Expansion of Modality: Peptides to Pseudo-Natural Macrocyclic Peptides

Despite peptides have been a considerable class as therapeutics from the early 20th century, they were recognized an elusive modality due to the quick biodegradability and the low membrane permeability. In recent two decades, macrocyclic peptides have emerged as an expanded modality from standard class of peptides, owing their synthetic accessibility, high degree of specific binding, and the ability to target protein surfaces traditionally considered "undruggable". From the structural point of view, unusual side-chains, backbone, and macrocyclic structure are resembled to membrane permeable natural product peptides such as cyclosporin A, thus expected to overcome intrinsic drawbacks of peptides. In this review, we refer such natural product-like macrocyclic peptide ligands to as "pseudo-natural macrocyclic peptides", and describe advances of biotechnologies to discover de novo pseudo-natural macrocyclic peptide ligands and our recent research to further optimize such drug leads.