The assembly of synthetically difficult "drug-like" macrocyclic peptides

N-methylated macrocyclic peptides hold a unique position in modern drug discovery, owing to their superior affinity, specificity, and safety compared to small-molecule drugs, as well as their favorable physicochemical properties, faster distribution and generally lower immunogenicity compared to antibody drugs. As with all synthetic drug modalities, an efficient preparation method is a prerequisite for the drug discovery process based on this molecular format. However, the chemical synthesis of N-methylated macrocyclic peptides was a persistent challenge until very recent breakthroughs, mostly driven by the difficulties of assembling the multiple N-methylated linear precursors. This review focuses on two key aspects involving the generation of such peptides, aiming to provide practical guidance to peers sharing the same interest: the strategies of peptide cyclization and the chemistries of assembling sterically hindered linear precursors.