Disulfide Click Reaction for Stapling of S‐terminal Peptides

Author:

Yu Qing1,Bai Leiyang1,Jiang Xuefeng123ORCID

Affiliation:

1. Shanghai Key Laboratory of Green Chemistry and Chemical Process School of Chemistry and Molecular Engineering East China Normal University 3663 North Zhongshan Road Shanghai 200062 P. R. China

2. School of Chemistry and Chemical Engineering Henan Normal University Xinxiang, Henan 453007 P. R. China

3. State Key Laboratory of Organometallic Chemistry Shanghai Institute of Organic Chemistry Chinese Academy of Sciences 345 Lingling Road Shanghai 200032 P. R. China

Abstract

AbstractA disulfide click strategy is disclosed for stapling to enhance the metabolic stability and cellular permeability of therapeutic peptides. A 17‐membered library of stapling reagents with adjustable lengths and angles was established for rapid double/triple click reactions, bridging S‐terminal peptides from 3 to 18 amino acid residues to provide 18‐ to 48‐membered macrocyclic peptides under biocompatible conditions. The constrained peptides exhibited enhanced anti‐HCT‐116 activity with a locked α‐helical conformation (IC50=6.81 μM vs. biological incompetence for acyclic linear peptides), which could be unstapled for rehabilitation of the native peptides under the assistance of tris(2‐carboxyethyl)phosphine (TCEP). This protocol assembles linear peptides into cyclic peptides controllably to retain the diverse three‐dimensional conformations, enabling their cellular uptake followed by release of the disulfides for peptide delivery.

Funder

National Outstanding Youth Science Fund Project of National Natural Science Foundation of China

Science and Technology Commission of Shanghai Municipality

China Postdoctoral Science Foundation

Publisher

Wiley

Subject

General Medicine

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