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Cyclic peptide combined with RBD site of novel coronavirus as well as preparation method and application of cyclic peptide

A technology of cyclic peptides and viruses, which is applied in the field of cyclic peptides combined with the RBD site of the new coronavirus and its preparation and application, which can solve the problems of inability to inhibit the infection of the new coronavirus and the inability to bind

Active Publication Date: 2021-08-20
ANHUI UNIVERSITY
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Problems solved by technology

However, studies have shown that ACE2 natural sequence peptides cannot bind to the RBD site of SARS-CoV-2 and cannot inhibit the infection of human cells by the new coronavirus

Method used

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  • Cyclic peptide combined with RBD site of novel coronavirus as well as preparation method and application of cyclic peptide
  • Cyclic peptide combined with RBD site of novel coronavirus as well as preparation method and application of cyclic peptide
  • Cyclic peptide combined with RBD site of novel coronavirus as well as preparation method and application of cyclic peptide

Examples

Experimental program
Comparison scheme
Effect test

Embodiment 1

[0037] Embodiment 1: synthetic hydrazine-2-Cl-Trt resin

[0038]Weigh 268 mg of 2-CI-Trt-Cl resin (loading capacity: 0.56 mmol / g, 150 umol) into a solid-phase synthesis tube, add 3 mL of DMF to swell for 20 minutes. The resin was sequentially washed three times with DCM and twice with DMF. Add 3.5 mL 5% hydrazine hydrate (125 μL hydrazine hydrate + 3.33 mL DMF), shake at room temperature for 30 min, discard the waste liquid, and repeat once. Add 2.5 mL of 20% MeOH / DMF (2 mL DMF + 0.5 mL MeOH) and shake at room temperature to block the reaction for 20 min, wash with DMF for 5 times to obtain hydrazine-2-Cl-Trt resin.

Embodiment 2

[0039] Example 2: Fmoc solid-phase synthesis of linear hydrazide peptides

[0040] The resin prepared in Example 1 was transferred to a solid-phase synthesis tube, and the DMF mixture of DIC / Oxyma / 6-aminocaproic acid (10eq DIC: 10eq Oxyma: 10eq 6-aminocaproic acid, 2mL DMF) was added, React at 55°C for 40 minutes. After the resin was washed with DMF, 2 mL of blocking reagent (acetic anhydride: 2,6-lutidine: DMF=5:6:89) was added to block unlinked amine groups. After 2 min, the resin was washed three times with DMF. Then add 20% piperidine in DMF, shake at room temperature for 8 minutes, and discard the reaction solution. Repeat the 20% piperidine treatment step. After cleaning the resin three times with DMF, add the DMF mixture of DIC / Oxyma / Fmoc-Ser(tBu)-OH (10eq DIC:10eq Oxyma:10eq Fmoc-Ser(tBu)-OH, 2mL DMF), React for 40 minutes. Next, repeat the above operation for amino acid condensation, and condense Fmoc-protected amino acids Leu, Arg, Asp, Arg, Asp, Glu, Cys, Val, ...

Embodiment 3

[0042] Example 3: Side chain cyclization of linear hydrazide peptides

[0043] Dissolve 10 mg of linear peptide in 2.0 mL of DMF:H 2 O mixture (2:1, v:v), 1.4 mg of 4,4-dibromomethylbiphenyl was dissolved in 0.1 mL of DMF and added to the mixture with 1.0 M NH 4 HCO 3 The pH of the reaction mixture was adjusted to 8.0. After reacting at room temperature in a vibrating mixer for 2 h, add 3 mL of acetonitrile:H 2 O mixture (1:1, v:v, 0.1% TFA) to quench the reaction. After purification of the cyclized peptide by preparative HPLC and lyophilization, a white powder (~3 mg, 30%) was obtained as Figure 4 shown. The sequence of the side chain cyclized hydrazide polypeptide is as follows:

[0044]

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Abstract

The invention discloses a cyclic peptide combined with an RBD site of novel coronavirus as well as a preparation method and application of the cyclic peptide, and particularly relates to a cyclic polypeptide molecule obtained through in-vitro amino acid side chain cyclization, amino acid point mutation and dimerization modification on the basis of an angiotensin converting enzyme 2 (ACE2) core sequence combined with the RBD of novel coronavirus. The cyclic polypeptide disclosed by the invention can be used for preparing a polypeptide drug with an SARS-CoV-2 virus inhibition effect, or used for preparing a detection reagent for detecting SARS-CoV-2, and a bioactive lead molecule with commercial value is provided for treatment and detection of SARS-CoV-2.

Description

technical field [0001] The invention relates to a cyclic peptide that binds to the RBD site of the new coronavirus at a nanomolar level and a preparation method thereof. Background technique [0002] An effective way to inhibit SARS-CoV-2 infection is to block the interaction between SARS-CoV-2 spike RBD and ACE2 receptor. Most of the antibody drugs targeting the new coronavirus on the market can bind to the RBD site on the surface of SARS-CoV-2 with high affinity. However, antibody drug molecules are large in size, require low temperature for storage, and are extremely expensive to prepare. Compared with antibody drugs, peptide drugs have small molecular size, can be stored at room temperature, and are easy to chemically synthesize and modify at low cost. The recent structure of ACE2 and RBD protein complex shows that ACE2 mainly binds to the viral RBD through a helical polypeptide sequence. Based on this, several international research groups proposed to use a helical p...

Claims

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Application Information

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Patent Type & Authority Applications(China)
IPC IPC(8): C07K14/00C07K1/16C07K1/04A61K38/16A61P31/14G01N33/569G01N33/68
CPCC07K14/00A61P31/14G01N33/56983G01N33/6893A61K38/00G01N2333/165Y02P20/55
Inventor 方葛敏陈凯卿杰朱汉英武梦席痛快
Owner ANHUI UNIVERSITY
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