title: Natural product-like macrocyclic N-methyl-peptide inhibitors against a ubiquitin ligase uncovered from a ribosome-expressed de novo library.
abstract: Naturally occurring peptides often possess macrocyclic and N-methylated backbone. These features grant them structural rigidity, high affinity to targets, proteolytic resistance, and occasionally membrane permeability. Because such peptides are produced by either nonribosomal peptide synthetases or enzymatic posttranslational modifications, it is yet a formidable challenge in degenerating sequence or length and preparing libraries for screening bioactive molecules. Here, we report a new means of synthesizing a de novo library of "natural product-like" macrocyclic N-methyl-peptides using translation machinery under the reprogrammed genetic code, which is coupled with an in vitro display technique, referred to as RaPID (random nonstandard peptides integrated discovery) system. This system allows for rapid selection of strong binders against an arbitrarily chosen therapeutic target. Here, we have demonstrated the selection of anti-E6AP macrocyclic N-methyl-peptides, one of which strongly inhibits polyubiqutination of proteins such as p53.
authors.affiliation: Department of Chemistry and Biotechnology, Graduate School of Engineering, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-8656, Japan.
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Yamagishi
authors.forename: Ikuo
authors.initials: I
authors.lastname: Shoji
authors.forename: Shoji
authors.initials: S
authors.lastname: Miyagawa
authors.forename: Takashi
authors.initials: T
authors.lastname: Kawakami
authors.forename: Takayuki
authors.initials: T
authors.lastname: Katoh
authors.forename: Yuki
authors.initials: Y
authors.lastname: Goto
authors.forename: Hiroaki
authors.initials: H
authors.lastname: Suga
mesh_terms: D000595:Amino Acid Sequence; D001688:Biological Products / Q000737:chemistry; D047028:Macrocyclic Compounds / Q000737:chemistry*; D008745:Methylation; D019151:Peptide Library; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D012270:Ribosomes / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D054875:Ubiquitination / Q000187:drug effects
chemical_list: D001688:Biological Products; D047028:Macrocyclic Compounds; D019151:Peptide Library; D010455:Peptides; D016159:Tumor Suppressor Protein p53; D044767:Ubiquitin-Protein Ligases