Polypeptide helical conformation stabilizing method

A technology of helical conformation and linear peptides, which is applied in peptide preparation methods, chemical instruments and methods, peptides, etc., can solve problems such as unfavorable optimization of polypeptide structure and function, unfavorable optimization of peptide activity, etc.

Inactive Publication Date: 2020-10-20
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, it should be pointed out that hydrogen bond mimics need to utilize the environmentally unfriendly olefin metathesis reaction, while the N-terminal hydrogen bond cap needs to introduce highly polar hydrogen bond donors and hydrogen bond donors into the template, which is not conducive to the activity of the polypeptide optimization
In addition, the above two N-terminal nucleation templates can currently only be used to construct single-turn cyclized helical peptides
Fixed nucleation template position is very unfavorable for peptide structure and function optimization

Method used

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  • Polypeptide helical conformation stabilizing method
  • Polypeptide helical conformation stabilizing method
  • Polypeptide helical conformation stabilizing method

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0034] Example 1: Preparation of a cross-linked helix-stabilized polypeptide between the N-terminus of the polypeptide and the sulfhydryl group at the 4th side chain of the N-terminus

[0035]The fourth amino acid Ala at the N-terminal of the model peptide was mutated to Cys, and a new sequence peptide was designed, which was ARACRAARAKARAD. Through mature Fmoc solid-phase synthesis, we can obtain this linear peptide. The specific synthesis process of solid-phase synthesis of linear peptides includes the following steps:

[0036] (1) Swelling Rink Amide-AM Resin (loading capacity 0.33mmol / g, 30μmol): 90mg of resin was added to the solid phase synthesis tube, 2mL of DMF solution was added, and the reaction was shaken at room temperature for 15min;

[0037] (2) Fmoc deprotection: Add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube, react at room temperature for 10 min, discard the solution, then add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube...

Embodiment 2

[0044] Example 2: Preparation of a cross-linked helix-stabilized polypeptide between the N-terminus of the polypeptide and the 5th side chain sulfhydryl group at the N-terminus

[0045] The fifth amino acid Arg at the N-terminal of the model peptide was mutated to Cys, and a new sequence peptide was designed, which was ARAACAARAKARAD. Through mature Fmoc solid-phase synthesis, we can obtain this linear peptide. The specific synthesis process of solid-phase synthesis of linear peptides includes the following steps:

[0046] (1) Swelling Rink Amide-AM Resin (loading capacity 0.33mmol / g, 30μmol): 90mg of resin was added to the solid phase synthesis tube, 2mL of DMF solution was added, and the reaction was shaken at room temperature for 15min;

[0047] (2) Fmoc deprotection: Add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube, react at room temperature for 10 min, discard the solution, then add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube for 10...

Embodiment 3

[0054] Example 3: Preparation of a cross-linked helix-stabilized polypeptide between the N-terminus of the polypeptide and the 8th side chain sulfhydryl group at the N-terminus

[0055] The 8th amino acid Arg at the N-terminal of the model peptide was mutated to Cys, and a new sequence peptide was designed, which was ARAARAACAKARAD. Through mature Fmoc solid-phase synthesis, we can obtain this linear peptide. The specific synthesis process of solid-phase synthesis of linear peptides includes the following steps:

[0056] (1) Swelling Rink Amide-AM Resin (loading capacity 0.33mmol / g, 30μmol): 90mg of resin was added to the solid phase synthesis tube, 2mL of DMF solution was added, and the reaction was shaken at room temperature for 15min;

[0057] (2) Fmoc deprotection: add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube, react at room temperature for 10 min, discard the solution, then add 1 mL of 20% piperidine / DMF mixed solution to the synthesis tube for 10 m...

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Abstract

The invention discloses a polypeptide spiral conformation stabilizing method. According to the method, covalent crosslinking is carried out between polypeptide N-terminal amino and N-terminal fourth,fifth, eighth or twelfth side chain sulfydryl through chemical bonds. According to the invention, single-turn, double-turn and three-turn cyclized conformational locking helical peptides can be constructed through covalent crosslinking of the N-terminal amino groups and side chains, and the helical peptides are beneficial to deep optimization of the structure of helical polypeptides and discoveryof high-activity polypeptide inhibitors. According to the method disclosed by the invention, the short-sequence polypeptide can keep a stable helical conformation in an aqueous solution, and the problem that the short linear polypeptide does not have the stable helical conformation is solved.

Description

technical field [0001] The invention relates to a method for stabilizing the helical conformation of polypeptides, which enables short-sequence polypeptides to maintain a stable helical conformation in aqueous solution and solves the problem that short linear polypeptides do not have a stable helical conformation. Background technique [0002] Abnormal protein-protein interactions are the biochemical essence of many diseases, but traditional small molecules are considered to have limited ability to target protein-protein interactions. Polypeptides with helical structures are often observed on protein-protein interaction surfaces. Helical peptides at this interface provide an ideal mimotope for intervening in protein-protein interactions. However, it should be pointed out that the direct truncated short-sequence linear polypeptide does not have a stable conformation in solution, and has poor enzymatic stability, so it is generally not considered to have drug potential. In r...

Claims

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Application Information

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IPC IPC(8): C07K1/36C07K1/30C07K1/20C07K1/107C07K1/06C07K1/04
CPCC07K1/36C07K1/30C07K1/20C07K1/1077C07K1/06C07K1/04Y02P20/55
Inventor 方葛敏武梦周兆才汤扬陈晓旭
Owner ANHUI UNIVERSITY
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