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Novel growth hormone releasing hormone analog peptides and application thereof in preparing medicines for treating infertility

A growth hormone and hormone-releasing technology, applied in the field of medicine and biology, can solve the problems of low activity and short half-life

Active Publication Date: 2015-04-29
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

[0005] Although hGHRH analogs have great potential applications in biomedicine, their short half-life and low activity are major limitations

Method used

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  • Novel growth hormone releasing hormone analog peptides and application thereof in preparing medicines for treating infertility
  • Novel growth hormone releasing hormone analog peptides and application thereof in preparing medicines for treating infertility
  • Novel growth hormone releasing hormone analog peptides and application thereof in preparing medicines for treating infertility

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0046] Example 1: Synthesis of novel growth hormone releasing hormone analogues:

[0047] 1. Monomer peptide synthesis process: manual chemical solid-phase peptide synthesis (SYMPHONY 12-channel peptide synthesizer, software version.201, Protein Technologies Inc.), operation steps:

[0048] 1. Resin swelling: put Dawang resin (wang resin, purchased from Tianjin Nankai Synthetic Technology Co., Ltd.) into a reaction pot, add dichloromethane (DCM, Dikma Technologies Inc.) 15ml / g in Dawang resin, shake 30min.

[0049] 2. Connect the first amino acid: Remove the solvent through sand core suction filtration, add 3 mmol of the first Fmoc-AA amino acid at the C-terminal (all Fmoc-amino acids are provided by Suzhou Tianma Pharmaceutical Group Fine Chemicals Co., Ltd.), and then Add 4-dimethylaminopyridine (DMAP) and N,N'-dicyclohexylcarbodiimide (DCC) in 10 millimolar amounts, and finally dimethylformamide (DMF) (purchased from Dikma Technologies Inc.) Dissolve and shake for 30min. ...

Embodiment 2

[0072] Example 2: Hormone releasing activity in vitro:

[0073] 1. In vitro pituitary gland stimulation method: S-D female mice (about 8 weeks old, weighing 200±20 g) were purchased from the Experimental Animal Center of Guangzhou University of Traditional Chinese Medicine. All experimental animals were kept and used in accordance with institutional guidelines. During feeding, the rats were reared alternately between light and dark at 12:12 hours, and the feeding temperature was 26±1°C. Rats died suddenly by dislocation, and all pituitary glands were removed within 30 minutes. After washing with sterilized lactated Ringer's buffer (LRB), the pituitary gland was immediately placed in a 1×10 cm glass tube with 1 ml of LRB, and kept at 37°C. All glass tubes are kept warm for 5h (P 1 ,P 2 ,I 3 ,I 4 and I 5 , representing different periods of 5-hour incubation, and each period represents 1 hour), while shaking gently every 5 minutes, after every 1 hour, gently suck out the b...

Embodiment 3

[0080] Embodiment 3: Rat pituitary growth hormone release inhibition analysis:

[0081] According to the pituitary GH release activity test (P 1 , P 2 , I 3 , I 4 , I 5 ), can determine growth hormone release inhibition method, in I 3 -I 5 During the incubation, 0.482 or 1.927 μM growth hormone inhibitory hormone (GHIH) was added to tubes containing 1.927 μM GHRH dimer, respectively. No peptide P 2 The incubation was used as a blank and the S2 peptide was used as a standard control. Rat pituitary growth hormone levels were determined by rat growth hormone ELISA kit.

[0082] According to the 5-h pituitary culture assay, at I 3 -I 5 During the incubation, when 1.927 μM GHRH peptide appeared, the addition of 0.482 or 1.927 μM GHIH peptide showed a significant inhibitory effect, and the inhibitory effect was proportional to the GHIH peptide dose and incubation time ( Figure 14 ). in I 3 -I 5 Among them, the inhibition of 1.927 μM GHIH was significantly more than th...

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Abstract

The invention discloses novel growth hormone releasing hormone analog peptides and an application thereof in preparing medicines for treating infertility. Experiments discover that 2D, 2E or 2F peptide has obviously high hypophysis GH releasing activity and hypophysis hormone releasing specificity. Tested by the conjugation reaction of an in-vitro GHRH dimer peptide and a hypophysis GHRH receptor, 2D, 2E and 2F dimer peptides have extremely high hypophysis receptor binding activity, wherein the 2F dimer peptide has the maximum binding activity. With the 2F peptide as the representative, infertility model treatment finds out that, compared with a normal saline group and a pure cyclophosphamide control group, in the 2F dimer peptide group, the spermatocytes and the spermatogonia in the seminiferous tubules are obviously increased, the seminiferous tubule cells are arranged in order and large in volume, the cavities of the seminiferous tubules are reduced and even disappear, and dose dependency is shown. All the facts indicate that the GHRH peptides with the 2F peptide as the representative have an obvious effect of stimulating the proliferation and the maturation of spermatogonia / oogonia, thereby promoting reproduction; and as a result, the novel growth hormone releasing hormone analog peptides can be applied to medicines for treating infertility.

Description

Technical field: [0001] The invention belongs to the field of medicine and biology, and in particular relates to four novel GH-releasing hormone analogous peptides and their application in the preparation of medicines for treating infertility. Background technique: [0002] Human growth hormone releasing hormone (hGHRH), secreted by the hypothalamus, promotes the pituitary gland to synthesize and release the neuroendocrine peptide of human growth hormone (hGH). Maturation of the preproprotein hGHRH(1-107 / 8) precursor consists of a series of proteolytic processing steps leading to the final mature form hGHRH(1–44)NH 2 , hGHRH(1–37)OH and hGHRH(1–40)OH. Among these GHRH molecules, the shortest sequence with 51% biological activity was hGHRH(1–29), known as the core peptide. Human hypothalamic hGHRH has 93%, 93%, 89%, 89%, 86%, 73 %, 71% and 61%. [0003] Reports such as Ling N, relative to hGHRH (1-40) OH, D- 1 Tyr-hGHRH(1-40)OH, 1 Phe-hGHRH(1-40)OH, 1 Trp-hGHRH(1-40)OH...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/60A61K38/25A61P15/08
CPCA61K38/25C07K14/60A61K38/00
Inventor 唐松山张娟辉游娟张旭东周东李红枝李秋莹郭小元唐婧晅
Owner 深圳纳福生物医药有限公司
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