A Practical Palladium-Catalyzed Cysteine Arylation Platform for Late-Stage Functionalization of Peptides and Proteins
- 1Lanzhou University , , ,
Abstract
Site-selective modification of cysteine residues is central to the construction of peptide- and protein-based probes and therapeutics, yet existing methods are often constrained by linkage instability, narrow substrate scope, or harsh, nonbiocompatible reaction conditions. Here we report a palladium-catalyzed, site-selective cysteine arylation of peptides and proteins using readily accessible aryl thianthrenium salts. Enabled by the RuPhos-Pd-G3 catalyst, the reaction proceeds in aqueous buffer at 37 °C without added base, photoinitiator, or organic cosolvent, and tolerates a broad range of electron-rich, -neutral, and -deficient arylating reagents bearing diverse functional groups. Modification occurs with exclusive cysteine selectivity even amid numerous competing nucleophilic residues, enabling the installation of drug fragments, biotin, carbohydrates, fluorophores, and clickable handles onto unprotected peptides and the native protein BSA. As a methodological proof of concept, we further employ this strategy to assemble a receptor-targeting peptide-drug conjugate, establishing aryl thianthrenium salts as a versatile, biocompatible platform for stable aryl-thioether bioconjugation.
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BibTeX
@article{guo2026practical,
title = {{A Practical Palladium-Catalyzed Cysteine Arylation Platform for Late-Stage Functionalization of Peptides and Proteins}},
author = {Quanping Guo and Chunlin Wang and Xin Ma and Wenbo Mao and Pengyu Liu and Kuan Chen and Qingyu Hu and Mengran Wang and Qiao Chen and Zhaoqing Xu},
journal = {JACS Au},
year = {2026},
month = oct,
doi = {10.1021/jacsau.6c01159},
url = {https://pubs.acs.org/jaaucr/article/6/10/5868/5446510/A-Practical-Palladium-Catalyzed-Cysteine-Arylation},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - A Practical Palladium-Catalyzed Cysteine Arylation Platform for Late-Stage Functionalization of Peptides and Proteins
AU - Quanping Guo
AU - Chunlin Wang
AU - Xin Ma
AU - Wenbo Mao
AU - Pengyu Liu
AU - Kuan Chen
AU - Qingyu Hu
AU - Mengran Wang
AU - Qiao Chen
AU - Zhaoqing Xu
PY - 2026
DA - 2026/10/07
JO - JACS Au
DO - 10.1021/jacsau.6c01159
UR - https://pubs.acs.org/jaaucr/article/6/10/5868/5446510/A-Practical-Palladium-Catalyzed-Cysteine-Arylation
AB - Site-selective modification of cysteine residues is central to the construction of peptide- and protein-based probes and therapeutics, yet existing methods are often constrained by linkage instability, narrow substrate scope, or harsh, nonbiocompatible reaction conditions. Here we report a palladium-catalyzed, site-selective cysteine arylation of peptides and proteins using readily accessible aryl thianthrenium salts. Enabled by the RuPhos-Pd-G3 catalyst, the reaction proceeds in aqueous buffer at 37 °C without added base, photoinitiator, or organic cosolvent, and tolerates a broad range of electron-rich, -neutral, and -deficient arylating reagents bearing diverse functional groups. Modification occurs with exclusive cysteine selectivity even amid numerous competing nucleophilic residues, enabling the installation of drug fragments, biotin, carbohydrates, fluorophores, and clickable handles onto unprotected peptides and the native protein BSA. As a methodological proof of concept, we further employ this strategy to assemble a receptor-targeting peptide-drug conjugate, establishing aryl thianthrenium salts as a versatile, biocompatible platform for stable aryl-thioether bioconjugation.
SN - 2691-3704
ER -