A Solid‐Phase Approach to Accessing Bisthioether‐Stapled Peptides Resulting in a Potent Inhibitor of PRC2 Catalytic Activity

Stapled peptides have emerged as a new class of therapeutics to effectively target intractable protein–protein interactions. Thus, efficient and versatile methods granting easy access to this class of compounds and expanding the scope(s) of the currently available ones are of great interest. Now, a solid phase approach is described for the synthesis of bisthioether stapled peptides with multiple architectures, including single‐turn, double‐turn, and double‐stapled macrocycles. This method allows for ligation with all‐hydrocarbon linkers of various lengths, avoiding the use of unnatural amino acids and expensive catalysts, and affords cyclopeptides with remarkable resistance to proteolytic degradation. The potential of this procedure is demonstrated by applying it to generate a stapled peptide that shows potent in vitro inhibition of methyltransferase activity of the polycomb repressive complex 2 (PRC2) of proteins. The chemoselective ligation of cysteine residues on a solid phase using a variety of aliphatic electrophiles is achieved by a new stapling method. This approach can be applied to the preparation of single‐turn, double‐turn, and double‐stapled peptides. Its application has led to the identification of a potent inhibitor of the catalytic activity of the polycomb‐repressive group of proteins (PRC2).