Photoinduced C–S Cleavage in Thiols and Oligopeptides to Initiate Controlled Radical Polymerization

Conjugating synthetic polymers to therapeutic peptides is a powerful strategy to improve their stability and enable less frequent dosing. While numerous methods have broadened the chemical space of accessible polymers, many rely on multi-step syntheses that reduce the overall yield of the final conjugate. Herein, we report a user-friendly, photocatalyst-free method to initiate polymerization via photoinduced cleavage of C–S bonds in native cysteine residues, coupled with reversible addition-fragmentation chain transfer (RAFT) polymerization. Under optimized conditions, a variety of acrylate and acrylamide monomers underwent controlled polymerization from monomeric cysteine units and unprotected (oligo)peptides. We also extended this method to initiate polymerization from other thiol-containing small molecules, including those that yield non-stabilized C-centered radicals. The resulting polymers have narrow mass distributions, good agreement between theoretical and experimental molar masses, and exceptionally high α-chain-end fidelities (>99%). Collectively, these results establish an efficient, selective approach to initiating controlled radical polymerization via C–S cleavage, which can be broadly applied to designing peptide-polymer conjugates and other functional composite materials.