids or bases.
  • the term "lumenal dilatation” refers to dilation of the bowel or bowel tube.
  • enteritis due to intestinal damage, mucus exudation, intestinal pneumatosis or effusion, microbial overgrowth and other factors, the intestinal lumen is dilated and the intestine is thicker than the normal intestine.
  • Recurrent enteritis is common in clinical practice, such as inflammatory bowel disease causing intestinal dilation, or tumors causing intestinal dilation and intestinal obstruction.
  • Embodiment 1 chemical synthesis of polypeptide
  • the synthesis of peptide compounds adopts the conventional solid-phase synthesis method of automatic peptide synthesizer, and the chemical synthesis of peptides is carried out through the processes of resin swelling, deprotection, washing, amino acid activation, and condensation.
  • Amino acid connection Pour the activated protected amino acid solution into the reactor, and add an appropriate amount of DCM cleaning tools. Nitrogen gas bubbling reaction at room temperature for 1 to 3 hours, ninhydrin method to detect whether the amino acid connection is complete, if complete, drain. The resin was washed 5 times with DMF, 100ml/time, 3min/time, and drained. See Table 2 for the consumption of each amino acid and condensing agent.
  • Chromatographic column dynamic axial compression column 80*250mm, filler: Daisogel C18 (SP-100-8-ODS-P)
  • UV detection wavelength 220nm
  • the double charge peak indicates that the target molecule binds 2 protons, and the triple charge peak indicates that the target molecule binds 3 protons; N/A indicates that it is difficult to weigh, and the actual weight is not included.
  • Embodiment 2 Polypeptide compound has the effect experiment of alleviating colitis
  • mice wild-type AB strain zebrafish, which were reproduced by natural pair mating. Age is 3 days after fertilization (3dpf) Zebrafish. All zebrafish were raised in fish culture water at 28°C (water quality: add 200mg of instant sea salt to every 1L of reverse osmosis water, the conductivity is 450-550 ⁇ S/cm; the pH is 6.5-8.5; the hardness is 50-100mg/L CaCO 3 ). ) requirements.
  • polypeptide group prepare 20.0 mg/mL stock solution with ultrapure water, and store at -20°C.
  • Positive control group prednisone, white powder, batch number C10016501, Shanghai Macklin Biochemical Technology Co., Ltd., stored at 4°C; prepared into 15.0mg/mL mother solution with DMSO, and stored at -20°C.
  • each experimental group randomly selected 10 zebrafish and placed them under a dissecting microscope to take pictures.
  • the NIS-Elements D 3.20 advanced image processing software was used to analyze and collect data, analyze the intestinal lumen area of zebrafish, and use the statistical analysis results of this index to evaluate the colitis-relieving efficacy of the samples.
  • Statistical results are expressed as mean ⁇ SE.
  • SPSS26.0 software was used for statistical analysis, and p ⁇ 0.05 indicated that the difference was statistically significant.
  • polypeptide compound groups such as compounds 1, 4, 5, 6, 12, and 15 had significant statistical differences compared with the model control group (p ⁇ 0.05;p ⁇ 0.01;p ⁇ 0.001), and the effect was better than that of the prednisone group.
  • Experimental results show that the polypeptide compound provided by the present application has the effect of alleviating colitis, specifically manifested as significantly alleviating intestinal lumen dilation.
  • the administration concentration gradient of the test substance set in this experimental system was 250 ⁇ g/mL, 500 ⁇ g/mL, and 1000 ⁇ g/mL.
  • the administration concentration gradient of the test substance set in this experimental system was 250 ⁇ g/mL, 500 ⁇ g/mL, and 1000 ⁇ g/mL.
  • Example 3 Evaluation of the therapeutic efficacy of polypeptide compounds on the SD rat acute inflammatory bowel disease (UC) model induced by TNBS
  • TNBS trinitrobenzenesulfonic acid
  • Acute colitis in rats induced by trinitrobenzenesulfonic acid (TNBS) is an immune response induced by cytokines secreted by Th1 cells.
  • the colon of animals in the model control group showed obvious atrophy and thickening of the intestinal wall, and the ratio of colon weight to length was significantly increased. Fissure-like ulcers were formed on the surface of the intestinal wall mucosa. It can be seen that the structure of the crypt is destroyed and hemorrhage.
  • the model is simple to make and has good repeatability.
  • the experimental animal model widely used in the evaluation of drugs for the treatment of inflammatory bowel disease.
  • the experimental animals male SD rats
  • the experimental animals were randomly grouped according to body weight parameters on the first day of the experiment, and there were 6 groups in total, namely the normal control group, the model control group, the positive drug mesalazine treatment group, the compound 1 low-dose treatment group, the compound 1 high-dose treatment group, the compound 6 low-dose treatment group, the compound 6 high-dose treatment group and the compound 12 treatment group, each with 10 animals/group.
  • compound 1 treatment dosage is 3.0mg/kg and 6.0mg/kg respectively
  • compound 6 treatment dosage is 1.4mg/kg and 2.8mg/kg respectively
  • compound 12 treatment dosage is 0.8mg/kg
  • positive control drug mesalazine treatment dosage is 30.0mg/kg
  • administration method is enema administration
  • administration frequency is once a day, continuous 14 days; (including but not limited to food intake, drinking water, activity level, and defecation, etc.) were collected dynamically, and based on the scoring standards for ulcerative colitis disease activity, the animals in each experimental group were scored for weight loss, feces morphology, and hematochezia after being induced by TNBS, and the disease activity of ulcerative colitis (DAI) was calculated.
  • DAI ulcerative colitis
  • the model control group animals showed obvious disease characteristics of ulcerative colitis, including weight growth inhibition, soft and loose stools, ulcerative colitis disease activity DAI score significantly increased, colonic atrophy, typical ulcer focus and colon fusion ulcer focus can be seen in general observation; the test compound 1 had a significant improvement effect on the weight growth inhibition state of the model animals under the set treatment plan, and the degree of improvement was statistically different from that of the model control group in the same period (P ⁇ 0.05). There is no obvious therapeutic effect on the inhibition of body weight growth in model animals.
  • 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 process of ulcerative colitis in model animals under the set treatment plan, and the fecal characteristics and body weight loss of the animals in the corresponding treatment group were significantly relieved, and the average DAI score showed a decline response, which was statistically different from that of the model control group during the same period (P ⁇ 0.05).
  • test compounds 1, 6 and 12 had significant therapeutic effects on the TNBS-induced colon gross damage state (colon adhesion, ulceration and inflammation), the area of colonic ulcers and the abnormal increase in the colon weight/length ratio.
  • TNBS was used to intervene enemas in male SD rats to induce lesions in their colons, and to establish a rat model of ulcerative colitis that conformed to the clinical characteristics.
  • the test compounds 1, 6 and 12 and the positive control drug mesalazine were treated; during the treatment cycle (D1-D14), by monitoring the changes in the body weight of the experimental animals, the disease activity DAI score of ulcerative colitis, the general damage performance of the colon (colon adhesions and ulcers and inflammation) scores, the ulcer area of the colon tissue and the colon weight/length ratio, the therapeutic effect of the test product on the TNBS-induced SD rat ulcerative colitis model was evaluated, and the results found:
  • test compound 1 has a significant improvement effect on the weight loss response of the model animals under the set treatment plan, and its degree of improvement is statistically different from that of the model control group during the same period (P ⁇ 0.05), while the test compounds 6, 12 and the positive control drug mesalamine did not show a significant weight improvement effect;
  • test compounds 1, 6 and 12 have obvious improvement effects on the disease process of ulcerative colitis in model animals under the set treatment plan, and their DAI scores are significantly lower than those of the model control group in the same period.
  • the therapeutic effect of test compound 1 is the most obvious.
  • the improvement of the therapeutic effect of test compounds 1 and 6 has a significant dose-dependent effect, while the positive control drug mesalazine has no obvious effect on the symptoms of ulcerative colitis in model animals;
  • test compounds 1, 6 and 12 had obvious therapeutic effects on the gross damage of the colon of the model animals under the set treatment plan. Compared with the model control group at the same period, the colon adhesion score, colon ulcer and inflammation score and colon tissue ulcer area were all significantly decreased, and the degree of improvement was statistically significant (P ⁇ 0.05). The test compound 1 had the most obvious therapeutic effect, and its improved therapeutic effect had a significant dose-dependence.
  • test compounds 1, 6 and 12 had a significant improvement effect on the colonic atrophy process of the model animals under the set treatment plan, and the colon weight/length ratio was significantly decreased compared with the model control group during the same period (P ⁇ 0.05).
  • Day 1 Collect cells in logarithmic growth phase, resuspend, count and detect activity using a cell counter. Dilute the cell suspension according to the plating density requirements, and add 90 ⁇ L of the cell suspension to each well of the 96-well plate (the cell plating density will be adjusted according to historical data or density optimization experiments). At the same time as plating, each cell was plated in 3 replicate wells as a T0 plate. All 96-well plates were placed in a constant temperature incubator at 37°C and 5% CO2 overnight.
  • Day 2 Replace the medium with the corresponding serum concentration according to the platemap, 90 ⁇ L per well.
  • Day 2 T0 plate reading and test compound treatment. Add 10 ⁇ L medium to each well of the T0 plate to make up the total volume to 100 ⁇ L. Add 50 ⁇ L to each well reagent. Mix and shake for 5 minutes to fully lyse the cells. Incubate at room temperature for 10 min to stabilize the luminescent signal (Note: Temperature, cell density, and edge effects can all cause uneven luminescent signals). Fluorescence signals were detected using EnVision Multi Label Reader.
  • Cisplatin was diluted as shown in Table 11 to prepare a 10X compound working solution. Add 10 ⁇ L of working solution (10X) to each well, and the final volume of each well of all plates is 100 ⁇ L. The cells were cultured in an incubator at 37°C with 5% CO2.
  • the compound to be tested was treated for 72 hours (reading the plate): observe under the microscope whether the state of the drug-dosed group and the control group is normal.
  • the experimental results show that the polypeptide compound 1 of the present application has the activity of promoting the proliferation of Caco-2 cells, which is specifically manifested as an increase in the cell viability after the intervention.
  • the above-mentioned polypeptide compound of the present invention has a short peptide chain and can be absorbed faster and better.
  • the experimental results show that the polypeptide compound provided by the present application has the activity of alleviating the expansion of the intestinal lumen of zebrafish colitis; in the model test of acute inflammatory bowel disease in rats, it has a significant therapeutic effect.
  • the above-mentioned polypeptide compound of the present invention has a remarkable effect of alleviating colitis, and can be used to prepare medicines for treating enteritis, especially medicines for ulcerative colitis.

Abstract

提供一种新多肽，在斑马鱼炎症性肠病模型及大鼠炎症性肠病模型药效试验中，表现出了明显的缓解肠腔扩张效果，能够用于制备治疗肠炎药物，尤其是溃疡性结肠炎药物。

Description

多肽化合物及其治疗肠炎的用途 技术领域
本发明涉及一种新多肽及其应用，本发明的多肽具有显著的治疗炎症性肠病的效果，尤其是具有治疗溃疡性结肠炎的效果。
背景技术
肠炎是由于各种原因引起的肠道炎症反应，如肠道细菌、病毒等病原维生素感染或受到免疫损害、放射线损害、饮食刺激、药物刺激等因素。临床表现主要有发热、恶心、呕吐、腹痛、腹泻、稀水便或黏液脓血便，部分患者还可有里急后重感。
肠炎按照炎症表现可分为：特异性肠炎和非特异性肠炎。特异性肠炎又包括炎症性肠病、坏死性肠病以及菌群失调性肠炎。其中，作为较常见的炎症性肠病，是一种累及到肠道的，特发性的，非感染所导致的肠道的、慢性的、持续性、复发性、炎症性的疾病。临床表现为腹痛腹泻，检验脓血便，甚至有发热，腹块，消瘦营养不良等症状。炎症性肠病是一种慢性的长期的疾病，需要进行长期的积极的治疗。
一般特异性肠炎有明确病因，比如细菌性肠炎、伪膜性肠炎、病毒性肠炎、放射性肠炎等,都是有明确病因的一类肠炎，而非特异性肠炎没有明确病因，考虑由免疫系统疾病导致，比如溃疡性结肠炎、克罗恩病等等。炎症性肠病又包括溃疡性结肠炎和克罗恩病。溃疡性结肠炎是一种病因尚不十分清楚的慢性非特异性肠道炎症性疾病，最常发生于青壮年期。临床表现为持续或反复发作的腹泻、黏液脓血便伴腹痛、里急后重和不同程度的全身症状。可有皮肤、黏膜、关节、眼、肝、胆等肠外表现。并发症包括中毒性巨结肠、肠穿孔、下消化道大出血、上皮内瘤变以及癌变。我国缺少确切的UC发病率数据，基于区域性的流行病学调查提示我国的UC发病率为0.42-2.22/10万。虽然与西方国家相比发病率仍然较低，然而与20年前相比，呈明显上升趋势。病变主要累及结肠黏膜及黏膜下层，范围自直肠远端结肠开始，逆行向近端发展，甚至累及全结肠，5％可累及末端回肠，呈连续性分布。溃疡性结肠炎的临床主要表现为腹泻、腹痛和黏液脓血便，病因尚未完全清楚，目前认为与感染、免疫异常、遗传和精神因素有关。此外，肠炎患者通常会有肠腔扩张(亦称为肠道扩张或肠管扩张)等症状，可能是炎症破坏了控制正常肠道的神经与肌肉调节机制，肠腔内压力使肠腔壁扩张超过其正常活动度。或者微生物过度生长及其产生的毒素，粘液渗出等造成的。缓解或抑制肠腔扩张有助于肠炎的治疗。
目前常用于治疗溃疡性结肠炎的药物虽具有一定的预防和治疗效果，但仍存在吸收较慢，治疗周期较长，治疗效果不明显等缺点。
发明内容
为了克服现有技术的不足和缺陷，本发明的目的在于提供一种新多肽化合物及其应用。本发明的发明人发现，本发明的多肽化合物能有效或显著缓解或抑制肠腔扩张，从而起到治疗肠炎的作用。
第一方面，本发明涉及式(I)的化合物或其生理学上相容的盐，其中所述式(I)的化合物如下：
H-Xa-Z1-Z2-Z3-Z4-Xb-OH   (I)
其中
Z1为Pro、Ala、Gly、D-Pro或缺失；
Z2为Val、Ala、D-Val、Ile或缺失；
Z3为Pro、Ala、Gly、D-Pro或缺失；
Z4为Gln、Ala、Glu、Ile、D-Gln或缺失；
条件是：Z1、Z2、Z3和Z4中至多有2个是缺失的。
Xa为含有0-10个氨基酸残基的序列；
Xb为含有0-9个氨基酸残基的序列。
在一实施方案中，Z1、Z2、Z3和Z4中有2个是缺失的。在一实施方案中，Z1和Z2是缺失的。在一实施方案中，Z3和Z4是缺失的。在一实施方案中，Z1、Z2、Z3和Z4中有1个是缺失的。在一实施方案中，Z1是缺失的。在一实施方案中，Z4是缺失的。在一实施方案中，Z1、Z2、Z3和Z4中有0个是缺失的。
在一实施方案中，Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为D-Pro；Z2为Val；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Val；Z3为Ala；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Ile；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Val；Z3为Pro；以及Z4为缺失。在一实施方案中，Z1为Pro；Z2为Ala；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为Gly；Z2为Val；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Val；Z3为Gly；以及Z4为Gln。在一实施方案中，Z1为Ala；Z2为Val；Z3为Pro；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Glu。在一实施方案中，Z1为Pro；Z2为Val；Z3为D-Pro；以及Z4为Gln。在一实施方案中，Z1为Pro；Z2为Val；Z3为Pro；以及Z4为D-Gln。
在一实施方案中，Xa为Xa10-Xa9-Xa8-Xa7-Xa6-Xa5-Xa4-Xa3-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中
Xa10为Gly或缺失，
Xa9为Gly、Pro、Ser或缺失，
Xa8为Pro、Glu、Ser或缺失，
Xa7为Arg、Glu、Thr、Ser或缺失，
Xa6为Lys、Thr、Ala、Asp、Glu、Arg、Ser或缺失，
Xa5为Asp、Ala、Val、Arg、Phe、Ile、Pro、Lys、Glu或缺失，
Xa4为Val、Phe、Pro、Pyro-Glu、Lys、Leu、Ile、Ala、Asp或缺失，
Xa3为Tyr、Leu、Pro、Asp、Arg、Glu、Lys、Tys、Val、Ile或缺失，
Xa2为D-Lys、Lys、Ala、Arg、Val、Glu、Tyr或缺失，以及
Xa1为Glu、Ala、D-Glu、Tyr、Gln、Asp、Asn或缺失。
在一实施方案中，Xa为Xaa-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，Xa2-Xa1为Lys-Glu-*、Arg-Glu-*、Val-Tyr-*、Glu-Glu-*、Lys-Gln-*、Lys-D-Glu-*或Tyr-Glu-*，以及Xaa为Xa10-Xa9-Xa8-Xa7-Xa6-Xa5-Xa4-Xa3-，其中Xa10为Gly或缺失，Xa9为Gly、Pro、Ser或缺失，Xa8为Pro、Glu、Ser或缺失，Xa7为Arg、Glu、Thr、Ser或缺失，Xa6为Lys、Thr、Ala、Asp、Glu、Arg、Ser或缺失，Xa5为Asp、Ala、Val、Arg、Phe、Ile、Pro、Lys、Glu或缺失，Xa4为Val、Phe、Pro、Pyro-Glu、Lys、Leu、Ile、Ala、Asp或缺失，以及Xa3为Tyr、Leu、Pro、Asp、Arg、Glu、Lys、Tys、Val、Ile或缺失。在一实施方案中，Xaa为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-或缺失，其中最右侧的连接符-表示与-Xa2-Xa1连接。在一实施方案中，Xa为Xaa-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中Xa2-Xa1为Lys-Glu-*，以及Xaa为如上所定义。
在一实施方案中，Xa为Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中Xa1为Glu、Ala、D-Glu、Asp、Asn或缺失。
在一实施方案中，Xa为Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中Xa2为Lys， 以及Xa1为Glu、D-Glu或Gln。
在一实施方案中，Xa为Glu-*、Ala-*、D-Glu-*、Asp-*、Asn-*、Lys-Glu-*、D-Lys-Glu-*、Ala-Glu-*、Lys-Gln-*、Lys-D-Glu-*、Lys-Ala-*、Arg-Lys-Asp-Val-Tyr-Lys-Glu-*、Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-*、Val-Pro-Pro-Lys-Glu-*、Pyro-Glu-Leu-Lys-Glu-*、Arg-Lys-Asp-Val-Tyr-*、Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-*、Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-*、Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-*、Val-Pro-Tys-Lys-Glu-*、Pro-Ala-Tys-Lys-Glu-*、Arg-Lys-Asp-Val-Tyr-Glu-*、Ser-Ser-Glu-Asp-Ile-Lys-Glu-*或缺失，其中*表示与Z1-Z2-Z3-Z4连接的位置。
在一实施方案中，Xb为**-Xb1-Xb2-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中**表示与Z1-Z2-Z3-Z4连接的位置，其中
Xb1为Ala、D-Ala或缺失，
Xb2为Lys、Ala、D-Lys、Arg或缺失，
Xb3为Pro、Gly、D-Pro、Ser、Val、Ala或缺失，
Xb4为Arg、Ala、Ser、Pro、D-Arg或缺失，
Xb5为Lys、Ala、D-Lys、Glu、Tyr或缺失，
Xb6为Val、Asp、D-Val、Ala或缺失，
Xb7为Ala、D-Ala、Ile或缺失，
Xb8为Ala、D-Ala、Lys或缺失，以及
Xb9为Gln、Ala、Glu、Asn、D-Gln或缺失。
在一实施方案中，Xb为**-Xb1-Xb2-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中**表示与Z1-Z2-Z3-Z4连接的位置，其中
Xb1为Ala或D-Ala，
Xb2为Lys、Ala或D-Lys，
Xb3为Pro、Gly、或Ala，
Xb4为Arg或D-Arg，
Xb5为Lys或缺失，
Xb6为Val、D-Val、Ala或缺失，
Xb7为Ala或缺失，
Xb8为Ala或缺失，以及
Xb9为Gln、Asn、D-Gln或缺失。
在一实施方案中，Xb为**-Xb1-Xb2-Xbb，其中**表示与Z1-Z2-Z3-Z4连接的位置，Xb1-Xb2-为**-Ala-Lys-、**-Ala-Lys-、**-Ala-D-Lys-、**-Ala-Ala-或**-D-Ala-Lys-，Xbb为-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中Xb3为Pro、Gly、D-Pro、Ser、Val、Ala或缺失，Xb4为Arg、Ala、Ser、Pro、D-Arg或缺失，Xb5为Lys、Ala、D-Lys、Glu、Tyr或缺失，Xb6为Val、Asp、D-Val、Ala或缺失，Xb7为Ala、D-Ala、Ile或缺失，Xb8为Ala、D-Ala、Lys或缺失，以及Xb9为Gln、Ala、Glu、Asn、D-Gln或缺失；或者Xb3为Pro、Gly、或Ala，Xb4为Arg或D-Arg，Xb5为Lys或缺失，Xb6为Val、D-Val、Ala或缺失，Xb7为Ala或缺失，Xb8为Ala或缺失，以及Xb9为Gln、Asn、D-Gln或缺失。在一实施方案中，Xbb为-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-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Ala-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Ala-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-Ala、-Gly-Arg-Lys-Val-Ala-Ala-Gln、-D-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-D-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-D-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-D-Ala-Gln、-Ser-Ser-Glu-Asp-Ile-Lys-Glu、-Pro-Arg-Lys-Val-Ala-Ala-Asn、-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-D-Val-Ala-Ala-Gln、-Ala-Arg-Lys-Val-Ala-Ala-Gln、 -Pro-Arg-Lys-Ala-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-D-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-D-Gln或缺失，其中最左侧的连接符-表示与Xb1-Xb2连接。在一实施方案中，Xb为**-Xb1-Xb2-Xbb，其中**表示与Z1-Z2-Z3-Z4连接的位置，Xb1-Xb2-为**-Ala-Lys-、Xbb如上述所定义。
在一实施方案中，Xb为**-Ala-。
在一实施方案中，Xb为**-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-Pro-Arg-Lys、**-Arg-Lys-Val-Ala、**-Ala-Lys-Pro-Arg-Lys-Val-Ala、**-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala、**-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-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-Gln、**-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或缺失，其中**表示与Z1-Z2-Z3-Z4连接的位置。
在一实施方案中，Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Gln；Xa为Xaa-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中Xa2-Xa1为Lys-Glu-*，以及Xb为**-Xb1-Xb2-Xbb，其中**表示与Z1-Z2-Z3-Z4连接的位置，Xb1-Xb2-为**-Ala-Lys-，其中Xaa和Xbb如上所定义。
在一实施方案中，所述化合物选自：
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物1)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物2)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物3)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物4)；
Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物5)；
Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物6)；
Lys-Glu-Pro-Val(化合物7)；
Val-Ala-Ala-Gln(化合物8)；
Glu-Pro-Val-Pro(化合物9)；
Lys-Pro-Arg-Lys(化合物10)；
Ala-Lys-Pro-Arg(化合物11)；
Pro-Val-Pro-Gln(化合物12)；
Val-Pro-Gln-Ala(化合物13)；
Pro-Gln-Ala-Lys(化合物14)；
Arg-Lys-Val-Ala(化合物15)；
Lys-Val-Ala-Ala(化合物16)；
Gln-Ala-Lys-Pro(化合物17)；
Pro-Arg-Lys-Val(化合物18)；
Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物19)；
Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物20)；
Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物21)；
Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物22)；
Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物23)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物24)；
Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物25)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln(化合物26)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln(化合物27)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln(化合物28)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln(化合物29)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala(化合物30)；
Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物31)；
Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物32)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物33)；
Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物34)；
Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物35)；
Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物36)；
Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物37)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物38)；
Pro-Val-Pro-Gln-Ala(化合物39)；
Pro-Val-Pro-Glu-Ala(化合物40)；
Pro-Val-Pro-Ile-Ala(化合物41)；
Pro-Val-Pro-Ala(化合物42)；
Glu-Pro-Val-Pro-Gln-Ala(化合物43)；
Pro-Val-Pro-Gln-Ala-Lys(化合物44)；
Glu-Pro-Val-Pro-Gln-Ala-Arg(化合物45)；
Ala-Pro-Val-Pro-Gln-Ala-Lys(化合物46)；
Glu-Pro-Val-Pro-Ala-Ala-Lys(化合物47)；
Glu-Pro-Val-Pro-Gln-Ala-Ala(化合物48)；
Asp-Pro-Val-Pro-Gln-Ala-Lys(化合物49)；
Asn-Pro-Val-Pro-Gln-Ala-Lys(化合物50)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala(化合物51)；
Glu-Pro-Ala-Pro-Gln-Ala-Lys(化合物52)；
Glu-Ala-Val-Pro-Gln-Ala-Lys(化合物53)；
Glu-Pro-Val-Ala-Gln-Ala-Lys(化合物54)；
Glu-Pro-Val-Pro-Glu-Ala-Lys(化合物55)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val(化合物56)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物57)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro(化合物58)；
Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物59)；
Pro-Val-Pro-Gln-Ala-Lys-Pro(化合物60)；
D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物61)；
Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物62)；
Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物63)；
Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物64)；
Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物65)；
Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物66)；
Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物67)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物68)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物69)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln(化合物70)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln(化合物71)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln(化合物72)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln(化合物73)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln(化合物74)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln(化合物75)；
Glu-Gly-Val-Pro-Gln-Ala-Lys(化合物76)；
Glu-Pro-Val-Gly-Gln-Ala-Lys(化合物77)；
D-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物78)；
Glu-D-Pro-Val-Pro-Gln-Ala-Lys(化合物79)；
Glu-Pro-D-Val-Pro-Gln-Ala-Lys(化合物80)；
Glu-Pro-Val-D-Pro-Gln-Ala-Lys(化合物81)；
Glu-Pro-Val-Pro-D-Gln-Ala-Lys(化合物82)；
Glu-Pro-Val-Pro-Gln-D-Ala-Lys(化合物83)；
Glu-Pro-Val-Pro-Gln-Ala-D-Lys(化合物84)；
Lys-Glu-Pro-Val-Pro(化合物85)；
Glu-Pro-Val-Pro-Gln(化合物86)；
Lys-Glu-Pro-Val-Pro-Gln(化合物87)；
Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物88)；
Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物89)；
Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物90)；
Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物91)；
Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物92)；
Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物93)；
Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln(化合物94)；
Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物95)；
Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物96)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gl n(化合物97)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物98)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln(化合物99)；
Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物100)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu(化合物101)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr(化合物102)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu(化合物103)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn(化合物104)；
Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物105)；
Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物106)；
Val-Pro-Gln-Ala(化合物107)；或
Val-Pro-Gln-Ala-Lys(化合物108)。
在一实施方案中，所述化合物选自：
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物1)；
Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物63)；
Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物96)；
Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物100)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn(化合物104)；
Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物6)；
Pro-Val-Pro-Gln(化合物12)；
Glu-Pro-Val-Ala-Gln-Ala-Lys(化合物54)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物57)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物68)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln(化合物72)；
Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物89)；
Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物92)；
Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln(化合物94)；
Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物95)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gl n(化合物97)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物98)；
Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物105)；
Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物106)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物4)；
Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物5)；
Glu-Pro-Val-Pro(化合物9)；
Lys-Pro-Arg-Lys(化合物10)；
Arg-Lys-Val-Ala(化合物15)；
Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物25)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln(化合物26)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln(化合物29)；
Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物31)；
Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物34)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物38)；
Glu-Pro-Val-Pro-Gln-Ala-Ala(化合物48)；
Asp-Pro-Val-Pro-Gln-Ala-Lys(化合物49)；
Asn-Pro-Val-Pro-Gln-Ala-Lys(化合物50)；
Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala(化合物51)；
Glu-Ala-Val-Pro-Gln-Ala-Lys(化合物53)；
Glu-Pro-Val-Pro-Glu-Ala-Lys(化合物55)；
Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物62)；
Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物65)；
Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物66)；
Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物67)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln(化合物70)；
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln(化合物75)；
Glu-Pro-Val-Pro-Gln-D-Ala-Lys(化合物83)；
Lys-Glu-Pro-Val-Pro(化合物85)；
Glu-Pro-Val-Pro-Gln(化合物86)；
Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物88)；
Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物90)；
Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物93)；
Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln(化合物99)；或
Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu(化合物103)。
第二方面，本发明提供了所述多肽化合物或其生理学上相容的盐在制备用于治疗肠炎的药物中的用途；或者治疗肠炎的方法，所述方法包括对受试者给药治疗有效量的所述多肽化合物或其生理学上相容的盐；或者所述多肽化合物或其生理学上相容的盐，其用于治疗肠炎。
进一步地，肠炎包括特异性肠炎和非特异性肠炎。进一步地，特异性肠炎包括炎症性肠病、坏死性肠病以及菌群失调性肠炎。
进一步地，炎症性肠病包括溃疡性结肠炎。
进一步地，本发明提供了药物组合物，所述药物组合物包含本发明的多肽化合物或其生理学上相容的盐，以及可药用赋形剂。
进一步地，药物的剂型包括片剂、胶囊剂、溶液剂、散剂和丸剂。
本发明提供的新多肽及其应用的有益效果：
本发明的上述多肽的肽链短，因而吸收更快更好。实验结果表明，本申请提供的多肽在大鼠急性炎症性肠病模型试验中，表现出了明显的缓解肠腔扩张效果；在大鼠急性炎症性肠病模型试验中，具备显著的治疗效果。本发明的上述多肽具有显著的缓解结肠炎的功效，能够用于制备治疗肠炎药物，尤其是溃疡性结肠炎药物。
附图说明
图1示出了多肽固相合成步骤示意图；
图2示出了多肽的质谱图。
具体实施方式
以下是结合具体试验对本发明的说明，并不是对本发明保护范围的限制。
如本申请(包括所附权利要求书)所用，除非上下文另外清楚地指示，否则单数形式的词语如“一个/一种(a、an)”和“所述(the)”包括它们对应的复数指代物。
除非上下文另外清楚地指示，否则术语“或”用于意指术语“和/或”，并且可与术语“和/或”互换使用。
术语“有效量”或“治疗有效量”是指活性成分(诸如化合物)的如下量，当向受试者施用以治疗疾病或者疾病或障碍的至少一种临床症状时足以影响对所述疾病、障碍或症状的这种治疗。“治疗有效量”可以随化合物，疾病、障碍和/或疾病或障碍的症状，疾病、障碍和/或疾病或障碍的症状的严重程度，待治疗的受试者的年龄和/或待治疗的受试者的体重而变化。在任何给定的情况下，适当的量对于本领域技术人员来说可以是清楚的，或者可以通过常规实验来确定。在一些实施方案中，“治疗有效量”是本申请公开的至少一种化合物和/或其至少一种立体异构体、和/或其至少一种其可药用盐对“治疗”(如上所定义)受试者的疾病或障碍有效的量。在组合疗法的情况下，“治疗有效量”是指用于有效治疗疾病、障碍或病症的组合对象的总量。
术语“生理学上相容的盐”是指生理学上相容的(即药理学上可接受的)并且对将被施用本发明化合物的个体基本上无毒的盐形式。本发明化合物的生理学上相容的盐包括由适宜的、 无毒的有机或无机酸或无机碱形成的常规的和化学计量的酸加成盐或碱加成盐。
术语“肠腔扩张”是指肠道扩张或肠管扩张。肠炎患者中因肠道受损，粘液渗出，肠管积气或者积液，微生物过度生长等多种因素引起的肠腔扩张肠管比正常肠管粗，临床常见反复性肠炎例如炎症性肠病导致肠管扩张，或者肿瘤造成肠管扩张，肠道不通。
本申请所所使用的，各氨基酸缩写如下所示
表1溶剂、试剂等英文及其缩写的中文名称
实施例1：多肽的化学合成
多肽化合物的合成采用全自动多肽合成仪常规固相合成方法，经过树脂溶胀、脱保护、洗涤、氨基酸活化、缩合过程，进行多肽的化学合成。
以Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物1)为例，多肽固相合成步骤示意图参见图1。
步骤一、多肽的全保护肽树脂制备
(1)树脂溶胀：称取2-Chlorotrityl Chloride Resin 7.71g(SD＝0.73mmol/g)，加入到有筛板的合成管中，用100ml二氯甲烷(DCM)溶胀。
(2)制备Fmoc-Gln(Trt)-树脂：按树脂、Fmoc-Gln(Trt)-OH、DIPEA，以1:1.78:4.31的摩尔比分别称取Fmoc-Gln(Trt)-OH、DIPEA，加入合成管中。室温下氮气(N2)鼓泡震荡1～3小时，抽干；然后分别用二甲基甲酰胺(DMF)洗涤5次，100ml/次，抽干树脂。
(3)脱除Fmoc保护基：向反应器中加入100ml的20％哌啶-DMF(v/v)溶液，氮气鼓泡反应20min，抽干；然后用DMF洗涤5次，100ml/次，3分钟/次，抽干，茚三酮法检测Fmoc脱除结果。
(4)氨基酸预活化：在250ml烧杯中加入15mmol的Fmoc保护的氨基酸、15mmol HOBt、15mmol DIC，用100ml DMF溶解，室温下搅拌、待用。
(5)氨基酸连接：将已活化的保护氨基酸溶液倒入反应器中，补加适量的DCM清洗用具。室温下氮气鼓泡反应1～3小时，茚三酮法检测氨基酸连接是否完全，若完全，抽干。树脂用DMF洗涤5次，100ml/次，3min/次，抽干。每一种氨基酸、缩合剂的用量见表2。
(6)第一个氨基酸缩合完成后，重复步骤(4)和(5)，按照氨基酸顺序延长肽链至最后一个氨基酸偶联完毕。
(7)树脂肽用DMF洗涤4次，150ml/次，3min/次；再用DCM洗涤5次，150ml/次，3min/次，抽干。
表2氨基酸、缩合剂的用量
步骤二、切割
(1)在合成管中加入切割剂(TFA:TIPS:H2O＝95:2.5:2.5，v/v)100ml，氮气鼓泡反应1.5～3小时。
(2)切割反应完成后，将切割剂抽滤至250ml圆底烧瓶中。真空浓缩至原切割剂体积的四分之一后，加入10倍现有体积的甲基叔丁基醚，沉降得白色固体。将所得混合物过滤，并用50ml甲基叔丁基醚分别清洗3次后，将所得粗肽产品置于砂芯漏斗在通风橱中氮气吹干，使溶剂挥发至粗肽为粉末状。得到粗肽9.04g，粗产率74.7％。
步骤三、纯化、换盐和冻干
多肽HPLC直接换盐(醋酸盐)
A.色谱参数
色谱柱：动态轴向压缩柱80*250mm，填料：Daisogel C18(SP-100-8-ODS-P)
洗脱液A1：0.1M乙酸
洗脱液A2：0.025M乙酸—0.1M乙酸铵
洗脱液B：乙腈
流速：180ml/min
紫外检测波长：220nm
B.操作步骤
a)用水和/或乙腈溶解粗肽，并经0.45μm滤膜过滤
b)95％A1+5％B平衡色谱柱
c)进样
d)95％A2+5％B平衡色谱柱
e)A1和B梯度洗脱
f)收集目的肽洗脱液
g)旋蒸浓缩
h)冷冻干燥
纯化粗肽8.26g，得纯肽4.92g，纯化收率59.5％。
以与合成化合物1类似的方式，合成其他化合物。结果参见表3和说明书其他部分。
表3合成的多肽化合物





注释：双电荷峰表示目标分子结合2个质子，三电荷峰表示目标分子结合3个质子；N/A代表称量有难度，未计实际重量。
化合物1：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C73H127N23O20；m/z：m/z：549.65904([M+3H]3+)，823.98493([M+2H]2+)，1646.96346([M+H]+).
1H 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).
化合物2：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C57H100N18O15；m/z：426.59680([M+3H]3+)，639.39021([M+2H]2+)，1277.77023([M+H]+).
1H NMR(600MHz,DMSO-d6)δ4.57(dd,J＝8.7,4.9Hz,1H),4.41–4.11(m,10H),3.83(s,1H),3.78(t,J＝6.5Hz,1H),3.54(d,J＝73.5Hz,7H),3.08(d,J＝7.0Hz,2H),2.74–2.68(m,7H),2.32(d,J＝9.1Hz,2H),2.23–2.17(m,2H),2.05–1.46(m,AcOH,56H),1.43–1.22(m,7H),1.17(d,J＝7.0Hz,3H),0.82(dd,J＝19.6,6.7Hz,6H).
化合物3：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C51H88N16O14；m/z：383.89927([M+3H]3+)，575.34276([M+2H]2+)，1149.67551([M+H]+).
1H 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).
化合物4：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C40H69N11O12；m/z：448.76653([M+2H]2+)，896.52058([M+H]+).
1H NMR(600MHz,DMSO-d6)δ4.56(dd,J＝9.0,4.9Hz,1H),4.39(dd,J＝8.3,4.4Hz,1H),4.31–4.24(m,3H),4.13(dd,J＝9.1,5.1Hz,2H),3.78(dd,J＝7.9,4.3Hz,1H),3.67–3.51(m,4H),2.75–2.70(m,4H),2.38–2.29(m,2H),2.14(t,J＝7.8Hz,2H),2.04–1.47(m,AcOH,33H),1.35–1.28(m,4H),1.19(d,J＝7.2Hz,3H),0.85(dd,J＝22.1,6.8Hz,6H).
化合物5：Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C33H60N12O9；m/z：385.24021([M+2H]2+)，769.46971([M+H]+).
1H 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,AcOH,10H),1.62–1.40(m,8H),1.19(d,J＝7.2Hz,8H),0.73(dd,J＝6.7,4.0Hz,6H).
化合物6：Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C34H57N9O11；m/z：768.42641([M+H]+).
1H 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).
化合物7：Lys-Glu-Pro-Val(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C21H37N5O7；m/z：472.27768([M+H]+).
1H NMR(600MHz,D2O)δ4.43(dd,J＝10.2,4.0Hz,1H),4.27(dd,J＝8.3,5.3Hz,1H),3.85–3.80(m,2H),3.68–3.60(m,1H),3.59–3.46(m,1H),2.80(t,J＝7.6Hz,2H),2.22–2.14(m,2H),2.10–2.06(m,1H),1.96–1.64(m,AcOH,11H),1.52–1.47(m,2H),1.29–1.22(m,2H),0.71(dd,J＝15.3,6.9Hz,6H).
化合物8：Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C16H29N5O6；m/z：388.2187([M+H]+).
1H NMR(600MHz,D2O)δ4.25(q,J＝7.2Hz,1H),4.17(q,J＝7.2Hz,1H),4.05(dd,J＝8.5,4.8Hz,1H),3.67(d,J＝6.0Hz,1H),2.23–2.14(m,2H),2.13–2.05(m,1H),2.04–1.95(m,1H),1.85–1.76(m,1H),1.28(dd,J＝7.2,5.0Hz,6H),0.90(dd,J＝10.3,6.9Hz,6H).
化合物9：Glu-Pro-Val-Pro(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C20H32N4O7；441.23562([M+H]+).
1H 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).
化合物10：Lys-Pro-Arg-Lys(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C23H45N9O5；264.68527([M+2H]2+)，528.36210([M+H]+).
1H NMR(600MHz,DMSO-d6)δ4.42(dd,J＝8.2,5.2Hz,1H),4.23(t,J＝6.7Hz,1H),4.14(dd,J＝8.9,5.2Hz,1H),4.09(d,J＝7.9Hz,1H),3.64(dd,J＝9.9,6.6Hz,1H),3.45–3.40(m,1H),3.07(s,2H),2.72(t,J＝6.3Hz,4H),2.11–2.04(m,1H),1.92–1.66(m,AcOH,18H),1.56–1.48(m,8H),1.45–1.38(m,2H),1.33–1.29(m,2H).
化合物11：Ala-Lys-Pro-Arg(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C20H38N8O5；236.15638([M+2H]2+)，471.30462([M+H]+).
1H NMR(600MHz,D2O))δ4.55(dd,J＝8.3,5.6Hz,1H),4.34(dd,J＝8.4,5.9Hz,1H),4.09–3.96(m,2H),3.82–3.74(m,1H),3.64–3.55(m,1H),3.12(t,J＝6.9Hz,2H),2.93(t,J＝7.6Hz,2H),2.28–2.20(m,1H),2.04–1.83(m,3H),1.82(s,AcOH,6H),1.79–1.60(m,6H),1.58–1.51(m,2H),1.42(d,J＝7.1Hz,5H).
化合物12：Pro-Val-Pro-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C20H33N5O6；m/z：440.25122([M+H]+).
1H NMR(600MHz,D2O)δ4.33–4.18(m,3H),3.97(dd,J＝8.9,4.8Hz,1H),3.74–3.65(m,1H),3.53–3.46(m,1H),3.25–3.16(m,2H),2.29–2.22(m,1H),2.17–2.10(m,3H),1.99–1.66(m,AcOH,12H),0.82(d,J＝6.8Hz,3H),0.76(d,J＝6.7Hz,3H).
化合物13：Val-Pro-Gln-Ala(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C18H31N5O6；m/z：414.23575([M+H]+).
1H 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).
化合物14：Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C19H34N6O6；m/z：222.13480([M+2H]2+)，443.26183([M+H]+).
1H NMR(600MHz,D2O)δ4.28(dd,J＝8.7,6.1Hz,1H),4.25–4.15(m,2H),4.01(dd,J＝8.1,5.2Hz,1H),3.34–3.22(m,2H),2.86(t,J＝7.5Hz,2H),2.37–2.29(m,1H),2.26(t,J＝7.6Hz,2H),2.00–1.84(m,5H),1.73–1.64(m,1H),1.62–1.50(m,3H),1.30–1.24(m,5H).
化合物15：Arg-Lys-Val-Ala(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C20H40N8O5；m/z：237.16465([M+2H]2+)，473.32087([M+H]+).
1H 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).
化合物16：Lys-Val-Ala-Ala(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C17H33N5O5；m/z：388.25660([M+H]+).
1H NMR(600MHz,D2O)δ4.18(q,J＝7.1Hz,1H),4.03–3.91(m,3H),2.87(t,J＝7.7Hz,2H),1.98–1.89(m,1H),1.83–1.74(m,AcOH,6H),1.60–1.53(m,2H),1.36–1.27(m,2H),1.26(d,J＝7.2Hz,3H),1.19(d,J＝7.2Hz,3H),0.83(d,J＝6.8Hz,6H).
化合物17：Gln-Ala-Lys-Pro(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C19H34N6O6；m/z：443.26161([M+H]+).
1H NMR(600MHz,D2O)δ4.48(dd,J＝8.2,5.6Hz,1H),4.26–4.20(m,1H),4.10(dd,J＝8.5,5.4Hz,1H),3.91(t,J＝6.6Hz,1H),3.68–3.61(m,1H),3.55–3.43(m,1H),2.88(t,J＝7.5Hz,2H),2.39–2.27(m,2H),2.15–1.96(m,3H),1.92–1.69(m,8H),1.66–1.49(m,3H),1.43–1.29(m,2H),1.28–1.22(m,3H).
化合物18：Pro-Arg-Lys-Val(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C22H42N8O5；m/z：250.17158([M+2H]2+)，499.33464([M+H]+).
1H NMR(600MHz,D2O)δ4.27(dd,J＝8.7,6.0Hz,1H),4.24–4.17(m,2H),3.88(d,J＝6.2Hz,1H),3.33–3.20(m,2H),3.09–3.02(m,2H),2.85(t,J＝7.5Hz,2H),2.37–2.28(m,1H),1.98–1.86(m,4H),1.78(s,AcOH,6H),1.72–1.42(m,8H),1.38–1.23(m,2H),0.75(dd,J＝11.2,6.8Hz,6H).
化合物19：Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C70H120N22O20；m/z：530.64499([M+3H]3+)，795.46224([M+2H]2+)，1589.91350([M+H]+).
1H 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).
化合物20：Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C71H125N23O18；m/z：530.32804([M+3H]3+)，794.98683([M+2H]2+)，1588.96546([M+H]+).
1H 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).
化合物21：Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C71H125N23O20；m/z：540.99125([M+3H]3+)，810.98235([M+2H]2+)，1620.94722([M+H]+).
1H NMR(600MHz,D2O)δ4.45(dd,J＝9.4,4.9Hz,1H),4.30–4.24(m,3H),4.24–4.11(m,8H),4.02(dd,J＝8.4,4.9Hz,1H),3.97(d,J＝7.6Hz,1H),3.89(t,J＝6.7Hz,1H),3.79–3.66(m,2H),3.60–3.47(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).
化合物22：Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C71H125N23O20；m/z：540.99088([M+3H]3+)，810.98168([M+2H]2+)，1620.95237([M+H]+).
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).
化合物23：Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C71H124N22O19；m/z：398.24191([M+4H]4+)，530.65344([M+3H]3+)，795.97791([M+2H]2+).
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).
化合物24：Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C70H120N22O20；m/z：398.23245([M+4H]4+)，530.64075([M+3H]3+)，795.45752([M+2H]2+).
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).
化合物25：Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C71H123N23O20；m/z：405.48935([M+4H]4+)，540.31677([M+3H]3+)，809.97144([M+2H]2+).
1H NMR(600MHz,D2O)δ4.51(dd,J＝9.5,4.4Hz,1H),4.48–4.41(m,2H),4.32–4.25(m,3H),4.21(dd,J＝8.1,6.7Hz,1H),4.19–4.12(m,5H),4.02(dd,J＝8.4,4.9Hz,1H),3.97(d,J＝7.6Hz,1H),3.92–3.85(m,1H),3.74–3.64(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).
化合物26：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C71H125N23O20；m/z：405.99350([M+4H]4+)，540.98883([M+3H]3+)，810.97961([M+2H]2+).
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).
化合物27：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C70H120N20O20；m/z：391.23177([M+4H]4+)，781.45496([M+2H]2+).
1H 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).
化合物28：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C70H120N22O20；m/z：398.23303([M+4H]4+)，530.64142([M+3H]3+)，795.45850([M+2H]2+).
1H NMR(600MHz,D2O)δ4.52–4.42(m,2H),4.33(dd,J＝8.4,5.8Hz,1H),4.30–4.24(m,3H),4.23–4.09(m,6H),4.02(dd,J＝8.5,4.8Hz,1H),3.95(d,J＝7.5Hz,1H),3.92–3.85(m,1H),3.79–3.73(m,1H),3.72–3.67(m,2H),3.62–3.42(m,3H),3.08(t,J＝6.9Hz,2H),2.87(t,J＝7.6Hz,4H),2.30–2.25(m,2H),2.24–2.10(m,7H),2.02–1.65(m,AcOH,29H),1.64–1.48(m,8H),1.42–1.29(m,4H),1.28–1.19(m,12H),0.90–0.75(m,12H).
化合物29：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C71H123N23O20；m/z：405.48969([M+4H]4+)，540.31714([M+3H]3+)，809.97205([M+2H]2+).
1H 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),3.79–3.66(m,3H),3.61–3.47(m,3H),3.08(t,J＝6.9Hz,2H),2.86(q,J＝8.0Hz,6H),2.28(t,J＝7.6Hz,2H),2.23–2.13(m,7H),2.02–1.46(m,AcOH,47H),1.42–1.18(m,20H),0.85(dd,J＝14.2,6.7Hz,6H).
化合物30：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C71H124N22O19；m/z：398.24493([M+4H]4+)，530.65551([M+3H]3+)，795.47815([M+2H]2+)，1589.94194([M+H]+).
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),4.31–4.24(m,3H),4.24–4.20(m,1H),4.20–4.09(m,5H),4.02–3.96(m,2H),3.93–3.86(m,1H),3.80–3.74(m,1H),3.74–3.67(m,2H),3.63–3.43(m,3H),3.08(t,J＝6.9Hz,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).
化合物31：Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C70H123N23O20；m/z：402.49240([M+4H]4+)，536.31955([M+3H]3+)，803.97442([M+2H]2+)，1606.91471([M+H]+).
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).
化合物32：Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(TOF-HRMS)，分子式：C70H123N23O20；m/z：402.49278([M+4H]4+)，536.31975([M+3H]3+)，803.97422([M+2H]2+)，1606.92969([M+H]+).
1H NMR(600MHz,D2O)δ4.51(dd,J＝9.7,4.4Hz,1H),4.46(dd,J＝9.4,4.9Hz,1H),4.36(dd,J＝8.3,5.9Hz,1H),4.28(dd,J＝8.3,6.1Hz,1H),4.24–4.14(m,6H),4.03(dd,J＝8.3,4.9Hz,1H),3.97(dd,J＝10.0,7.5Hz,2H),3.90(t,J＝6.8Hz,1H),3.87–3.78(m,2H),3.76–3.67(m,2H),3.61–3.54(m,1H),3.54–3.47(m,1H),3.08(t,J＝6.9Hz,2H),2.91–2.83(m,6H),2.26–2.13(m,8H),2.03–1.87(m,9H),1.87–1.45(m,AcOH,33H),1.44–1.28(m,6H),1.26(dd,J＝18.4,7.2Hz,9H),0.89–0.79(m,12H).
化合物33：Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C70H123N23O20；m/z：402.48917([M+4H]4+)，536.31647([M+3H]3+)，803.97101([M+2H]2+).
1H NMR(600MHz,D2O)δ4.51(dd,J＝9.6,4.4Hz,1H),4.34(dd,J＝8.4,5.8Hz,1H),4.31–4.11(m,9H),4.03(dd,J＝8.4,4.9Hz,1H),3.97(d,J＝7.6Hz,1H),3.92–3.86(m,1H),3.85–3.74(m,3H),3.74–3.66(m,1H),3.62–3.52(m,2H),3.06(t,J＝7.0Hz,2H),2.91–2.83(m,6H),2.31–2.11(m,8H),2.03–1.43(m,AcOH,45H),1.40–1.27(m,6H),1.27–1.23(m,9H),0.91–0.77(m,12H).
化合物34：Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C67H119N23O20；m/z：392.48178([M+4H]4+)，522.97314([M+3H]3+)，784.45752([M+2H]2+).
1H NMR(600MHz,D2O)δ4.51(dd,J＝9.6,4.4Hz,1H),4.35(dd,J＝8.3,5.9Hz,1H),4.25–4.12(m,7H),4.03(dd,J＝8.4,4.8Hz,1H),3.96(dd,J＝10.6,7.5Hz,2H),3.92–3.86(m,1H),3.85–3.77(m,4H),3.75–3.68(m,1H),3.60–3.53(m,1H),3.06(t,J＝7.0Hz,2H),2.92–2.83(m,6H),2.28–2.12(m,7H),2.05–1.41(m,AcOH,42H),1.40–1.27(m,6H),1.27–1.24(m,9H),0.85(dd,J＝11.0,6.7Hz,6H),0.80(dd,J＝6.8,5.1Hz,6H).
化合物35：Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式:C64H115N23O20；m/z：382.47363([M+4H]4+)，509.62903([M+3H]3+)，763.93982([M+2H]2+).
1H 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).
化合物36：Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C67H119N23O20；m/z：392.48172([M+4H]4+)，522.97314([M+3H]3+)，783.95605([M+2H]2+).
1H NMR(600MHz,D2O)δ4.32(d,J＝8.0Hz,1H),4.28(dd,J＝8.2,6.7Hz,1H),4.25–4.12(m,8H),4.03(dd,J＝8.4,4.8Hz,1H),3.97(d,J＝7.6Hz,1H),3.92–3.83(m,2H),3.83–3.73(m,4H),3.60–3.53(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).
化合物37：Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C67H119N23O20；m/z：392.48172([M+4H]4+)，522.97314([M+3H]3+)，783.95605([M+2H]2+).
1H 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),2.01–1.45(m,AcOH,43H),1.42–1.26(m,6H),1.26–1.20(m,9H),0.83–0.77(m,12H).
化合物38：Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C51H88N16O14；m/z：383.89569([M+3H]3+)，575.33978([M+2H]2+).
1H NMR(600MHz,D2O)δ4.45(dd,J＝9.2,5.0Hz,1H),4.39(dd,J＝8.3,6.4Hz,1H),4.29–4.21(m,4H),4.19–4.12(m,3H),4.01(dd,J＝7.8,5.5Hz,1H),3.78–3.73(m,1H),3.72–3.67(m,1H),3.61–3.48(m,4H),3.08(t,J＝6.8Hz,2H),2.88–2.83(m,4H),2.30–2.26(m,4H),2.20–2.13(m,3H),2.08–1.46(m,AcOH,38H),1.39–1.22(m,7H),0.86(dd,J＝10.3,6.7Hz,6H).
化合物39：Pro-Val-Pro-Gln-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C23H38N6O7；m/z：511.2871([M+H]+).
1H NMR(600MHz,D2O)δ4.41(d,J＝7.3Hz,1H),4.38–4.32(m,2H),4.20(dd,J＝8.7,5.9Hz,1H),4.11–4.04(m,1H),3.85–3.77(m,1H),3.62(dt,J＝10.3,7.2Hz,1H),3.39–3.29(m,2H),2.39–2.31(m,3H),2.28–2.20(m,1H),2.08–1.90(m,AcOH,10H),1.86–1.80(m,1H),1.26(d,J＝7.3Hz,3H),0.94(d,J＝6.8Hz,3H),0.88(d,J＝6.8Hz,3H).
化合物40：Pro-Val-Pro-Glu-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C23H37N5O8；m/z：512.27081([M+H]+).
1H NMR(600MHz,D2O)δ4.41(d,J＝7.3Hz,1H),4.38–4.32(m,2H),4.23(dd,J＝8.9,5.6Hz,1H),4.13–4.09(m,1H),3.86–3.76(m,1H),3.62(dt,J＝10.2,7.2Hz,1H),3.38–3.28(m,2H),2.43–2.35(m,3H),2.26–2.16(m,1H),2.12–1.72(m,AcOH,12H),1.28(d,J＝7.2Hz,3H),0.94(d,J＝6.8Hz,3H),0.87(d,J＝6.8Hz,3H).
化合物41：Pro-Val-Pro-Ile-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C24H41N5O6；m/z：496.31158([M+H]+).
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).
化合物42：Pro-Val-Pro-Ala
高分辨质谱(Orbitrap-HRMS)，分子式：C18H30N4O5；m/z：383.22791([M+H]+).
1H NMR(600MHz,D2O)δ4.36(d,J＝7.2Hz,1H),4.30(dd,J＝8.5,6.3Hz,1H),4.24(dd,J＝8.1,6.5Hz,1H),4.00(q,J＝7.2Hz,1H),3.79–3.72(m,1H),3.60–3.52(m,1H),3.31–3.23(m,2H),2.33–2.26(m,1H),2.20–2.13(m,1H),2.09–1.69(m,AcOH,10H),1.21(d,J＝7.3Hz,3H),0.88(d,J＝6.9Hz,3H),0.81(d,J＝6.8Hz,3H).
化合物43：Glu-Pro-Val-Pro-Gln-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C28H45N7O10；m/z：640.32892([M+H]+).
1H 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).
化合物44：Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C29H50N8O8；m/z：320.19421([M+2H]2+).
1H NMR(600MHz,D2O)δ4.29–4.19(m,3H),4.13–4.06(m,2H),3.95(dd,J＝8.2,5.1Hz,1H),3.73–3.68(m,1H),3.52–3.47(m,1H),3.24–3.16(m,2H),2.79(t,J＝7.5Hz,2H),2.25–2.19(m,3H),2.14–2.08(m,1H),1.97–1.57(m,AcOH,17H),1.53–1.45(m,3H),1.21–1.17(m,5H),0.82(d,J＝6.8Hz,3H),0.75(d,J＝6.7Hz,3H).
化合物45：Glu-Pro-Val-Pro-Gln-Ala-Arg(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N11O11；m/z：398.71835([M+2H]2+)，796.42944([M+H]+).
1H NMR(600MHz,D2O)δ4.38(dd,J＝8.3,6.4Hz,1H),4.27–4.19(m,3H),4.19–4.10(m,2H),4.03(dd,J＝8.3,4.9Hz,1H),3.78–3.70(m,1H),3.60–3.46(m,3H),3.07–3.02(m,2H),2.30(t,J＝7.2Hz,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).
化合物46：Ala-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C32H55N9O9；m/z：355.71259([M+2H]2+)， 710.41809([M+H]+).
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).
化合物47：Glu-Pro-Val-Pro-Ala-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C32H54N8O10；m/z：356.20514([M+2H]2+)，711.40198([M+H]+).
1H NMR(600MHz,D2O)δ4.45(dd,J＝8.4,6.4Hz,1H),4.33–4.27(m,3H),4.21(dd,J＝15.1,7.2Hz,2H),4.07(dd,J＝8.1,5.1Hz,1H),3.86–3.75(m,1H),3.67–3.54(m,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).
化合物48：Glu-Pro-Val-Pro-Gln-Ala-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H50N8O11；m/z：356.18692([M+2H]2+)，711.36597([M+H]+).
1H NMR(600MHz,D2O)δ4.34(dd,J＝8.3,6.5Hz,1H),4.24–4.16(m,3H),4.12–4.06(m,2H),4.03–3.99(m,1H),3.73–3.65(m,1H),3.56–3.41(m,3H),2.35(t,J＝7.3Hz,2H),2.22–2.18(m,2H),2.15–2.07(m,2H),2.04–1.73(m,AcOH,11H),1.71–1.63(m,2H),1.18(dd,J＝11.2,7.2Hz,6H),0.80(dd,J＝13.0,6.8Hz,6H).
化合物49：Asp-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C33H55N9O11；m/z：377.70767([M+2H]2+)，754.40814([M+H]+).
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).
化合物50：Asn-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C33H56N10O10；m/z：377.21542([M+2H]2+)，753.42365([M+H]+).
1H 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).
化合物51：Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C59H102N18O16；m/z：440.59735([M+3H]3+)，660.39252([M+2H]2+).
1H 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,4H),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).
化合物52：Glu-Pro-Ala-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C32H53N9O11；m/z：370.6998([M+2H]2+)，740.39221([M+H]+).
1H NMR(600MHz,D2O)δ4.43(q,J＝7.1Hz,1H),4.33(dd,J＝8.4,6.5Hz,1H),4.26(dd,J＝8.4,5.8Hz,1H),4.22(dd,J＝7.6,4.6Hz,1H),4.18–4.11(m,2H),4.01(dd,J＝8.3,5.0Hz,1H),3.67(dt,J＝10.0,6.7Hz,1H),3.61–3.54(m,1H),3.53–3.44(m,2H),2.84(t,J＝7.5Hz,2H),2.30(t,J＝7.2Hz,2H),2.25(t,J＝7.6Hz,2H),2.21–2.12(m,2H),2.08–1.77(m,AcOH,11H),1.77–1.63(m,3H),1.60–1.49(m,3H),1.24(dd,J＝10.4,7.1Hz,6H).
化合物53：Glu-Ala-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C32H55N9O11；m/z：371.7081([M+2H]2+)，742.4089([M+H]+).
1H NMR(600MHz,D2O)δ4.23–4.18(m,3H),4.13–4.06(m,2H),3.95(dd,J＝8.3,5.0Hz,1H),3.85–3.82(m,1H),3.73–3.66(m,1H),3.53–3.47(m,1H),2.79(t,J＝7.5Hz,2H),2.22–2.17(m,4H),2.13–2.07(m,1H),1.99–1.70(m,AcOH,9H),1.69–1.59(m,2H),1.53–1.45(m,3H),1.26–1.12(m,9H),0.79(d,J＝6.7Hz,3H),0.76(d,J＝6.7Hz,3H).
化合物54：Glu-Pro-Val-Ala-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C32H55N9O11；m/z：371.70767([M+2H]2+)，742.40802([M+H]+).
1H 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).
化合物55：Glu-Pro-Val-Pro-Glu-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H56N8O12；m/z：385.2083([M+2H]2+)，769.4092([M+H]+).
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).
化合物56：Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C56H97N17O15；m/z：416.91827([M+3H]3+)，624.87354([M+2H]2+).
1H 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).
化合物57：Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C45H76N14O13；m/z：511.29254([M+2H]2+).
1H NMR(600MHz,D2O)δ4.39(dd,J＝8.6,5.5Hz,1H),4.32(dd,J＝8.3,6.5Hz,1H),4.22–4.13(m,4H),4.10–4.03(m,2H),3.93(dd,J＝7.9,5.2Hz,1H),3.72–3.60(m,2H),3.54–3.40(m,4H),3.00(t,J＝6.9Hz,2H),2.80(t,J＝7.5Hz,2H),2.24–2.18(m,4H),2.14–2.06(m,3H), 1.98–1.70(m,AcOH,19H),1.69–1.60(m,4H),1.55–1.47(m,4H),1.45–1.39(m,2H),1.34–1.24(m,2H),1.16(d,J＝7.1Hz,3H),0.80(dd,J＝10.4,6.7Hz,6H).
化合物58：Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C39H64N10O12；m/z：433.24188([M+2H]2+)，865.47662([M+H]+).
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).
化合物59：Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C40H69N13O10；m/z：298.18314([M+3H]3+)，446.77118([M+2H]2+)，892.53497([M+H]+).
1H 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).
化合物60：Pro-Val-Pro-Gln-Ala-Lys-Pro(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N9O9；m/z：368.7207([M+2H]2+)，736.4343([M+H]+).
1H NMR(600MHz,D2O)δ4.46(dd,J＝8.4,5.6Hz,1H),4.34(d,J＝7.4Hz,1H),4.29(dd,J＝8.5,6.2Hz,1H),4.27–4.24(m,1H),4.16–4.07(m,3H),3.78–3.70(m,1H),3.66–3.60(m,1H),3.58–3.45(m,2H),3.30–3.22(m,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,19H),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).
化合物61：D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4978([M+4H]4+)，549.6611([M+3H]3+)，823.9882([M+2H]2+).
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).
化合物62:Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4976([M+4H]4+)，549.6608([M+3H]3+).
1H NMR(600MHz,D2O)δ4.50(dd,J＝9.8,4.4Hz,1H),4.37(dd,J＝9.4,4.9Hz,1H),4.25–4.03(m,10H),3.95(dd,J＝8.5,4.8Hz,1H),3.89(d,J＝7.7Hz,1H),3.83(t,J＝6.6Hz,1H),3.74–3.68(m,1H),3.64–3.55(m,2H),3.52–3.38(m,2H),3.00(t,J＝6.9Hz,2H),2.83–2.75(m,6H),2.20(t,J＝7.6Hz,2H),2.12–2.06(m,6H),1.92–1.41(m,AcOH,47H),1.32–1.13(m,15H),0.78(dd,J＝9.7,6.7Hz,6H),0.73(dd,J＝6.8,4.1Hz,6H).
化合物63:Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4976([M+4H]4+)，549.6609([M+3H]3+)，823.9878([M+2H]2+).
1H NMR(600MHz,D2O)δ4.45(dd,J＝9.4,4.4Hz,1H),4.37(dd,J＝9.4,4.9Hz,1H),4.29–4.25(m,1H),4.21–4.04(m,8H),3.96–3.94(m,1H),3.89(d,J＝7.7Hz,1H),3.79(d,J＝6.9 Hz,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).
化合物64:Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4978([M+4H]4+)，549.6609([M+3H]3+)，823.9878([M+2H]2+).
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),3.67–3.50(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).
化合物65:Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4979([M+4H]4+)，549.6612([M+3H]3+)，823.9883([M+2H]2+).
1H 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),3.82(t,J＝6.7Hz,1H),3.65(d,J＝6.8Hz,3H),3.57–3.36(m,3H),3.00(t,J＝6.9Hz,2H),2.82–2.75(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).
化合物66:Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4978([M+4H]4+)，549.6611([M+3H]3+)，823.9881([M+2H]2+).
1H NMR(600MHz,D2O)δ4.44–4.35(m,2H),4.26–4.04(m,10H),3.94(dd,J＝8.5,4.8Hz,1H),3.89(d,J＝7.7Hz,1H),3.82(t,J＝6.8Hz,1H),3.76–3.68(m,1H),3.64(d,J＝8.7Hz,2H),3.55–3.37(m,3H),3.00(t,J＝6.9Hz,2H),2.83–2.75(m,6H),2.19–2.05(m,9H),2.02–1.38(m,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).
化合物67:Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4961([M+4H]4+)，549.6615([M+3H]3+)，823.9886([M+2H]2+).
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).
化合物68:Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4977([M+4H]4+)，549.6615([M+3H]3+)，823.9879([M+2H]2+).
1H 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).
化合物69:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4976([M+4H]4+)，549.6608([M+3H]3+).
1H NMR(600MHz,D2O)δ4.42(dt,J＝8.2,4.3Hz,2H),4.26(dd,J＝8.4,5.9Hz,1H),4.23–4.14(m,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),2.23–2.05(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).
化合物70:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4978([M+4H]4+)，549.6611([M+3H]3+)，823.9883([M+2H]2+).
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＝35.9,8.3Hz,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).
化合物71:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4976([M+4H]4+)，549.6609([M+3H]3+)，823.9878([M+2H]2+).
1H 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),1.32–1.14(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).
化合物72:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4976([M+4H]4+)，549.6609([M+3H]3+)，823.9876([M+2H]2+).
1H NMR(600MHz,D2Oδ4.45–4.35(m,2H),4.26(dd,J＝8.4,5.9Hz,1H),4.21–4.05(m,9H),3.94–3.88(m,2H),3.82(t,J＝6.8Hz,1H),3.73–3.57(m,3H),3.55–3.37(m,3H),2.99(t,J＝6.8Hz,2H),2.82–2.75(m,6H),2.23–2.06(m,9H),1.96–1.36(m,AcOH,50H),1.32–1.14(m,15H),0.78(dd,J＝13.9,6.7Hz,6H),0.73(d,J＝6.7Hz,6H).
化合物73:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4977([M+4H]4+)，549.6609([M+3H]3+)，823.9879([M+2H]2+).
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).
化合物74:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4977([M+4H]4+)，549.6610([M+3H]3+)，823.9879([M+2H]2+).
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).
化合物75:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H127N23O20；m/z：412.4978([M+4H]4+)， 549.6611([M+3H]3+)823.9881([M+2H]2+).
1H NMR(600MHz,D2O)δ4.49–4.42(m,2H),4.32(dd,J＝8.4,5.8Hz,1H),4.27–4.10(m,9H),4.04(dd,J＝8.4,4.6Hz,1H),3.96(d,J＝7.4Hz,1H),3.90–3.84(m,1H),3.73(d,J＝7.7Hz,1H),3.71–3.64(m,2H),3.60–3.32(m,3H),3.06(t,J＝6.9Hz,2H),2.89–2.79(m,6H),2.28–2.06(m,9H),1.99–1.47(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).
化合物76:Glu-Gly-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H53N9O11；m/z：364.7022([M+2H]2+)，728.3929([M+H]+).
1H 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).
化合物77:Glu-Pro-Val-Gly-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H53N9O11；m/z：364.7004([M+2H]2+)，728.3932([M+H]+).
1H 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).
化合物78:D-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N9O11；m/z：384.716([M+2H]2+)，768.4245([M+H]+).
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).
化合物79:Glu-D-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N9O11；m/z：384.7159([M+2H]2+)，768.4244([M+H]+).
1H 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).
化合物80:Glu-Pro-D-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N9O11；m/z：384.7158([M+2H]2+)，768.4241([M+H]+).
1H NMR(600MHz,D2O)δ4.46(d,J＝7.3Hz,1H),4.36(dd,J＝8.3,6.6Hz,1H),4.30–4.20(m,3H),4.17(dd,J＝8.1,6.1Hz,1H),4.03–4.00(m,1H),3.72–3.66(m,1H),3.63–3.57(m,2H),3.53–3.49(m,1H),2.85(t,J＝7.5Hz,2H),2.36–2.21(m,6H),2.18–2.13(m,1H),2.05–1.78(m,AcOH,17H),1.70–1.66(m,1H),1.58–1.51(m,3H),1.28–1.23(m,6H),0.78(dd,J＝15.0,6.7Hz,6H).
化合物81:Glu-Pro-Val-D-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C34H57N9O11；m/z：384.7157([M+2H]2+)，768.4240([M+H]+).
1H 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).
化合物82:Glu-Pro-Val-Pro-D-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H53N9O11；m/z：384.7158([M+2H]2+)，768.4242([M+H]+).
1H 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).
化合物83:Glu-Pro-Val-Pro-Gln-D-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H53N9O11；m/z：384.7159([M+2H]2+)，768.4243([M+H]+).
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).
化合物84:Glu-Pro-Val-Pro-Gln-Ala-D-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H53N9O11；m/z：384.7160([M+2H]2+)，768.4246([M+H]+).
1H 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).
化合物85:Lys-Glu-Pro-Val-Pro(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C26H44N6O8；m/z：454.2655([M+2H]2+)，569.3287([M+H]+).
1H 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).
化合物86:Glu-Pro-Val-Pro-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C25H40N6O9；m/z：569.2919([M+H]+).
1H 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).
化合物87:Lys-Glu-Pro-Val-Pro-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C31H52N8O10；m/z：349.1971([M+2H]2+)，697.3868([M+H]+).
1H 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＝7.5 Hz,2H),2.28–2.13(m,6H),2.00–1.73(m,AcOH,17H),1.60–1.54(m,2H),1.36–1.28(m,2H),0.86(d,J＝6.8Hz,3H),0.83(d,J＝6.6Hz,3H).
化合物88:Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C92H152N26O24；m/z：502.2934([M+4H]4+)，669.3699([M+3H]3+).
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,2H),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).
化合物89:pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C84H145N25O24；m/z：468.7766([M+4H]4+)，624.6998([M+3H]3+)，936.5460([M+2H]2+).
1H NMR(600MHz,D2O)δ4.47–4.42(m,2H),4.32–4.10(m,13H),4.02(dd,J＝8.4,4.8Hz,1H),3.96(d,J＝7.6Hz,1H),3.82–3.60(m,3H),3.58–3.45(m,3H),3.07(t,J＝6.9Hz,2H),2.90–2.80(m,6H),2.45–2.36(m,1H),2.31–2.24(m,4H),2.23–2.03(m,7H),1.99–1.44(m,AcOH,47H),1.39–1.19(m,15H),0.85(dd,J＝12.5,6.8Hz,6H),0.81–0.77(m,9H),0.75(d,J＝6.0Hz,3H).
化合物90:Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C90H148N26O24；m/z：495.2855([M+4H]4+)，660.0449([M+3H]3+)，989.5637([M+2H]2+).
1H 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).
化合物91:Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C103H174N32O28；m/z：578.0856([M+4H]4+)，770.4463([M+3H]3+)，1155.1642([M+2H]2+).
1H 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).
化合物92:Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C70H116N20O20；m/z：390.2233([M+4H]4+)，519.9619([M+3H]3+)，779.4393([M+2H]2+).
1H NMR(600MHz,D2O)δ6.96(d,J＝8.6Hz,2H),6.67(d,J＝8.5Hz,2H),4.49(dd,J＝8.4,5.3Hz,1H),4.38(t,J＝8.0Hz,1H),4.31–4.23(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),1.97–1.65(m,AcOH,29H),1.61–1.45(m,13H),1.26(dd,J＝11.1,7.4Hz,10H),0.83(dd,J＝19.0,6.7Hz,6H),0.72(d,J＝5.6Hz,6H).
化合物93:Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C64H104N18O19；m/z：715.3917([M+2H]2+).
1H NMR(600MHz,D2O)δ6.96(d,J＝8.6Hz,2H),6.66(d,J＝8.5Hz,2H),4.48–4.42(m,3H),4.26–4.12(m,6H),4.02(dd,J＝8.2,5.0Hz,1H),3.95–3.89(m,2H),3.77–3.68(m,1H),3.56–3.47(m,2H),3.43–3.36(m,1H),3.10–3.04(m,2H),2.87–2.80(m,6H),2.54(dd,J＝16.0,5.1Hz,1H),2.45(dd,J＝16.0,8.4Hz,1H),2.27(t,J＝7.6Hz,2H),2.17–2.08(m,4H),1.98–1.66(m,AcOH,27H),1.65–1.45(m,9H),1.26(dd,J＝11.3,7.4Hz,7H),0.84(dd,J＝13.0,6.7Hz,6H),0.70(dd,J＝6.8,2.8Hz,6H).
化合物94:Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C50H80N14O14；m/z：367.8727([M+3H]3+)，551.3051([M+2H]2+)，1101.6030([M+H]+).
1H NMR(600MHz,D2O)δ4.45(dd,J＝8.9,4.8Hz,1H),4.36–4.22(m,4H),4.04–3.98(m,1H),3.90(dd,J＝7.0,5.8Hz,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,AcOH,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).
化合物95:Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-G ln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C113H188N34O31；m/z：504.6906([M+5H]5+)，630.6115([M+4H]4+)，840.4796([M+3H]3+).
1H NMR(600MHz,D2O)δ7.22(t,J＝7.4Hz,2H),7.16(t,J＝7.3Hz,1H),7.12–7.07(m,2H),4.47–4.41(m,3H),4.35–4.03(m,19H),4.02(dd,J＝8.4,4.8Hz,1H),3.95(d,J＝3.6Hz,1H),3.86(s,1H),3.75(s,1H),3.68(t,J＝8.5Hz,2H),3.58–3.42(m,5H),3.06(t,J＝6.9Hz,4H),2.91–2.81(m,7H),2.29–2.11(m,12H),2.00–1.19(m,AcOH,80H),1.14(d,J＝7.1Hz,3H),1.06(d,J＝6.3Hz,3H),0.84(dd,J＝13.7,6.7Hz,6H),0.81–0.76(m,9H),0.72(d,J＝5.6Hz,3H).
化合物96:Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C74H118N20O22；m/z：547.2972([M+3H]3+)，820.4424([M+2H]2+).
1H NMR(600MHz,D2O)δ7.21(dd,J＝8.2,6.6Hz,2H),7.16(t,J＝7.3Hz,1H),7.12–7.07(m,2H),4.50–4.42(m,2H),4.36–4.22(m,4H),4.21–4.09(m,7H),4.07–4.00(m,2H),3.93(d,J＝16.5Hz,1H),3.84(d,J＝16.5Hz,1H),3.78–3.70(m,1H),3.68–3.60(m,1H),3.56–3.42(m,4H),3.10–2.97(m,3H),2.90–2.82(m,3H),2.29–2.09(m,9H),2.00–1.81(m,AcOH,19H),1.77–1.66(m,5H),1.61–1.37(m,9H),1.26(dd,J＝11.9,7.4Hz,5H),1.14(d,J＝7.2Hz,3H),1.05(d,J＝6.4Hz,3H),0.84(dd,J＝15.5,6.7Hz,6H),0.77(d,J＝5.9Hz,3H),0.72(d,J＝5.7Hz,3H).
化合物97:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C105H179N31O35；m/z：488.0708([M+5H]5+)， 609.8367([M+4H]4+)，812.7799([M+3H]3+).
1H NMR(600MHz,D2O)δ4.48–4.41(m,3H),4.34(t,J＝5.4Hz,1H),4.31(dd,J＝8.4,5.8Hz,1H),4.28–4.22(m,3H),4.22–4.09(m,11H),4.04–3.88(m,5H),3.81–3.72(m,3H),3.71–3.62(m,2H),3.59–3.43(m,3H),3.07(t,J＝6.9Hz,2H),2.90–2.80(m,8H),2.58(dd,J＝16.0,6.3Hz,1H),2.48(dd,J＝16.0,7.9Hz,1H),2.29–2.09(m,13H),2.00–1.47(m,AcOH,51H),1.40–1.20(m,18H),1.12–1.05(m,1H),0.89–0.70(m,18H).
化合物98:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C66H109N17O26；m/z：519.5973([M+3H]3+)，778.8925([M+2H]2+).
1H 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,AcOH,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).
化合物99:Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C52H85N13O21；m/z：614.806([M+2H]2+)，1228.605([M+H]+).
1H 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,9H),2.01–1.51(m,AcOH,21H),1.34–1.22(m,3H),1.08–1.01(m,1H),0.89–0.80(m,6H),0.76–0.70(m,6H).
化合物100:Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C88H150N26O23；m/z：389.0348([M+5H]5+)，480.0415([M+4H]4+)，647.7197([M+3H]3+).
1H NMR(600MHz,D2O)δ4.49–4.42(m,2H),4.34–4.06(m,13H),4.05–4.00(m,2H),3.96(d,J＝7.6Hz,1H),3.80–3.73(m,1H),3.69(d,J＝9.8Hz,4H),3.58–3.45(m,5H),3.07(t,J＝6.9Hz,2H),2.88–2.83(m,6H),2.27(t,J＝7.7Hz,3H),2.20–2.11(m,9H),2.01–1.45(m,AcOH,55H),1.24(dd,J＝21.5,7.2Hz,16H),0.97(d,J＝6.9Hz,3H),0.88–0.78(m,15H).
化合物101:Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C66H109N17O26；m/z：519.5978([M+3H]3+)，778.8933([M+2H]2+).
1H 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).
化合物102Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C53H82N12O15；m/z：564.3073([M+2H]2+).
1H 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).
化合物103:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H126N22O21；m/z：824.4799([M+2H]2+).
1H NMR(600MHz,D2O)δ4.49(dd,J＝9.6,4.4Hz,1H),4.45(dd,J＝9.4,4.9Hz,1H),4.36–4.05(m,11H),4.01–3.96(m,2H),3.92–3.87(m,1H),3.82–3.64(m,3H),3.60–3.46(m,3H),3.07(t,J＝7.0Hz,2H),2.88–2.83(m,6H),2.29–2.09(m,9H),1.99–1.46(m,AcOH,47H),1.39–1.20(m,16H),0.85(dd,J＝14.2,6.7Hz,6H),0.80(dd,J＝6.7,3.7Hz,6H).
化合物104:Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C72H125N23O20；m/z：408.9938([M+4H]4+)，544.9891([M+3H]3+)，816.9801([M+2H]2+).
1H NMR(600MHz,D2O)δ4.49(dd,J＝9.7,4.4Hz,1H),4.45(dd,J＝9.4,4.8Hz,1H),4.34–4.10(m,11H),3.96(d,J＝7.6Hz,1H),3.92–3.84(m,1H),3.78–3.66(m,3H),3.62–3.43(m,3H),3.07(t,J＝6.9Hz,2H),2.90–2.82(m,6H),2.63(dd,J＝15.1,4.9Hz,1H),2.53(dd,J＝15.1,8.1Hz,1H),2.30–2.11(m,7H),2.03–1.42(m,AcOH,44H),1.39–1.19(m,15H),0.85(dd,J＝14.0,6.7Hz,6H),0.80(dd,J＝6.8,3.0Hz,6H).
化合物105:Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C73H128N24O19；m/z：412.2515([M+4H]4+)，549.3327([M+3H]3+)，823.4955([M+2H]2+).
1H 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).
化合物106:Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C74H129N23O20；m/z：416.0015([M+4H]4+)，554.3328([M+3H]3+)，830.9956([M+2H]2+).
1H NMR(600MHz,D2O)δ4.50(dd,J＝9.6,4.4Hz,1H),4.45(dd,J＝9.3,4.9Hz,1H),4.36–4.22(m,4H),4.22–4.10(m,6H),4.02(dd,J＝8.4,4.9Hz,1H),3.96(d,J＝7.6Hz,1H),3.92–3.84(m,1H),3.82–3.74(m,1H),3.73–3.63(m,2H),3.61–3.41(m,3H),3.07(t,J＝6.9Hz,2H),2.90–2.82(m,6H),2.32–2.12(m,9H),2.00–1.46(m,AcOH,46H),1.43–1.05(m,17H),0.84(d,J＝6.8Hz,3H),0.80(dd,J＝6.8,4.3Hz,6H),0.75(t,J＝7.4Hz,3H).
化合物107:Val-Pro-Gln-Ala(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C18H31N5O6；m/z：414.2341([M+1H]+).
1H 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).
化合物108:Val-Pro-Gln-Ala-Lys(醋酸盐)
高分辨质谱(Orbitrap-HRMS)，分子式：C24H43N7O7；m/z：271.6681([M+2H]2+)，542.3289([M+1H]+).
1H NMR(600MHz,D2O)δ4.28(t,J＝7.6Hz,1H),4.13–4.06(m,2H),3.99(d,J＝5.5Hz,1H),3.94(dd,J＝8.2,5.1Hz,1H),3.60–3.54(m,1H),3.46–3.41(m,1H),2.78(t,J＝7.5Hz,2H),2.21(t,J＝7.6Hz,2H),2.17–2.09(m,2H),1.93–1.58(m,AcOH,11H),1.53–1.44(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).
实施例2：多肽化合物具有缓解结肠炎功效实验
实验动物：野生型AB品系斑马鱼，以自然成对交配繁殖方式进行。年龄为受精后3天 (3dpf)的斑马鱼。斑马鱼均饲养于28℃的养鱼用水中(水质：每1L反渗透水中加入200mg速溶海盐，电导率为450-550μS/cm；pH为6.5-8.5；硬度为50-100mg/L CaCO3)，实验动物使用许可证号为：SYXK(浙)2012-0171，饲养管理符合国际AAALAC认证(认证编号：001458)的要求。
实验方法：
(1)分组：多肽组：用超纯水配制成20.0mg/mL母液，-20℃储存。
阳性对照组：泼尼松，白色粉末，批号C10016501，上海麦克林生化科技有限公司，4℃储存；用DMSO配制成15.0mg/mL母液，-20℃分装储存。
正常对照组和模型对照组。
(2)实验方法：随机选取3dpf野生型AB品系斑马鱼于6孔板中，每孔(实验组)均处理30尾斑马鱼。除正常对照组外，其余各实验组均水溶给予TNBS建立斑马鱼肠粘膜损伤模型。28℃处理2天后，移除TNBS，分别水溶给予多肽化合物(浓度见表4)，阳性对照泼尼松15.0μg/mL，同时设置正常对照组(健康组)和模型对照组(肠粘膜损伤组)，每孔(实验组)容量为3mL。28℃继续处理2天后，每个实验组随机选取10尾斑马鱼置于解剖显微镜下拍照，用NIS-Elements D 3.20高级图像处理软件分析并采集数据，分析斑马鱼肠腔面积，以该指标的统计学分析结果评价样品缓解结肠炎功效。统计学处理结果采用mean±SE表示。用SPSS26.0软件进行统计学分析，p＜0.05表明差异具有统计学意义。
实验结果：多肽化合物缓解结肠炎功效结果见表4所示：
表4多肽化合物缓解结肠炎功效评价实验结果(n＝10)
与模型对照组比较，*p<0.05，**p<0.01，***p<0.001
根据表4数据可知，化合物1、4、5、6、12、15等多肽化合物组相较于模型对照组产生了显著的统计学差异(p<0.05；p<0.01；p<0.001)，且效果优于泼尼松组。实验结果表明，本申请提供的多肽化合物具有缓解结肠炎功效，具体表现为显著缓解肠腔扩张。
本实验体系设定的受试物给药浓度梯度为250μg/mL、500μg/mL、1000μg/mL，通过统计各组干预后斑马鱼肠腔面积，可见绝大部分具有缓解结肠炎功效的受试物在1000μg/mL浓度下作用较为明显(p<0.05；p<0.01；p<0.001)。而继续提高受试物浓度进行干预则发现组内斑马鱼有死亡现象；因此，在后续多轮活性评价中各受试物多肽化合物统一采用1000μg/mL给药干预，结果汇总于表5。
表5多肽化合物缓解斑马鱼结肠炎肠腔扩张活性汇总
注释：每个化合物的缓解斑马鱼结肠炎肠腔扩张活性经多批试验完成，为便于比较，其抗肠腔扩张活性以相对当批次实验模型对照组比较：*p<0.05，**p<0.01，***p<0.001；ND表示未测试，“—”表示无活性“+”表示一定的缓解肠腔扩张作用，“#”表示实验中斑马鱼全部死亡，“&”表示实验中斑马鱼死亡13尾。
根据表4和表5数据可知，多肽组相较于模型对照组产生了显著的统计学差异(p<0.05、 p<0.01或p<0.001)，且效果优于泼尼松组。在本实验条件下，化合物1、4-6、9、10、12、15、25、26、29、31、34、38、48-51、53-55、57、62、63、65-68、70、72、75、83、85、86、88-90、92-100、103-106均具有显著缓解结肠炎功效，具体表现为缓解肠腔扩张(p<0.05)；化合物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和102具有一定缓解肠腔扩张作用。
实施例3：多肽化合物对TNBS诱导的SD大鼠急性炎症性肠病(UC)模型的治疗功效评价
目的：评价多肽化合物对TNBS诱导的SD大鼠急性炎症性肠病模型的治疗作用。
材料与方法：
本实验采用三硝基苯磺酸(TNBS)对实验动物雄性SD大鼠进行单次灌肠干预构建大鼠溃疡性结肠炎模型。三硝基苯磺酸(TNBS)诱导的大鼠急性结肠炎是Thl型细胞分泌的细胞因子诱导的免疫反应，模型对照组动物结肠出现明显萎缩及肠壁增厚反应，其结肠重量及长度比值显著升高，肠壁黏膜表面可见裂隙状溃疡灶形成，黏膜下层及肌层可见典型肉芽肿，内伴有以淋巴细胞及浆细胞为主的炎性细胞浸润，同时小血管及结蹄组织增生(纤维母细胞)明显，溃疡灶周围可见隐窝结构破坏及出血，该模型制作简单，重复性好，是广泛应用于评价治疗炎症性肠病药物的实验动物模型。实验动物(雄性SD大鼠)于实验首日根据体重参数进行随机分组，共6个组别，分别为正常对照组、模型对照组、阳性药物美沙拉嗪治疗组、化合物1低剂量治疗组、化合物1高剂量治疗组、化合物6低剂量治疗组、化合物6高剂量治疗组和化合物12治疗组，均为10只/组，分组当天(D0)，除正常对照组给予溶媒外，其余各实验组动物均经灌肠给予TNBS乙醇溶液进行模型诱导；模型诱导次日开始进行供试品及阳性对照药物治疗，化合物1治疗剂量分别为3.0mg/kg和6.0mg/kg，化合物6治疗剂量分别为1.4mg/kg和2.8mg/kg，化合物12治疗剂量为0.8mg/kg，阳性对照药物美沙拉嗪治疗剂量为30.0mg/kg，给药方式均为灌肠给药，给药频率均为每天1次，连续14天；实验治疗周期(D1-D14)内，对各实验组动物体重及一般临床观察指标(包括但不限于摄食、饮水、活动水平及排便等)进行动态采集，同时基于溃疡性结肠炎疾病活动度相关评分标准对各实验组动物经TNBS诱导后体重下降程度、粪便形态性状和便血等反应进行评分，计算溃疡性结肠炎疾病活动度(DAI)，每天一次，连续14天；于实验终点采集各实验组动物结肠组织，测量结肠长度及称重后采集未剖检图像，随后沿肠壁纵向将结肠剖开，采集剖检图像；基于《结肠大体形态表现评分标准》对各实验组动物结肠粘连和结肠溃疡及炎症进行大体损伤观察及评分；于体视显微镜下采集溃疡图像并计算结肠溃疡灶面积，随后进行常规固定，根据各项药效学检测指标的统计分析结果，评估供试多肽化合物在设定治疗方案下对溃疡性结肠炎疾病模型的治疗效应。
结果与结论：
本实验研究系统下，模型对照组动物出现明显溃疡性结肠炎的疾病特征，包括体重增长抑制、软便及稀便、溃疡性结肠炎疾病活动度DAI评分显著升高、大体观察可见结肠萎缩及典型溃疡灶和结肠融合性溃疡灶；供试化合物1在设定治疗方案下对模型动物体重增长抑制状态具有明显的改善效应，其改善程度与同期模型对照组动物体重变化程度相比具备统计学差异(P<0.05)，而供试化合物6和12则对模型动物体重增长抑制未见明显的改善治疗效应。
表6供试多肽化合物对模型动物体重变化的影响

注：所有数据均采用平均值(Mean)±标准差(SD)进行统计分析，*P<0.05,**P<0.01，***P<0.001,****P<0.0001表示模型对照组与正常对照组的统计分析结果，#P<0.05,##P<0.01,,表示供试多肽化合物治疗组动物与模型对照组的统计分析结果。
实验周期的DAI评分结果显示，供试化合物1、6和12在设定治疗方案下对模型动物溃疡性结肠炎疾病进程具有明显的改善效应，对应治疗组动物粪便性状病变特征和体重下降反应均出现明显缓解，DAI评分均值均呈现下降反应，与同期模型对照组相比具有明显统计学差异(P<0.05)，以化合物1的改善治疗效应最为明显，同时化合物1和6的治疗效应具备明显的剂量依赖性。
表7供试多肽化合物对模型动物DAI评分的影响
注：所有数据均采用平均值(Mean)±标准差(SD)进行统计分析，*P<0.05,**P<0.01，***P<0.001,****P<0.0001表示模型对照组与正常对照组的统计分析结果，#P<0.05,##P<0.01,###P<0.001,####P<0.0001表示供试多肽化合物治疗组动物与模型对照组的统计分析结果，+P<0.05,++P<0.01，+++P<0.001,++++P<0.0001表示化合物1或6剂量组间的统计分析结果。
实验终点大体解剖及结肠组织损伤评分结果表明，供试品化合物1、6和12对TNBS诱导的结肠大体损伤状态(结肠粘连和溃疡及炎症)、结肠溃疡灶面积和结肠重量/长度比值异常升高进程均具有明显的治疗效应，其改善程度与同期模型对照组相比均具备统计学差异(P<0.05)，以化合物1的治疗效应最为明显，同时其治疗效应具备明显的剂量依赖性。
表8供试多肽化合物对模型动物结肠大体损伤和溃疡面积的影响

注：所有数据均采用平均值(Mean)±标准差(SD)进行统计分析，*P<0.05,**P<0.01，***P<0.001,****P<0.0001表示模型对照组与正常对照组的统计分析结果，#P<0.05,##P<0.01,###P<0.001,####P<0.0001表示供试多肽化合物治疗组动物与模型对照组的统计分析结果，+P<0.05,++P<0.01，+++P<0.001,++++P<0.0001表示化合物1或6剂量组间的统计分析结果。
表9供试多肽化合物对模型动物结肠重量/长度比值的影响
注：所有数据均采用平均值(Mean)±标准差(SD)进行统计分析，*P<0.05,**P<0.01，***P<0.001,****P<0.0001表示模型对照组与正常对照组的统计分析结果，#P<0.05,##P<0.01,###P<0.001,####P<0.0001表示供试多肽化合物治疗组动物与模型对照组的统计分析结果，+P<0.05,++P<0.01，+++P<0.001,++++P<0.0001表示化合物1或6剂量组间的统计分析结果。
本试验采用TNBS对雄性SD大鼠进行灌肠干预，诱导其结肠发生病变，建立符合临床发病特征的大鼠溃疡性结肠炎模型。模型诱导次日开始进行供试化合物1、6和12和阳性对照药物美沙拉嗪治疗；治疗周期(D1-D14)内，通过监测实验动物体重变化、溃疡性结肠炎疾病活动度DAI评分、结肠大体损伤表现(结肠粘连和溃疡及炎症反应)评分、结肠组织溃疡面积和结肠重量/长度比值等指标的变化，评价供试品对TNBS诱导SD大鼠溃疡性结肠炎模型的治疗作用，结果发现：
1)实验动物经TNBS诱导后出现明显溃疡性结肠炎疾病表现，主要包括体重显著下降、溃疡性结肠炎疾病活动度评分(DAI评分)显著升高、结肠粘连及溃疡评分显著升高、结肠组织溃疡面积升高和结肠重量/长度比值显著升高，提示大鼠溃疡性结肠炎模型构建成功，适用于本实验药效学研究；
2)供试化合物1在设定治疗方案下对模型动物体重下降反应具有明显的改善效应，其改善程度与同期模型对照组相比具备统计学差异(P<0.05)，而供试化合物6、12和阳性对照药物美沙拉嗪则未呈现明显的体重改善效应；
3)供试化合物1、6和12在设定治疗方案下对模型动物溃疡性结肠炎疾病进程具有明显的改善效应，其DAI评分均较同期模型对照组呈现显著下降反应，以供试化合物1的治疗效应最为明显，同时供试化合物1和6的改善治疗效应具备明显的剂量依赖性，而阳性对照药物美沙拉嗪则对模型动物溃疡性结肠炎疾病症状未见明显影响；
4)供试化合物1、6和12在设定治疗方案下对模型动物结肠大体损伤表现具有明显治疗效应，与同期模型对照组相比，其结肠粘连评分、结肠溃疡及炎症评分和结肠组织溃疡灶面积均呈现显著下降，改善程度具备统计学意义(P<0.05)，供试化合物1的治疗效应最为明显，并且其改善治疗效应具有明显的剂量依赖性。
5)供试化合物1、6和12在设定治疗方案下对模型动物结肠萎缩进程具有明显改善效应，同期模型对照组相比，其结肠重量/长度比值显著下降(P<0.05)。
可见，本试验建立了符合临床发病特征的大鼠溃疡性结肠炎模型，在该模型上的药效评价结果表明供试化合物1、6和12均具备显著的治疗效果。
实施例4：多肽化合物对细胞CaCo-2的体外增殖影响研究
采用下述细胞系研究多肽化合物体外增殖：
表10细胞系信息
实验方法：
细胞会按照表10中所示培养条件复苏并维持。
第1天(细胞铺板):收集处于对数生长期的细胞，重悬后使用细胞计数仪计数并检测活性。按照铺板密度要求稀释细胞悬液，96孔板中每孔加入90μL的细胞悬液(细胞铺板密度将根据历史数据或者密度优化实验调整)。进行铺板同时，每个细胞铺3个复孔作为T0板。将所有96孔板放置于37℃，5％CO2的恒温培养箱中过夜。
第2天(换液):按照platemap更换对应血清浓度的培养基，每孔90μL。第2天:T0板读板和待测化合物处理。T0板中每孔加入10μL培养基将总体积补足至100μL。每孔加入50μL试剂。混合震荡5分钟以便细胞充分裂解。室温孵育10分钟以稳定发光信号(注意:温度、细胞密度和边缘效应均会导致发光信号不均匀)。使用EnVision Multi Label Reader检测荧光信号。待测化合物按对应分子量配置C1＝91.08μM，稀释C2＝9.108μM，C3＝0.9108μM。Cisplatin按照表11所示稀释，制备10X化合物工作液。每孔加入10μL工作液(10X)，所有板子每孔终体积为100μL。细胞置于37℃，5％CO2的培养箱培养。
第5天,待测化合物处理72小时(读板):在显微镜下观察加药组及对照组状态是否正常。每孔加入50μL CTG试剂。在摇床上混合5分钟以便细胞充分裂解。室温孵育10分钟以稳定发光信号。使用EnVision Multi Label Reader读取荧光信号。
表11 Cisplatin稀释后浓度
细胞活率(％)＝Lum待测化合物/Lum溶剂对照×100％.
实验结果：所选多肽化合物促增殖活性统计结果见表12所示：
本实验体系设定的受试物给药浓度梯度为C1＝91.08μM，稀释C2＝9.108μM，C3＝0.9108μM，以0.88％FBS为参照。实验结果表明，本申请的多肽化合物1具有促进Caco-2细胞增殖的活性，具体表现为干预后使得细胞活率增加。
综上所述，本发明的上述多肽化合物，其肽链短，吸收更快更好。实验结果表明，本申请提供的多肽化合物具有缓解斑马鱼结肠炎肠腔扩张活性；在大鼠急性炎症性肠病模型试验中，具备显著的治疗效果。本发明的上述多肽化合物具有显著的缓解结肠炎的功效，能够用于制备治疗肠炎药物，尤其是溃疡性结肠炎药物。
尽管本发明披露了上述实施例，但本发明的实施方式并不限于上述实施例，其他的任何未背离本发明的改变、修饰、替代、组合、简化，均应为等效的置换方式均包含在本发明的保护范围之内。

Claims (21)

  1. 式(I)的化合物或其生理学上相容的盐，其中所述式(I)的化合物如下：
    H-Xa-Z1-Z2-Z3-Z4-Xb-OH  (I)
    其中
    Z1为Pro、Ala、Gly、D-Pro或缺失；
    Z2为Val、Ala、D-Val、Ile或缺失；
    Z3为Pro、Ala、Gly、D-Pro或缺失；
    Z4为Gln、Ala、Glu、Ile、D-Gln或缺失；
    条件是：Z1、Z2、Z3和Z4中至多有2个是缺失的。
    Xa为含有0-10个氨基酸残基的序列；
    Xb为含有0-9个氨基酸残基的序列。
  2. 权利要求1的化合物或其生理学上相容的盐，其中Z1、Z2、Z3和Z4中有2个是缺失的；或Z1和Z2是缺失的；或Z3和Z4是缺失的；或Z1、Z2、Z3和Z4中有1个是缺失的；或Z1是缺失的；或Z4是缺失的；或Z1、Z2、Z3和Z4中有0个是缺失的。
  3. 权利要求1的化合物或其生理学上相容的盐，其中Z1、Z2、Z3和Z4中有0个是缺失的。
  4. 权利要求1的化合物或其生理学上相容的盐，其中Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Gln；或Z1为D-Pro；Z2为Val；Z3为Pro；以及Z4为Gln；或Z1为Pro；Z2为Val；Z3为Ala；以及Z4为Gln；或Z1为Pro；Z2为Ile；Z3为Pro；以及Z4为Gln；或Z1为Pro；Z2为Val；Z3为Pro；以及Z4为缺失；或Z1为Pro；Z2为Ala；Z3为Pro；以及Z4为Gln；或Z1为Gly；Z2为Val；Z3为Pro；以及Z4为Gln；或Z1为Pro；Z2为Val；Z3为Gly；以及Z4为Gln；或Z1为Ala；Z2为Val；Z3为Pro；以及Z4为Gln；或Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Glu；或Z1为Pro；Z2为Val；Z3为D-Pro；以及Z4为Gln；或Z1为Pro；Z2为Val；Z3为Pro；以及Z4为D-Gln。
  5. 权利要求1的化合物或其生理学上相容的盐，其中Z1为Pro；Z2为Val；Z3为Pro；以及Z4为Gln。
  6. 权利要求1-5中任一项的化合物或其生理学上相容的盐，其中Xa为Xa10-Xa9-Xa8-Xa7-Xa6-Xa5-Xa4-Xa3-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中
    Xa10为Gly或缺失，
    Xa9为Gly、Pro、Ser或缺失，
    Xa8为Pro、Glu、Ser或缺失，
    Xa7为Arg、Glu、Thr、Ser或缺失，
    Xa6为Lys、Thr、Ala、Asp、Glu、Arg、Ser或缺失，
    Xa5为Asp、Ala、Val、Arg、Phe、Ile、Pro、Lys、Glu或缺失，
    Xa4为Val、Phe、Pro、Pyro-Glu、Lys、Leu、Ile、Ala、Asp或缺失，
    Xa3为Tyr、Leu、Pro、Asp、Arg、Glu、Lys、Tys、Val、Ile或缺失，
    Xa2为D-Lys、Lys、Ala、Arg、Val、Glu、Tyr或缺失，以及
    Xa1为Glu、Ala、D-Glu、Tyr、Gln、Asp、Asn或缺失。
  7. 权利要求6的化合物或其生理学上相容的盐，其中Xa为Xaa-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，Xa2-Xa1为Lys-Glu-*、Arg-Glu-*、Val-Tyr-*、Glu-Glu-*、Lys-Gln-*、Lys-D-Glu-*或Tyr-Glu-*，以及Xaa为Xa10-Xa9-Xa8-Xa7-Xa6-Xa5-Xa4-Xa3-，其中Xa10为Gly或缺失，Xa9为Gly、Pro、Ser或缺失，Xa8为Pro、Glu、Ser或缺失，Xa7为Arg、Glu、Thr、Ser或缺失，Xa6为Lys、Thr、 Ala、Asp、Glu、Arg、Ser或缺失，Xa5为Asp、Ala、Val、Arg、Phe、Ile、Pro、Lys、Glu或缺失，Xa4为Val、Phe、Pro、Pyro-Glu、Lys、Leu、Ile、Ala、Asp或缺失，以及Xa3为Tyr、Leu、Pro、Asp、Arg、Glu、Lys、Tys、Val、Ile或缺失。
  8. 权利要求7的化合物或其生理学上相容的盐，其中Xaa为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-或缺失，其中最右侧的连接符-表示与-Xa2-Xa1连接。
  9. 权利要求7的化合物或其生理学上相容的盐，其中Xa为Xaa-Xa2-Xa1-*，其中*表示与Z1-Z2-Z3-Z4连接的位置，其中Xa2-Xa1为Lys-Glu-*，以及Xaa为如上所定义。
  10. 权利要求6的化合物或其生理学上相容的盐，其中Xa为Glu-*、Ala-*、D-Glu-*、Asp-*、Asn-*、Lys-Glu-*、D-Lys-Glu-*、Ala-Glu-*、Lys-Gln-*、Lys-D-Glu-*、Lys-Ala-*、Arg-Lys-Asp-Val-Tyr-Lys-Glu-*、Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-*、Val-Pro-Pro-Lys-Glu-*、Pyro-Glu-Leu-Lys-Glu-*、Arg-Lys-Asp-Val-Tyr-*、Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-*、Ser-Ser-Glu-Asp-Ile-Lys-Glu-LysGlu-*、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-*或缺失，其中*表示与Z1-Z2-Z3-Z4连接的位置。
  11. 权利要求1-10中任一项的化合物或其生理学上相容的盐，其中Xb为**-Xb1-Xb2-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中**表示与Z1-Z2-Z3-Z4连接的位置，其中
    Xb1为Ala、D-Ala或缺失，
    Xb2为Lys、Ala、D-Lys、Arg或缺失，
    Xb3为Pro、Gly、D-Pro、Ser、Val、Ala或缺失，
    Xb4为Arg、Ala、Ser、Pro、D-Arg或缺失，
    Xb5为Lys、Ala、D-Lys、Glu、Tyr或缺失，
    Xb6为Val、Asp、D-Val、Ala或缺失，
    Xb7为Ala、D-Ala、Ile或缺失，
    Xb8为Ala、D-Ala、Lys或缺失，以及
    Xb9为Gln、Ala、Glu、Asn、D-Gln或缺失。
  12. 权利要求11的化合物或其生理学上相容的盐，其中Xb为**-Xb1-Xb2-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中**表示与Z1-Z2-Z3-Z4连接的位置，其中
    Xb1为Ala或D-Ala，
    Xb2为Lys、Ala或D-Lys，
    Xb3为Pro、Gly、或Ala，
    Xb4为Arg或D-Arg，
    Xb5为Lys或缺失，
    Xb6为Val、D-Val、Ala或缺失，
    Xb7为Ala或缺失，
    Xb8为Ala或缺失，以及
    Xb9为Gln、Asn、D-Gln或缺失。
  13. 权利要求11或12的化合物或其生理学上相容的盐，其中Xb为**-Xb1-Xb2-Xbb，其中**表示与 Z1-Z2-Z3-Z4连接的位置，Xb1-Xb2-为**-Ala-Lys-、**-Ala-Lys-、**-Ala-D-Lys-、**-Ala-Ala-或**-D-Ala-Lys-，Xbb为-Xb3-Xb4-Xb5-Xb6-Xb7-Xb8-Xb9，其中Xb3为Pro、Gly、D-Pro、Ser、Val、Ala或缺失，Xb4为Arg、Ala、Ser、Pro、D-Arg或缺失，Xb5为Lys、Ala、D-Lys、Glu、Tyr或缺失，Xb6为Val、Asp、D-Val、Ala或缺失，Xb7为Ala、D-Ala、Ile或缺失，Xb8为Ala、D-Ala、Lys或缺失，以及Xb9为Gln、Ala、Glu、Asn、D-Gln或缺失；或者Xb3为Pro、Gly、或Ala，Xb4为Arg或D-Arg，Xb5为Lys或缺失，Xb6为Val、D-Val、Ala或缺失，Xb7为Ala或缺失，Xb8为Ala或缺失，以及Xb9为Gln、Asn、D-Gln或缺失。
  14. 权利要求13的化合物或其生理学上相容的盐，其中Xbb为-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-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Ala-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Ala-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-Ala、-Gly-Arg-Lys-Val-Ala-Ala-Gln、-D-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-D-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-D-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-D-Ala-Gln、-Ser-Ser-Glu-Asp-Ile-Lys-Glu、-Pro-Arg-Lys-Val-Ala-Ala-Asn、-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-D-Val-Ala-Ala-Gln、-Ala-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Ala-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-Gln、-Pro-D-Arg-Lys-Val-Ala-Ala-Gln、-Pro-Arg-Lys-Val-Ala-Ala-D-Gln或缺失，其中最左侧的连接符-表示与Xb1-Xb2连接。
  15. 权利要求13的化合物或其生理学上相容的盐，其中Xb为**-Xb1-Xb2-Xbb，其中**表示与Z1-Z2-Z3-Z4连接的位置，Xb1-Xb2-为**-Ala-Lys-、Xbb如上述所定义。
  16. 权利要求1的化合物或其生理学上相容的盐，其中Xb为**-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-Pro-Arg-Lys、**-Arg-Lys-Val-Ala、**-Ala-Lys-Pro-Arg-Lys-Val-Ala、**-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln、**-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala、**-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln、**-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln、**-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-Gln、**-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或缺失，其中**表示与Z1-Z2-Z3-Z4连接的位置。
  17. 权利要求1的化合物或其生理学上相容的盐，其中所述化合物选自：
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物1)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物2)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物3)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物4)；
    Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物5)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物6)；
    Lys-Glu-Pro-Val(化合物7)；
    Val-Ala-Ala-Gln(化合物8)；
    Glu-Pro-Val-Pro(化合物9)；
    Lys-Pro-Arg-Lys(化合物10)；
    Ala-Lys-Pro-Arg(化合物11)；
    Pro-Val-Pro-Gln(化合物12)；
    Val-Pro-Gln-Ala(化合物13)；
    Pro-Gln-Ala-Lys(化合物14)；
    Arg-Lys-Val-Ala(化合物15)；
    Lys-Val-Ala-Ala(化合物16)；
    Gln-Ala-Lys-Pro(化合物17)；
    Pro-Arg-Lys-Val(化合物18)；
    Ala-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物19)；
    Lys-Ala-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物20)；
    Lys-Glu-Ala-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物21)；
    Lys-Glu-Pro-Val-Ala-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物22)；
    Lys-Glu-Pro-Val-Pro-Ala-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物23)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Ala-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物24)；
    Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物25)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln(化合物26)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Ala-Lys-Val-Ala-Ala-Gln(化合物27)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Ala-Val-Ala-Ala-Gln(化合物28)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln(化合物29)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Ala(化合物30)；
    Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物31)；
    Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物32)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物33)；
    Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物34)；
    Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物35)；
    Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物36)；
    Lys-Glu-Gly-Val-Gly-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物37)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物38)；
    Pro-Val-Pro-Gln-Ala(化合物39)；
    Pro-Val-Pro-Glu-Ala(化合物40)；
    Pro-Val-Pro-Ile-Ala(化合物41)；
    Pro-Val-Pro-Ala(化合物42)；
    Glu-Pro-Val-Pro-Gln-Ala(化合物43)；
    Pro-Val-Pro-Gln-Ala-Lys(化合物44)；
    Glu-Pro-Val-Pro-Gln-Ala-Arg(化合物45)；
    Ala-Pro-Val-Pro-Gln-Ala-Lys(化合物46)；
    Glu-Pro-Val-Pro-Ala-Ala-Lys(化合物47)；
    Glu-Pro-Val-Pro-Gln-Ala-Ala(化合物48)；
    Asp-Pro-Val-Pro-Gln-Ala-Lys(化合物49)；
    Asn-Pro-Val-Pro-Gln-Ala-Lys(化合物50)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala(化合物51)；
    Glu-Pro-Ala-Pro-Gln-Ala-Lys(化合物52)；
    Glu-Ala-Val-Pro-Gln-Ala-Lys(化合物53)；
    Glu-Pro-Val-Ala-Gln-Ala-Lys(化合物54)；
    Glu-Pro-Val-Pro-Glu-Ala-Lys(化合物55)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val(化合物56)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物57)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro(化合物58)；
    Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物59)；
    Pro-Val-Pro-Gln-Ala-Lys-Pro(化合物60)；
    D-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物61)；
    Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物62)；
    Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物63)；
    Lys-Glu-Pro-D-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物64)；
    Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物65)；
    Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物66)；
    Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物67)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物68)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-D-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物69)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln(化合物70)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-D-Lys-Val-Ala-Ala-Gln(化合物71)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln(化合物72)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-D-Ala-Ala-Gln(化合物73)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-D-Ala-Gln(化合物74)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln(化合物75)；
    Glu-Gly-Val-Pro-Gln-Ala-Lys(化合物76)；
    Glu-Pro-Val-Gly-Gln-Ala-Lys(化合物77)；
    D-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物78)；
    Glu-D-Pro-Val-Pro-Gln-Ala-Lys(化合物79)；
    Glu-Pro-D-Val-Pro-Gln-Ala-Lys(化合物80)；
    Glu-Pro-Val-D-Pro-Gln-Ala-Lys(化合物81)；
    Glu-Pro-Val-Pro-D-Gln-Ala-Lys(化合物82)；
    Glu-Pro-Val-Pro-Gln-D-Ala-Lys(化合物83)；
    Glu-Pro-Val-Pro-Gln-Ala-D-Lys(化合物84)；
    Lys-Glu-Pro-Val-Pro(化合物85)；
    Glu-Pro-Val-Pro-Gln(化合物86)；
    Lys-Glu-Pro-Val-Pro-Gln(化合物87)；
    Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物88)；
    Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物89)；
    Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物90)；
    Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物91)；
    Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物92)；
    Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物93)；
    Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln(化合物94)；
    Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物95)；
    Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物96)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物97)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物98)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln(化合物99)；
    Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物100)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Ser-Ser-Glu-Asp-Ile-Lys-Glu(化合物101)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Val-Pro-Tyr(化合物102)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu(化合物103)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn(化合物104)；
    Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物105)；
    Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物106)；
    Val-Pro-Gln-Ala(化合物107)；或
    Val-Pro-Gln-Ala-Lys(化合物108)。
  18. 权利要求1的化合物或其生理学上相容的盐，其中所述化合物选自：
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物1)；
    Lys-Glu-D-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物63)；
    Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物96)；
    Val-Pro-Pro-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物100)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Asn(化合物104)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物6)；
    Pro-Val-Pro-Gln(化合物12)；
    Glu-Pro-Val-Ala-Gln-Ala-Lys(化合物54)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg(化合物57)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-D-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物68)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-D-Val-Ala-Ala-Gln(化合物72)；
    Pyro-Glu-Leu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物89)；
    Arg-Lys-Asp-Val-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物92)；
    Arg-Lys-Asp-Val-Tyr-Pro-Val-Pro-Gln(化合物94)；
    Gly-Pro-Glu-Thr-Ala-Phe-Leu-Arg-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物95)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物97)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物98)；
    Lys-Gln-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物105)；
    Lys-Glu-Pro-Ile-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物106)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物4)；
    Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物5)；
    Glu-Pro-Val-Pro(化合物9)；
    Lys-Pro-Arg-Lys(化合物10)；
    Arg-Lys-Val-Ala(化合物15)；
    Lys-Glu-Pro-Ala-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物25)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Ala-Arg-Lys-Val-Ala-Ala-Gln(化合物26)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Ala-Ala-Ala-Gln(化合物29)；
    Lys-Glu-Gly-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物31)；
    Lys-Glu-Pro-Val-Gly-Gln-Ala-Lys-Gly-Arg-Lys-Val-Ala-Ala-Gln(化合物34)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys(化合物38)；
    Glu-Pro-Val-Pro-Gln-Ala-Ala(化合物48)；
    Asp-Pro-Val-Pro-Gln-Ala-Lys(化合物49)；
    Asn-Pro-Val-Pro-Gln-Ala-Lys(化合物50)；
    Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala(化合物51)；
    Glu-Ala-Val-Pro-Gln-Ala-Lys(化合物53)；
    Glu-Pro-Val-Pro-Glu-Ala-Lys(化合物55)；
    Lys-D-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物62)；
    Lys-Glu-Pro-Val-D-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物65)；
    Lys-Glu-Pro-Val-Pro-D-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物66)；
    Lys-Glu-Pro-Val-Pro-Gln-D-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物67)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-D-Arg-Lys-Val-Ala-Ala-Gln(化合物70)；
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-D-Gln(化合物75)；
    Glu-Pro-Val-Pro-Gln-D-Ala-Lys(化合物83)；
    Lys-Glu-Pro-Val-Pro(化合物85)；
    Glu-Pro-Val-Pro-Gln(化合物86)；
    Val-Pro-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物88)；
    Pro-Ala-Tyr-Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Gln(化合物90)；
    Arg-Lys-Asp-Val-Tyr-Glu-Pro-Val-Pro-Gln-Ala-Lys(化合物93)；
    Ser-Ser-Glu-Asp-Ile-Lys-Glu-Pro-Val-Pro-Gln(化合物99)；或
    Lys-Glu-Pro-Val-Pro-Gln-Ala-Lys-Pro-Arg-Lys-Val-Ala-Ala-Glu(化合物103)。
  19. 权利要求1-18中任一项的化合物或其生理学上相容的盐在制备用于治疗肠炎的药物中的用途。
  20. 权利要求19的用途，其中肠炎包括特异性肠炎和非特异性肠炎；进一步地，特异性肠炎包括炎症 性肠病、坏死性肠病以及菌群失调性肠炎；进一步地，炎症性肠病包括溃疡性结肠炎。
  21. 一种药物组合物，所述药物组合物包含权利要求1-18中任一项的化合物或其生理学上相容的盐，以及可药用赋形剂。
PCT/CN2023/073068 2022-01-21 2023-01-19 多肽化合物及其治疗肠炎的用途 WO2023138644A1 (zh)

Priority Applications (1)

Application Number Priority Date Filing Date Title
CN202380012589.4A CN117858890A (zh) 2022-01-21 2023-01-19 多肽化合物及其治疗肠炎的用途

Applications Claiming Priority (2)

Application Number Priority Date Filing Date Title
CN202210070418.4 2022-01-21
CN202210070418 2022-01-21

Publications (1)

Publication Number Publication Date
WO2023138644A1 true WO2023138644A1 (zh) 2023-07-27

Family

ID=87347881

Family Applications (1)

Application Number Title Priority Date Filing Date
PCT/CN2023/073068 WO2023138644A1 (zh) 2022-01-21 2023-01-19 多肽化合物及其治疗肠炎的用途

Country Status (2)

Country Link
CN (1) CN117858890A (zh)
WO (1) WO2023138644A1 (zh)

Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108210886A (zh) * 2016-12-09 2018-06-29 上海风劲生物医药科技有限公司 Metrnl在防治溃疡性结肠炎中的应用
CN108478800A (zh) * 2018-04-02 2018-09-04 慎东 含mg53/其突变体的组合物在制备炎症性肠病药物的应用
CN110090295A (zh) * 2018-01-29 2019-08-06 武汉康理通科技有限公司 Ephrin-B1在制备治疗炎症性肠病的药物中的用途
CN111542335A (zh) * 2017-12-01 2020-08-14 斯特姆里姆有限公司 炎症性肠病的治疗药
CN112679589A (zh) * 2021-02-02 2021-04-20 上海珑欣生物医学科技有限公司 一种多肽片段d及其应用
CN112812158A (zh) * 2021-02-02 2021-05-18 上海珑欣生物医学科技有限公司 一种多肽片段c及其应用
CN112851774A (zh) * 2021-02-02 2021-05-28 上海珑欣生物医学科技有限公司 一种多肽片段b及其应用

Patent Citations (7)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
CN108210886A (zh) * 2016-12-09 2018-06-29 上海风劲生物医药科技有限公司 Metrnl在防治溃疡性结肠炎中的应用
CN111542335A (zh) * 2017-12-01 2020-08-14 斯特姆里姆有限公司 炎症性肠病的治疗药
CN110090295A (zh) * 2018-01-29 2019-08-06 武汉康理通科技有限公司 Ephrin-B1在制备治疗炎症性肠病的药物中的用途
CN108478800A (zh) * 2018-04-02 2018-09-04 慎东 含mg53/其突变体的组合物在制备炎症性肠病药物的应用
CN112679589A (zh) * 2021-02-02 2021-04-20 上海珑欣生物医学科技有限公司 一种多肽片段d及其应用
CN112812158A (zh) * 2021-02-02 2021-05-18 上海珑欣生物医学科技有限公司 一种多肽片段c及其应用
CN112851774A (zh) * 2021-02-02 2021-05-28 上海珑欣生物医学科技有限公司 一种多肽片段b及其应用

Also Published As

Publication number Publication date
CN117858890A (zh) 2024-04-09

Similar Documents

Publication Publication Date Title
JP3957751B2 (ja) 新規ドラスタチン誘導体、その製法及び使用
US20080299180A1 (en) Peptides based on the sequence of human lactoferrin and their use
JP2003526622A (ja) 老化防御効果を示すテトラペプチド、これを基にした薬理学的物質、及びその利用法
WO2009094850A1 (en) Recombinant ganoderma lucidium immunomodulatory protein (rlz-8) and uses thereof
JPH06503090A (ja) ノナペプチドのボンベシン拮抗薬
CN114209808A (zh) 一种多肽rk12用于制备治疗痤疮药物的应用
WO2023138644A1 (zh) 多肽化合物及其治疗肠炎的用途
CN108329381A (zh) 一种来源于麒麟菜的十六肽及其在制备防治恶性肿瘤转移药物中的应用
US20230295233A1 (en) Polypeptide for repairing mucosal damage or skin wound and use thereof
CA2405704C (en) Bombesin analogs for treatment of cancer
CN113583098B (zh) 一种来源于真菌的环状拟肽及其制备方法和应用
RU2255757C1 (ru) Пептидное соединение, восстанавливающее функцию органов дыхания
WO2022156189A1 (zh) 多肽化合物在预防或治疗炎症性肠病及其相关的肠纤维化中的应用
CN114106100B (zh) 用于修复皮肤创伤或黏膜损伤的多肽及其应用
CN103012555A (zh) 具有组织保护活性的新多肽的制备方法及在治疗中的应用
WO2024067535A1 (zh) 一种小肽及其在黏膜修复中的应用
TW202330573A (zh) 一種多肽在製備用於預防或治療皮膚損傷疾病產品中之應用
US6989371B1 (en) Bombesin analogs for treatment of cancer
TW202207967A (zh) 用於修復皮膚創傷或黏膜損傷的多肽及其應用
CN115944711A (zh) 四肽在制备用于黏膜损伤或皮肤损伤修复的药物中的应用
CN103044524A (zh) 新多肽的制备及在治疗中的应用
CN117720664A (zh) 一种人工拟肽二聚体及其制备方法与在制备抗痛风性关节炎药物中的应用
TW202014197A (zh) 含有二肽之醫藥組合物
CN102477078B (zh) 胸腺体液因子(THF)-γ2改构肽的制备及其药物组合物的用途
CN114377111A (zh) 一种化痰止咳的药物组合物

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 23742959

Country of ref document: EP

Kind code of ref document: A1