Polypeptide derivative with dual-receptor excitement effect and application of polypeptide derivative

A technology of peptide derivatives and derivatives, applied in the field of medicine and biology, can solve problems such as no drugs on the market

Pending Publication Date: 2021-11-09
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, treatments based on OXM or GLP-1 / GCGR dual agonists have shown potential application value for obesity and obese diabetes, but so far, no related drugs have been marketed

Method used

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  • Polypeptide derivative with dual-receptor excitement effect and application of polypeptide derivative
  • Polypeptide derivative with dual-receptor excitement effect and application of polypeptide derivative
  • Polypeptide derivative with dual-receptor excitement effect and application of polypeptide derivative

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0152] The basic linear sequence of the polypeptide provided by the present invention and the side chain modified derivative peptide are prepared according to the following general methods:

[0153] 1) Synthesis: Using the Fmoc strategy, use the PSI200 peptide synthesizer to synthesize step by step according to the following steps:

[0154] a) In the presence of an activator system, the Fmoc-amino acid-resin is obtained by coupling the resin solid phase carrier and the Fmoc-protected C-terminal amino acid; wherein, the synthesis of the C-terminal amidated polypeptide uses an amino resin, such as Rink Amide AM, Rink Amide , Rink MBHA, etc.; the Fmoc-amino acid and resin ratio (mol / mol) is 3 to 5:1, and the coupling activator is HOBT / DIC or HOBT / HBTU / DIEA.

[0155] b) Extension of the peptide chain: link amino acids in accordance with the amino acid sequence of the peptide sequence by solid-phase synthesis to obtain a peptide-resin conjugate with N-terminal and side chain protec...

Embodiment 2

[0167] Example 2 Effect on GLP-1 / GC receptor

[0168] The effect of the polypeptides on the GLP-1 / GC receptor was evaluated by the effect on GLP-1 / GC receptor-mediated cAMP production in vitro.

[0169] HEK293 cell lines stably expressing GLP-1R and GCGR are used for screening of GLP-1R agonists and GCGR agonists.

[0170] Test sample preparation: the compound was formulated into a 100μM stock solution, and gradually diluted to 1μM, 100nM, 10nM, 1nM, 10 -1 nM, 10 -2 nM, 10 -3 nM, H 2 O working concentration.

[0171] Positive control substance preparation:

[0172] GLP-1:

[0173] Storage method: 1mM storage solution dissolved in 0.1% BSA ultrapure water, and stored at -80°C.

[0174] Working concentration: 1μM, 100nM, 10nM, 1nM, 10 -1 nM, 10 -2 nM, 10 -3 nM and H 2 O (each well contains 0.1% BSA).

[0175] Glucagon (GC):

[0176] Storage method: 1mM DMSO solution, store in airtight at -80°C.

[0177] Working concentration: 1μM, 100nM, 10nM, 1nM, 10 -1 nM, 10 ...

Embodiment 3

[0192] Example 3 The hypoglycemic effect of embodiment 1 compound

[0193] The hypoglycemic effect of the compound of Example 1 was evaluated by a single-administration glucose load test in normal mice.

[0194] Methods: Kunming mice (male, body weight range 20-22g) were adaptively fed in the barrier environment animal room for 3 days and then divided into blank control group, model control group, positive control group and test compound group, with 5 mice in each group , fasting 6h. The blank control group and the model control group were given physiological saline, the dose of the test compound group and the positive control group was 30 nmol / kg, and the positive control drug was semaglutide. After 60min of administration, the model control group, the positive control group and the test compound group were treated with 2.5g / kg (0.01mL·g -1 Body weight) were given glucose by intragastric administration, and the blank control group was given distilled water, and the blood ...

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Abstract

The invention provides a polypeptide derivative, a modified derivative or salt thereof and use of the polypeptide derivative and the modified derivative or salt thereof. The polypeptide derivative, the modified derivative of the polypeptide derivative or the salt of the polypeptide derivative comprises a polypeptide with a sequence of the following general formula I: the general formula I: HX2QGTFTSDX10SKYLX15EX17X18AX20X21FX23AWLEX28X29X30, and definitions of X2, X10, X15, X17, X18, X20, X21, X23, X28, X29 and X30 are consistent with those of the claims and the description. The polypeptide derivative provided by the invention is a dual excitant of a GC/GLP-1 receptor, has a synergistic effect on energy metabolism, can be used for effectively reducing blood sugar while reducing body weight and improving a body fat level, and has a potential application value in the field of treatment of metabolic diseases such as diabetes and obesity.

Description

technical field [0001] The invention belongs to the technical field of medicine and biology, and in particular relates to a glucagon-derived peptide with dual receptor agonizing effects of glucagon / glucagon-like peptide-1 and its application. Background technique [0002] Obesity is a risk factor for many diseases and has become a global public health problem. In particular, common diseases such as metabolic syndrome, cardiovascular disease, and non-alcoholic fatty liver including type 2 diabetes mellitus (T2DM) are closely related to obesity in terms of incidence and progression. A number of large-scale clinical studies have found that compared with normal weight people, the incidence of cardiovascular and metabolic multiple diseases is between BMI25.0-29.9kg / m 2 、30.0–34.9kg / m 2 and BMI>35.0kg / m 2 Overweight, obese or severely obese people were 2 times, 5 times and 15 times higher, respectively (Lancet 2, e277–e285, 2017). Studies have shown that 80-90% of T2DM pati...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/04A61P3/06A61P1/16
CPCC07K14/605A61P3/10A61P3/04A61P3/06A61P1/16A61K38/00A61P3/00A61K38/26
Inventor 韩英梅刘巍刘冰妮孔维苓赵娜夏夏广萍商倩靳京孔晓华李玉荃王松会
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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