Late-stage hydrocarbon conjugation and cyclization in synthetic peptides and proteins.

Conventional S-alkylation of cysteine relies upon using activated electrophiles. Here we demonstrate high yielding and selective S-alkylation and S-lipidation of cysteines in unprotected synthetic peptides and proteins using weak electrophiles and a Zn2+ promoter. Linear or branched iodoalkanes can S-alkylate cysteine in an unprotected 38-residue Myc peptide fragment and in a 91-residue mini-protein Omomyc, highlighting selective late-stage synthetic modifications. Metal-assisted cysteine alkylation is also effective for incorporating dehydroalanine into unprotected peptides and for peptide cyclization via aliphatic thioether-crosslinks, including customising macrocycles to stabilize helical peptides for enhanced uptake and delivery to proteins inside cells. Chemoselective and efficient late-stage Zn2+-promoted cysteine alkylation in unprotected peptides and proteins promises many useful applications.