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Modification and dimerization preparation and application of novel growth hormone releasing hormone similar peptide

A technology for releasing hormones and growth hormones, applied in the field of medicine and biology

Active Publication Date: 2020-08-14
深圳纳福生物医药有限公司
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

1 P-GHRH shows high pituitary GH release in vitro but not in vivo

Method used

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  • Modification and dimerization preparation and application of novel growth hormone releasing hormone similar peptide
  • Modification and dimerization preparation and application of novel growth hormone releasing hormone similar peptide
  • Modification and dimerization preparation and application of novel growth hormone releasing hormone similar peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0039] Example 1: Preparation of monomeric peptides and dimers

[0040] 1. Monomer peptide synthesis process: Manual solid-phase peptide synthesis operation steps.

[0041] 1. Resin swelling: put amino resin (amino resin for C-terminal amidation sequence) (purchased from Tianjin Nankai Synthetic Technology Co., Ltd.) into the reaction pot, add dichloromethane (DCM, Dikma Technologies Inc.) 15ml / g resin, shake for 30min. SYMPHONY 12-channel polypeptide synthesizer (SYMPHONY model, software Version.201, Protein Technologies Inc.).

[0042] 2. Connect the first amino acid: Remove the solvent through sand core suction filtration, add 3 times the mole of the first Fmoc-amino acid at the C-terminal (all Fmoc-amino acids are provided by Suzhou Tianma Pharmaceutical Group Fine Chemicals Co., Ltd.), and then add 10 Doubling molar amounts of 4-dimethylaminopyridine (DMAP) and N,N'-dicyclohexylcarbodiimide (DCC), and finally adding dimethylformamide (DMF) (purchased from Dikma Technol...

Embodiment 2

[0082] Example 2: Determination of Growth Hormone Release Activity

[0083] 1. Growth hormone (GH) release test in mice: Kunming mice (female, weighing 18-22 g, purchased from the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine, n=6). The regime for the care and use of all experimental animals was consistent with the Guidelines for Laboratory Animals. During feeding, the mice were reared alternately between light and dark for 12:12 hours, and the feeding temperature was 26±1°C. The peptide was subcutaneously injected into the buttocks of Kunming mice at a dose of 0.0133 μmol / kg, and blood was collected from the eyeballs 1 hour after administration, and serum was collected by centrifugation at 6000 rpm for 30 minutes for GH determination. In the experiment, all novel monomeric peptides or dimeric peptides were dissolved with T-NaCl-PB solution (detailed in the administration setting), and the negative control group was injected with T-NaCl-PB...

Embodiment 3

[0089] Example 3: Treatment of Dimeric Peptides to Infertility Models

[0090] 1. Infertility model test method: Take 130 Chinese hamster males or 65 Chinese hamster females (five weeks old, 18-22g / only, provided by Sichuan Dashuo Experimental Animal Center. Because the preliminary experiment shows , the sensitivity of male mice to peptides is significantly weaker than that of female mice, so the infertility model of male mice is n=20, while the infertility model of female mice is n=10. Because the GHRH of Chinese hamsters has the highest 93% homology with humans), Divided into blank control group (20 male mice, 10 female mice) and model mice (110 male mice, 55 female mice). All model groups were intraperitoneally injected with cyclophosphamide (Jiangsu Hengrui Medicine Co., Ltd., H32020857, batch number 12032925) at 20 mg / kg, once a week, five times in total. After injection of cyclophosphamide in the fourth week, the model mice were divided into model control group (Placebo...

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Abstract

The invention provides application of a molecular allosteric body and dimer of a human growth hormone releasing hormone (hGHRH) similar peptide in treating GH deficiency, infertility, senile dementiaand diabetes and enhancing immunity. The dimer is formed by connecting two identical hGHRH similar peptide monomers containing a single cysteine molecule allosteric structure through a disulfide bondformed by cysteine, and an H-shaped structure (intramolecular single Ser-to-Cys substitution) is formed. A side chain epsilon-amino of one lysine of the GHRH similar peptide is also subjected to fattyacid chain modification. Through fatty acid modification, the GH sustained release time of the GHRH similar peptide monomer or dimer is prolonged in vivo, and the longest release time reaches 17 days. The invention finds that the GHRH dimer with long-acting activity has an Aib-to-2Ala substitution structure, an 18C-to-18C disulfide bond formation structure, a C20 fatty acid chain modification structure and a C-terminal amidation structure.

Description

technical field [0001] The invention belongs to the field of medicine and biology, and specifically relates to the preparation of various human new growth hormone releasing hormone analogous peptide monomers and dimers and their application in treatment. Background technique [0002] The central growth hormone-releasing hormone-somatotropin-insulin-like growth factor (GHRH-GH-IGFs) endocrine axis regulates cell growth and sex cell reproduction in the body. The complete sequence of human GHRH is hGHRH(1-44)NH 2 , hGHRH(1-29) is the core peptide with 51% biological activity. The in vitro or in vivo activity of novel hGHRH analog peptides and their dimers was determined by measuring growth hormone (GH) release values ​​by in vitro pituitary incubation or in vivo subcutaneous injection. [0003] The new study found that the effect of hGHRH molecules on peripheral tissues is different from that on the central nervous system. For example, in the central nervous system, the hypot...

Claims

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Application Information

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IPC IPC(8): C07K14/60A61K38/25A61P5/06A61P3/10A61P37/04A61P25/28A61P15/08
CPCC07K14/60A61P5/06A61P3/10A61P37/04A61P25/28A61P15/08A61K38/00C07K2319/00
Inventor 唐松山张旭东杨莉谭宏梅罗群唐婧晅
Owner 深圳纳福生物医药有限公司
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