Recent Advances in Non-Standard Macrocyclic Peptide Ligand Discovery using mRNA Display

Abstract

Advancements in platform technologies have facilitated the production of libraries consisting of macrocyclic peptides composed of natural and non-canonical amino acids for more drug-like characteristics. Identification of macrocyclic peptide ligands against targets of interest can be accomplished using mRNA display. Despite numerous successful in vitro selections for macrocyclic peptide ligands against extracellular targets, identifying macrocyclic peptide hits that can reach intracellular targets continue to be a challenge. Breakthroughs in defining the features of a macrocyclic peptide that promote cell permeability have recently been disclosed. Here, we review the successful selections of non-standard macrocyclic peptide ligands using mRNA display in the last five years and chemical optimization of a drug-like macrocyclic peptide ligand for targeting intracellular KRAS.