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A method for constructing stable three-membered cyclic peptide based on tetrafluorophthalonitrile

A technology of tetrafluorophthalonitrile and three-membered rings, which is applied in the field of polycyclic peptides, can solve the problems of complex products and difficult regulation, and achieve the effect of single product, high yield and precise structure regulation

Active Publication Date: 2019-03-22
XIAMEN UNIV
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  • Abstract
  • Description
  • Claims
  • Application Information

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Problems solved by technology

[0004] The purpose of the present invention is to overcome the problems of difficult regulation and complex products in the synthesis of three-membered cyclic peptides based on disulfide bonds, to provide a product that can improve the stability of cyclic peptides in a strong reducing environment in cells, and obtain a reduction-resistant environment and a structure that can be adjusted. A method for constructing stable three-membered cyclic peptides based on tetrafluorophthalonitrile

Method used

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  • A method for constructing stable three-membered cyclic peptide based on tetrafluorophthalonitrile
  • A method for constructing stable three-membered cyclic peptide based on tetrafluorophthalonitrile
  • A method for constructing stable three-membered cyclic peptide based on tetrafluorophthalonitrile

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Embodiment 1

[0031] Dissolve WGCKCGGKGGCGKGGGCGW (amidation and amination at both ends) in water, react 50 μM polypeptide with 200 μM compound 1 in 100 mM pH=7.4 phosphate buffered aqueous solution for 4 hours at room temperature, and obtain 6 tetrasubstituted products with a total yield of 70 %, its chromatogram is as image 3 . The corresponding three-membered cyclic peptide was obtained after purification, separation and freeze-drying by high performance liquid chromatography, and the resulting product was characterized by mass spectrometry m / z: 960.0 (M 2+ ),640.3(M 3+ ).

Embodiment 2

[0033] Dissolve WGCGGKGGPenGKGGGCGKGGGPenGW (amidation and amination at both ends respectively) in water, react 50 μM polypeptide with 200 μM compound 1 in 100 mM pH=7.4 phosphate buffered aqueous solution for 8 hours at room temperature, and obtain two tetrasubstituted products, the chromatograms are as follows Figure 4 (After 8h, two tetrasubstituted products were mainly obtained, the yield was 85%). The corresponding two three-membered cyclic peptides were obtained after purification, separation and lyophilization by high-performance liquid chromatography. The resulting product is characterized by mass spectrometry as m / z: 1102.8 (M 2+ ).

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Abstract

The invention discloses a method for building ternary cyclic peptide based on tetrofluoroterephthalonitrile, and relates to multi-element cyclic peptide. The method can improve stability of the cyclic peptide in strong reducing environments in cells, and the obtained ternary cyclic peptide is resistant to the reducing environments, controllable in structure and constrained in construction. The method includes the specific steps: dissolving polypeptide in solvents to obtain solution A, dissolving excessive compounds 1 in organic solvents to obtain solution B, adding mercaptan reducing agents into the solution A and the solution B, adjusting the solution to be alkaline by inorganic alkaline or organic alkaline, performing reaction, separating the solution by chromatography, and freeze-drying the solution to obtain the ternary cyclic peptide. The obtained ternary cyclic peptide can stably exist in the strong reducing environments, and the polypeptide with penicillamine replacing cysteine and small molecules react to obtain the ternary cyclic peptide with single products, high yield and accurately controllable structures.

Description

technical field [0001] The invention relates to polycyclic peptides, in particular to a method for constructing stable three-membered cyclic peptides based on tetrafluorophthalonitrile. Background technique [0002] There is a wide range of polycyclic peptides formed by disulfide bond pairing in nature with complex and diverse configurations, relatively stable structures, and the ability to specifically bind proteins, such as conotoxins, knottins, etc. (Muttenthaler, M.; B. Akondi, K.; F. Alewood, P. Current Pharmaceutical Design 2011, 17, 4226). Such polycyclic peptides are considered to have broad application prospects in the development of enzyme inhibitors or receptor antagonists. However, polycyclic peptides based on disulfide bonds are easily reduced in strongly reducing environments, which limits their application in bioreducing environments. At present, ring closure is mainly achieved by lactamization, olefin metathesis, click reaction, etc. (Zou, Y.; Spokoyny, A.M...

Claims

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Application Information

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Patent Type & Authority Patents(China)
IPC IPC(8): C07K5/103C07K5/00C07K1/16C07K1/02
CPCC07K5/00C07K5/1013
Inventor 吴川六刘威东郑艺武赵一兵
Owner XIAMEN UNIV
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