CHAPTER 11: Biological Synthesis and Affinity-based Selection of Small Macrocyclic Peptide Ligands

The high bioactivity and potential for drug-like pharmacokinetics exhibited by relatively small (<2 kDa) cyclic peptides makes them appealing candidates for drug discovery and development. Because molecules of this class can be synthesized ribosomally from genetic templates, extremely diverse libraries (in some cases in excess of 10¹² molecules) can be synthesized, and pooled libraries can be screened for activity/affinity against a desired target using selection-based approaches. Moreover, the development of genetic code reprogramming techniques now allows the synthesis of peptidic molecules composed of diverse non-canonical moieties, enabling the synthesis and screening of libraries with higher chemical diversity in more drug-like chemical space than can be achieved based on the 20 canonical amino acids alone. The present chapter reviews the development of different synthesis/screening techniques for the identification of macrocyclic peptide ligands to protein targets of interest, and the use of genetic code reprogramming techniques to expand the available chemical diversity of such approaches.