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Exendin-4 analog dimer and its preparation method and application

A technology of EXENDIN-4 and analogs, applied in the field of polypeptide complexes, which can solve the problems of short half-life and increased pain for patients

Active Publication Date: 2016-11-30
TIANJIN INSTITUTE OF PHARMA RESEARCH
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

[0005] However, the Exenatide drugs currently on the market still have the problem of short half-life. The general half-life of Exenatide (Exenatide) for medicinal use is only 2.4 hours, and it is injected twice a day, which greatly increases the suffering of patients.
Therefore, there is currently a need for a method to address the short in vivo half-life of Exenatide drugs

Method used

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  • Exendin-4 analog dimer and its preparation method and application
  • Exendin-4 analog dimer and its preparation method and application
  • Exendin-4 analog dimer and its preparation method and application

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0068] Embodiment 1: the solid-phase synthesis of polypeptide

[0069] Using the solid-phase peptide synthesis method of the Fmoc strategy (the amino acids used were purchased from Shanghai Jier Company), the CS336X instrument produced by CSBio Company was used to synthesize the EXENDIN-4 analogue monomer of the present invention. The method of synthesis was carried out according to the manufacturer's instruction manual.

[0070] Specifically, the Fmoc solid-phase polypeptide synthesis method is a process in which amino acids are gradually added from the C-terminus, that is, the carboxyl-terminus, to the N-terminus, that is, the amino-terminus, using the solid-phase carrier resin as a carrier.

[0071] In the present invention, the resin is Fmoc-wang resin (or 2-cl-trt resin), and the resin substitution degree is 0.10-0.34.

[0072] The protected amino acids used are: Fmoc-Tyr(tBu)-OH, Fmoc-Ile-OH, Fmoc-leu(tBu)-OH, Fmoc-Ala-OH, Fmoc-Thr(tBu)-OH, Fmoc-Val-OH , Fmoc-Lys(Boc...

Embodiment 2

[0079] Example 2: Hypoglycemic Function of EXENDIN-4 Analog Dimers

[0080] In this embodiment, the Exendin-4 analog monomers used are as follows: SEQ ID NO:2 and SEQ ID NO:2; SEQ ID NO:3 and SEQ ID NO:3; SEQ ID NO:4 and SEQ ID NO:4 ; SEQ ID NO:5 and SEQ ID NO:5; SEQ ID NO:6 and SEQ ID NO:6; SEQ ID NO:7 and SEQ ID7.

[0081] In this embodiment, dimers formed by Exendin-4 analog monomers (containing 1 cysteine) of different sequences can also be used, such as SEQ ID NO: 2 and SEQ ID NO: 3, SEQ ID NO :2 and SEQ ID NO:4, SEQ ID NO:2 and SEQ ID NO:5, SEQ ID NO:2 and SEQ ID NO:6, SEQ ID NO:2 and SEQ ID NO:7, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:3 and SEQ ID NO:5, SEQ ID NO:3 and SEQ ID NO:6, SEQ ID NO:3 and SEQ ID NO:7, SEQ ID NO:4 and SEQ ID NO:5, SEQ ID NO:4 and SEQ ID NO:6, SEQ ID NO:4 and SEQ ID NO:7, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:5 and SEQ ID NO:7 , SEQ ID NO:2 and SEQ ID NO:8.

[0082] Dissolve 1 mg of each of the 9 or 8 dimers in 1 mL of normal saline, and i...

Embodiment 3

[0083] Example 3: Effect of EXENDIN-4 Analog Dimer on Weight Loss in Rats

[0084] In this embodiment, the Exendin-4 analog monomer polypeptides used are as follows: SEQ ID NO:2 and SEQ ID NO:2; SEQ ID NO:3 and SEQ ID NO:3; SEQ ID NO:4 and SEQ IDNO: 4; SEQ ID NO:5 and SEQ ID NO:5; SEQ ID NO:6 and SEQ ID NO:6; SEQ ID NO:7 and SEQ ID7.

[0085] In this embodiment, dimers formed by Exendin-4 analog monomers (containing 1 cysteine) of different sequences can also be used, such as SEQ ID NO: 2 and SEQ ID NO: 3, SEQ ID NO :2 and SEQ ID NO:4, SEQ ID NO:2 and SEQ ID NO:5, SEQ ID NO:2 and SEQ ID NO:6, SEQ ID NO:2 and SEQ ID NO:7, SEQ ID NO:3 and SEQ ID NO:4, SEQ ID NO:3 and SEQ ID NO:5, SEQ ID NO:3 and SEQ ID NO:6, SEQ ID NO:3 and SEQ ID NO:7, SEQ ID NO:4 and SEQ ID NO :5, SEQ ID NO:4 and SEQ ID NO:6, SEQ ID NO:4 and SEQ ID NO:7, SEQ ID NO:5 and SEQ ID NO:6, SEQ ID NO:5 and SEQ ID NO:7, SEQ ID NO:2 and SEQ ID NO:8.

[0086] SD rats (200±20g, purchased from the SLAC Animal Laborat...

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Abstract

The present invention provides an EXENDIN-4 analogue dimer and its preparation method and application. The dimer is composed of two identical or different EXENDIN-4 analogue monomers through cysteine ​​to form an inter-monomer disulfide bond, the preparation of the EXENDIN-4 analog dimer includes the synthesis of EXENDIN-4 analog monomers by Fmoc solid-phase peptide synthesis method, and then the monomers are formed into dimers; and the EXENDIN-4 is similar Application of the biodimer in the preparation of medicines for treating diabetes, treating and / or preventing obesity or obesity-related diseases. The half-life of the EXENDIN-4 analogue dimer formed by the monomer of the present invention can reach more than 14 to 96 hours in vivo, which is significantly longer than the half-life of EXENDIN-4 administered alone (half-life is only 2.4 hours), which is greatly convenient its clinical promotion and application.

Description

technical field [0001] The present invention relates to the field of drugs related to diabetes, in particular, the present invention relates to a polypeptide complex capable of prolonging the half-life of glucagon-like peptide (EXENDIN-4) in vivo. The invention also relates to the preparation method and application of the polypeptide. Background technique [0002] Diabetes mellitus is a metabolic disorder syndrome characterized by chronic hyperglycemia associated with genetic factors and multiple environmental factors. Because diabetes is also accompanied by many complications, it has become the third largest health killer after malignant tumors and cardiovascular diseases. In 1984, the glucagon-like peptide (EXENDIN-4) drug was discovered, which is an incretin with 30 amino acids. The main reason for the limitation of EXENDIN-4 as a hypoglycemic drug is that the in vivo half-life of EXENDIN-4 is only 3-5 minutes. [0003] Exenatide is a linear polypeptide composed of 39 ...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K14/575C07K19/00C07K1/06C07K1/04A61K38/22A61P3/04A61P3/10
Inventor 王玉丽郑学敏黄长江龚珉徐为人汤立达
Owner TIANJIN INSTITUTE OF PHARMA RESEARCH
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