Discovery of a Serine‐Directed Chemical Reaction for Site‐Specific Protein Modification via Phage Display Screening

Conventional biocompatible chemistry typically depends on unnatural functional groups, such as alkynes and azides. Here, we present a natural amino acid-based alternative by leveraging phage display to discover Cu^II-assisted serine arylation (CASA), a serine-selective strategy for chemical protein modification, achieved through a Cu^II-mediated hydroxyl-arylation reaction. CASA enables fast and precise modification of a single serine hydroxyl group within complex proteins while leaving the other amino acids, including serines at other sites, unmodified. CASA demonstrates robust performance in on-demand modification of diverse recombinant proteins, including therapeutic antibodies, with single-residue precision. The system's ability to selectively target individual proteins within crude cell lysates suggests its potential for applications in complex biological environments and positions it as a versatile tool for protein engineering.