Achieving cysteine-selective peptide/protein bioconjugation via tunable triazine-pyridine chemistry.

ABSTRACT: The development of cysteine (Cys)-selective bioconjugation reagents with enhanced stability remains a critical challenge for therapeutic applications such as antibody-drug conjugates (ADCs). Leveraging the modular 1,3,5-triazine scaffold, we report the design and optimization of triazine-pyridinium chemistry (TPC) reagents for selective Cys labeling. Through systematic structural modifications and computational studies, we identified reagent 9b, featuring a para-N,N-dimethylaminopyridinium leaving group and ethoxy substitution, as the most efficient and selective candidate for selective protein labeling. 9b demonstrated near-quantitative Cys labeling (>95% yield) under physiological conditions (pH 7.4) while suppressing tyrosine reactivity, a limitation o

SUBMITTER: Wang C 

PROVIDER: S-EPMC12674134 | biostudies-literature | 2025 Dec

REPOSITORIES: biostudies-literature