Preparation and application of novel ghrelin-like peptide modification and dimerization

A technology for releasing hormones and growth hormones, which is applied in the field of medicine and biology to achieve the effect of long half-life and long-lasting activity

Active Publication Date: 2021-08-31
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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  • Preparation and application of novel ghrelin-like peptide modification and dimerization
  • Preparation and application of novel ghrelin-like peptide modification and dimerization
  • Preparation and application of novel ghrelin-like peptide modification and dimerization

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0041] Example 1: Preparation of monomeric peptides and dimers

[0042] 1. Monomer peptide synthesis process: Manual solid-phase peptide synthesis operation steps.

[0043] 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.).

[0044] 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

[0084] Example 2: Determination of Growth Hormone Release Activity

[0085] 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

[0091] Example 3: Treatment of Dimeric Peptides to Infertility Models

[0092] 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., National Drug Approval 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...

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Abstract

The invention provides the molecular degeneration of human growth hormone release hormone (HGHRH) peptides and its di clustering in the treatment of GH deficiency, infertility, dementia, diabetes, and enhanced immunity.The di agent of the present invention is two similar HGHRH -like peptide monomers that contain a single beurine molecular degeneration are connected by a sulfur (sulfurine formed by cysteine, and form an H -shaped structure (internal single ser → CYS inside the molecule → CYSreplace).The present invention also modifies the fatty acid chain of one of the lysine ε‑ amino groups of one of the lysine in the GHRH -like peptide.Extend the GHRH -like peptide monomer or di -polycatus in the body through fatty acid decoration, up to 17 days in the GH in the body.The present invention found that GHRH diodes with long -term activity have AIB → 2 ALA replacement, 18 C‑ 18 C formal sulfur formation, C20 fatty acid chain modification, and C -side amineization 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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Patent Type & Authority Patents(China)
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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