Late‐Stage Functionalization of Peptides on the Solid Phase

Chemical modification is a means of tailoring the structure and function of peptides. This is of particular interest in the field of peptide drug development. Methods that enable straightforward modification of peptides with non-canonical residues are therefore in high demand. On-resin late-stage functionalization is a powerful, cost- and time-efficient tool for modifying peptides. It also allows for high-throughput experimentation, making it well suited to streamlining the development of peptide therapeutics. In this minireview, we provide an overview of the chemical approaches for on-resin late-stage peptide functionalization , most of which have been developed over the past decade. These reactions range from nucleophilic substitution and carbonyl chemistry to metal catalysis and photocatalysis. Many of the presented approaches have been shown to be compatible with short and long peptides, and to modulate their bioactivity. Impressive examples of peptide library synthesis in high-throughput formats demonstrate the enormous potential of late-stage peptide functionalization for the development of peptide therapeutics in the years to come.