title: Technologies for the synthesis of mRNA-encoding libraries and discovery of bioactive natural product-inspired non-traditional macrocyclic peptides.
abstract: In this review, we discuss emerging technologies for drug discovery, which yields novel molecular scaffolds based on natural product-inspired non-traditional peptides expressed using the translation machinery. Unlike natural products, these technologies allow for constructing mRNA-encoding libraries of macrocyclic peptides containing non-canonical sidechains and N-methyl-modified backbones. The complexity of sequence space in such libraries reaches as high as a trillion (>1012), affording initial hits of high affinity ligands against protein targets. Although this article comprehensively covers several related technologies, we discuss in greater detail the technical development and advantages of the Random non-standard Peptide Integration Discovery (RaPID) system, including the recent identification of inhibitors against various therapeutic targets.
authors.affiliation: Department of Chemistry, Graduate School of Science, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
authors.forename: Kenichiro
authors.initials: K
authors.lastname: Ito
authors.forename: Toby
authors.initials: T
authors.lastname: Passioura
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D000595:Amino Acid Sequence; D020650:Combinatorial Chemistry Techniques; D055808:Drug Discovery / Q000379:methods*; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology; D015723:Gene Library; D005815:Genetic Code; D006801:Humans; D008969:Molecular Sequence Data; D010456:Peptides, Cyclic / Q000096:biosynthesis / Q000737:chemistry / Q000235:genetics / Q000494:pharmacology*; D016337:RNA, Catalytic / Q000737:chemistry; D012333:RNA, Messenger / Q000235:genetics*; D014158:Transcription, Genetic
chemical_list: D004791:Enzyme Inhibitors; D010456:Peptides, Cyclic; D016337:RNA, Catalytic; D012333:RNA, Messenger