EXENDIN-4 analogue dimer and preparation method and application thereof

A technology of EXENDIN-4 and analogues, applied in the field of polypeptide complexes, can solve problems such as short half-life and increased pain of patients

Active Publication Date: 2014-06-04
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, a

Method used

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  • EXENDIN-4 analogue dimer and preparation method and application thereof
  • EXENDIN-4 analogue dimer and preparation method and application thereof
  • EXENDIN-4 analogue dimer and preparation method and application thereof

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 invention provides EXENDIN-4 analogue dimer and a preparation method and application thereof. The dimer is prepared from two same or different EXENDIN-4 analogues by forming a disulfide bond between the monomers through cysteine. The preparation method of the EXENDIN-4 analogue dimer comprises the steps of synthesizing an EXENDIN-4 analogue monomer by an Fmoc solid-phase polypeptide synthesis method, and forming the dimer from the monomer. The invention also provides an application of the EXENDIN-4 analogue dimer in preparing a medicine for treating diabetes mellitus and treating and/or preventing obesity or obesity-related diseases. The in-vivo half-life period of the EXENDIN-4 analogue dimer formed from the monomer provided by the invention can exceed 14-96 hours, which is obviously prolonged as compared with the half-life period (only 2.4 hours) of EXENDIN-4 in separate administration, thereby greatly facilitating the clinical popularization 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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IPC IPC(8): C07K14/575C07K19/00C07K1/06C07K1/04A61K38/22A61P3/04A61P3/10
CPCC07K14/575A61K38/00
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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