Electrochemical Late‐Stage Stitching of Tryptophan Peptides via N─S Bond Formation
Abstract
Abstract Late‐stage diversification of peptides via selective modification of endogenous amino acid side chains provides a powerful strategy to access analogues with enhanced bioactivity and tailored physicochemical properties, thereby facilitating peptide‐based drug discovery. However, precise manipulation of short peptides comprising canonical amino acids—particularly control over backbone conformation—remains a formidable challenge. Herein, we present a robust electrochemical strategy for constructing macrocyclic peptides through direct incorporation of diverse aryl sulfur linkers. This method enables tryptophan (Trp)‐selective crosslinking via electrochemical reaction with aryl thiosulfonates, leading to efficient formation of S─N bonds. The resulting sulfur‐bridged multi‐aryl macrocycles act as conformationally adaptive scaffolds that reshape the peptide backbone architecture. This conformational remodeling grants access to previously inaccessible structural spaces that are critical for modulating biological activity.
Article Details
Authors (7)
Xinwei Hu
Department of Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P.R. China
Zaimu Cao
Department of Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P.R. China
Mu Chen
Chun‐Dong Huang
College of Chemistry & Chemical Engineering and Key Laboratory For Preparation and Application of Ordered Structural Materials of Guangdong Province Shantou University Shantou China
Shao‐Fei Ni
College of Chemistry & Chemical Engineering and Key Laboratory For Preparation and Application of Ordered Structural Materials of Guangdong Province Shantou University Shantou China
Shou‐Kun Zhang
Department of Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P.R. China
Zhixiong Ruan
Department of Guangzhou Municipal and Guangdong Provincial Key Laboratory of Molecular Target & Clinical Pharmacology and the State Key Laboratory of Respiratory Disease School of Pharmaceutical Sciences Guangzhou Medical University Guangzhou 511436 P.R. China