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Glucagon analogue, and preparation method and application thereof

A technique for glucagon and analogues, applied in the field of glucagon analogues and their preparation

Active Publication Date: 2020-06-30
HANGZHOU HEZE PHARMA TECH +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

Therefore, the weight loss effect of this class of GLP-1 analogues needs to be improved

Method used

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  • Glucagon analogue, and preparation method and application thereof
  • Glucagon analogue, and preparation method and application thereof
  • Glucagon analogue, and preparation method and application thereof

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preparation example Construction

[0076] The fifth aspect of the present invention provides the preparation method of the glucagon analog provided in the first aspect of the present invention, and the preparation method may include: preparing the glucagon analog by chemical synthesis; the preparation method also It may include: cultivating the host cell provided by the fourth aspect of the present invention under appropriate conditions to express the glucagon-like polypeptide fragment, isolating and purifying the glucagon-like polypeptide fragment, and then extracting the A long-acting carrier is chemically cross-linked to the glucagon-like polypeptide fragment. The glucagon analogs of the present invention can be prepared by standard peptide synthesis methods, e.g., by standard solid-phase or liquid-phase methods, stepwise or by fragment assembly, and isolation and purification of the final glucagon-like polypeptide fragments, pancreatic Glucagon analog products, or any combination by recombinant and syntheti...

Embodiment 1

[0122] Preparation of glucagon derivative FC382K14D21:

[0123]

[0124] HSQGT FTSDY SKYXD SQAAQ DFVQW LMNGG PSSGA PPPS-OH

[0125] X14=K(palmitoyl-γE) (SEQ ID NO.16)

[0126] Fmoc-protected amino acids were purchased from Chengdu Zhengyuan Biochemical Technology Co., Ltd., and the following amino acids were used during the extended synthesis of polypeptides: Fmoc-L-Ala-OH, Fmoc-L-Asn(Trt)-OH, Fmoc-L-Asp( OtBu)-OH, Fmoc-L-Cys(Trt)-OH, Fmoc-L-Gln(Trt)-OH, Fmoc-L-Glu(OtBu)-OH, Fmoc-Gly-OH, Fmoc-L-His( Trt)-OH, Fmoc-L-Ile-OH, Fmoc-L-Leu-OH, Fmoc-L-Lys(Boc)-OH, Fmoc-L-Met-OH, Fmoc-L-Phe-OH, Fmoc- L-Pro-OH, Fmoc-L-Ser(tBu)-OH, Fmoc-L-Thr(tBu)-OH, Fmoc-L-Trp(Boc)-OH, Fmoc-L-Tyr(tBu)-OH, Fmoc-L-Val-OH.

[0127] Synthesis of Fmoc-Ser(tBu)-King Resin:

[0128] Weigh 12.95 g of Wang resin (Tianjin Nankai Hecheng Technology Co., Ltd.) with a degree of substitution of 0.58 mmol / g, add it to a solid-phase reaction column, add 100 mL of DCM to swell the resin for 30 minutes, and was...

Embodiment 2

[0138] Preparation of glucagon derivative FC382K14W07:

[0139]

[0140] HSQGT FTSDY SKYXD SQAAQ DFVQW LMNGG PSSGA PPPS-OH

[0141] X14=K(octadecanoyl-γE) (SEQ ID NO.81)

[0142] The synthesis method is the same as in Example 1, wherein K14 is coupled with Fmoc-Lys(Staroyl-Glu-OtBu)-OH (Hangzhou Hesu Chemical Technology Co., Ltd.), the obtained crude peptide is purified by RP-HPLC, and finally freeze-dried to obtain Refined peptide (97.3%). MS: m / z 4569.02 (M+H) + .

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Abstract

The invention relates to the technical field of biology, specifically to a glucagon analogue, and a preparation method and an application thereof. The glucagon analogue provided by the invention comprises a glucagon-like polypeptide fragment, wherein a long-acting carrier is cross-linked on the glucagon-like polypeptide fragment. According to the glucagon analogue provided by the invention, only 2-3 amino acids of a polypeptide chain are mutated on the basis of a natural Glucagon sequence, and the risk of immunogenicity is extremely low, so a C-terminal sequence of a listed drug Exenatide (with a trade name of Bydureon) is additionally introduced, and higher security is achieved. Furthermore, the glucagon analogue provided by the invention has extremely high GLP-1R and GCGR agonistic activity, and surprisingly, the glucagon analogue has significant change in in-vitro activity before and after fatty acid crosslinking.

Description

technical field [0001] The invention relates to the field of biotechnology, in particular to a glucagon analogue and its preparation method and application. Background technique [0002] Diabetes can be divided into type 1 diabetes and type 2 diabetes according to pathological features. Type 1 diabetes is mainly manifested by insufficient insulin secretion and requires daily insulin injections; while type 2 diabetes is caused by the body's inability to use insulin effectively. Among them, patients with type 2 diabetes account for the vast majority. It is estimated that about 80-90% of patients with type 2 diabetes are significantly obese (Center for disease control and prevention (CDC) National Diabetes Fact Sheet, 2014). [0003] Among the currently marketed protein drugs, GLP-1R (GLP-1 receptor) agonists are mainly used for the treatment of type 2 diabetes, such as liraglutide (Liraglutide, trade name and ), Semeglutide (trade name )wait. Liraglutide is a chemical...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/605A61K38/26A61P3/10A61P3/06A61P1/16A61P3/04
CPCC07K14/605A61P3/10A61P3/06A61P1/16A61P3/04A61K38/00A61K38/26A61P3/00C07K19/00
Inventor 黄岩山
Owner HANGZHOU HEZE PHARMA TECH
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