Macrocyclizing DNA-Encoded Peptides via Visible-Light-Mediated Desulfurisation

DNA-encoded library technology (DELT) facilitates the generation of billions of DNA-tagged macrocycles containing noncanonical amino acids, synthesized through diverse cyclization strategies. The varied appended residues and ring conformations expand chemical space, enabling the identification of hit compounds with improved properties such as higher binding affinity, enhanced metabolic stability, and increased oral bioavailability. This study expands the on-DNA chemical toolkit by introducing a DNA-compatible C(sp3)-C(sp3) bond formation method via a visible-light-mediated desulfurative macrocyclization. This reaction proceeds efficiently under mild conditions, exhibiting broad substrate scope and good conversions. Notably, the reaction condition is com-patible with free amines, allowing for late-stage modifications and the preparation of covalent DNA-encoded macrocyclic libraries.