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Polypeptide as agonist of growth hormone secretagogue receptor and use thereof

A receptor agonist and secretagogue technology, applied in the field of biomedicine, to achieve the effect of novel structure, high agonist activity, and less toxic and side effects

Pending Publication Date: 2021-06-29
CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0004] By analyzing the structure of GHRP-6, researchers have discovered some GHRP analogs, which can combine with GHSR-1a to produce agonistic activity, cause signal transduction, and thus regulate the secretion of growth hormone, but they all have clinical development. certain limitations

Method used

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  • Polypeptide as agonist of growth hormone secretagogue receptor and use thereof
  • Polypeptide as agonist of growth hormone secretagogue receptor and use thereof
  • Polypeptide as agonist of growth hormone secretagogue receptor and use thereof

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1-43

[0172] Embodiment 1-43: Preparation of compound 1-43

[0173] 1. Deprotection: Weigh 0.23g (0.1mmol) of Rink Amide resin and place it in a peptide synthesis reactor, then prepare the deprotection reagent according to the above concentration, add it to the resin, react at room temperature, drain, and again Add piperidine / DMF, react at room temperature, drain and wash with DMF until the test is qualified.

[0174] 2. Condensation reaction: add amino acid and condensing agent to DMF to activate respectively under ice bath conditions, then add activated base to react to obtain activation solution, finally add activation solution to resin, react at room temperature, and use 5% ninhydrin The color reagent makes the resin develop color, and the resin changes color. Drain the solvent and wash it with DMF. After passing the test, drain the solvent, and the condensation reaction is complete at this time.

[0175] 3. Repeat the above deprotection and condensation reactions until the syn...

Embodiment 44

[0187] Embodiment 44: The agonist activity evaluation experiment of polypeptide compound to GHSR-1a (IC 50 )

[0188] The screening of GHSR-1a active compounds is accomplished by recombinantly expressing the receptor. The use of recombinant expression of GHSR-Ia offers several advantages, such as the ability to express the receptor in defined cell systems allowing for easier differentiation of compound responses to GHSR-Ia from responses to other receptors. For example, GHSR-1a can be expressed in cell lines such as HEK293, COS7, and CHO, which usually express GHSR-1a without expression vectors, and the same cell lines without expression vectors can be used as controls.

[0189] The activity of GHSR-1a can be measured using different techniques, for example, by detecting changes in the intracellular conformation of GHSR-1a, changes in G-protein coupling activity, and / or changes in intracellular messengers. Preferably, methods such as the determination of intracellular Ca 2+...

Embodiment 45

[0220] Example 45: Inhibition of Cytochrome P450 Oxidase (CYP450) by Polypeptide Compounds

[0221] The metabolic process of drugs in vivo can be divided into phase I reaction (catabolism) and phase II reaction (anabolism). Phase I reactions include oxidation, reduction, and hydrolysis reactions, mainly catalyzed by cytochrome P450 (CYP450) enzymes. CYP450 enzymes are mainly distributed in the liver, so they are also called liver drug enzymes. Induction and inhibition of CYP450 enzymes have important clinical implications and can lead to clinical drug interactions. Therefore, the inhibition test of CYP450 is often used as a safety index to evaluate the druggability of drugs.

[0222] Cytochrome P450-containing human liver microsomes (0.253 mg / mL protein) were mixed with test compounds (0.05-50 μM), CYPs substrates (10 μM acetaminophen, 5 μM diclofenac, 30 μM mephenytoin, 5 μM dextromethorphan hydrobromide methorphan, 2 μM midazolam), 1.0 mM NADP and incubated at 37° C. for ...

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Abstract

The invention provides a polypeptide as an agonist of a growth hormone secretagogue receptor (GHSR). The polypeptide has a structure as shown in formula I, or a stereoisomer, a mixture and a pharmaceutically acceptable salt thereof. Experimental results show that the provided polypeptide compound can effectively show relatively high agonistic activity on GHSR-1a, has a novel structure and small toxic and side effects, and has the potential of becoming a clinical candidate compound.

Description

technical field [0001] The invention relates to the technical field of biomedicine, in particular to a polypeptide as a growth hormone secretagogue receptor agonist and its application. Background technique [0002] Somatropin is released from the somatotroph cells of the pituitary gland and stimulates the growth of all capable tissue growth, also has some effect on metabolic processes and causes a switch in energy metabolism from carbohydrate to fatty acid metabolism. The release of growth hormone from somatotroph cells is regulated by two hypothalamic neuropeptides, ghrelin-releasing hormone (stimulatory release) and ghrelin-releasing hormone (ghrelin-releasing hormone), which is inhibitory. Growth Hormone Secretagogue Receptor (GHSR), also known as ghrelin receptor, is a G protein-coupled receptor composed of 7 transmembrane α-helices, mostly distributed in the pituitary, stomach, Intestines and other parts also regulate the release of growth hormone in somatotroph cells...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K7/02C07K7/06C07K5/107A61K38/08A61K38/07A61P3/00A61P5/06A23L33/18
CPCC07K7/02C07K7/06C07K5/1016A61P3/00A61P5/06A23L33/18A61K38/00A23V2002/00A23V2200/30Y02P20/55
Inventor 孟广鹏付晓平李四军谭啟海宋攀刘爽徐苗左成高剑李元波
Owner CHENGDU SINTANOVO BIOTECHNOLOGV CO LTD
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