DNA-Compatible Conditions for the Formation of N‑Methyl Peptide Bonds

DNA-encoded libraries (DELs) are a powerful platform in drug discovery. Peptides have unique properties that make them attractive pharmaceutical candidates. N-methylation of the peptide backbone can confer beneficial properties such as increased proteolytic stability and membrane permeability. Herein, we evaluate different DEL reaction systems and report a DNA-compatible protocol for forming N-methylated amide bonds. The DNA-compatible, bis(trichloromethyl)carbonate-mediated amide coupling is efficient for the formation of N-methyl peptide bonds, which promises to increase the opportunity to identify passively cell-permeable macrocyclic peptide hits by DNA-encoded technology.