A Cysteine‐Directed Proximity‐Driven Crosslinking Method for Native Peptide Bicyclization

Efficient and site-specific modification of native peptides proteins is desirable for synthesizing antibody-drug conjugates as well constructing chemically modified peptide libraries using genetically encoded platforms such phage display. In particular, there much interest in efficient multicyclization due to the appeals multicyclic therapeutics. However, conventional approaches synthesis require orthogonal protecting groups or non-proteinogenic clickable handles. Herein, we report a cysteine-directed proximity-driven strategy bicyclic from simple natural precursors. This linear bicycle transformation initiates with rapid cysteine labeling, which then triggers amine-selective cyclization. bicyclization proceeds rapidly under physiologic conditions, yielding Cys-Lys-Cys, Lys-Cys-Lys N-terminus-Cys-Cys stapling pattern. We demonstrate utility power this by fused M13 phage, paving way display novel libraries.