title: Programming peptidomimetic syntheses by translating genetic codes designed de novo.
abstract: Although the universal genetic code exhibits only minor variations in nature, Francis Crick proposed in 1955 that "the adaptor hypothesis allows one to construct, in theory, codes of bewildering variety." The existing code has been expanded to enable incorporation of a variety of unnatural amino acids at one or two nonadjacent sites within a protein by using nonsense or frameshift suppressor aminoacyl-tRNAs (aa-tRNAs) as adaptors. However, the suppressor strategy is inherently limited by compatibility with only a small subset of codons, by the ways such codons can be combined, and by variation in the efficiency of incorporation. Here, by preventing competing reactions with aa-tRNA synthetases, aa-tRNAs, and release factors during translation and by using nonsuppressor aa-tRNA substrates, we realize a potentially generalizable approach for template-encoded polymer synthesis that unmasks the substantially broader versatility of the core translation apparatus as a catalyst. We show that several adjacent, arbitrarily chosen sense codons can be completely reassigned to various unnatural amino acids according to de novo genetic codes by translating mRNAs into specific peptide analog polymers (peptidomimetics). Unnatural aa-tRNA substrates do not uniformly function as well as natural substrates, revealing important recognition elements for the translation apparatus. Genetic programming of peptidomimetic synthesis should facilitate mechanistic studies of translation and may ultimately enable the directed evolution of small molecules with desirable catalytic or pharmacological properties.
authors.affiliation: Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, 75 Francis Street, Boston, MA 02115, USA. aforster@rics.bwh.harvard.edu
authors.forename: Anthony C
authors.initials: AC
authors.lastname: Forster
authors.forename: Zhongping
authors.initials: Z
authors.lastname: Tan
authors.forename: Madhavi N L
authors.initials: MN
authors.lastname: Nalam
authors.forename: Hening
authors.initials: H
authors.lastname: Lin
authors.forename: Hui
authors.initials: H
authors.lastname: Qu
authors.forename: Virginia W
authors.initials: VW
authors.lastname: Cornish
authors.forename: Stephen C
authors.initials: SC
authors.lastname: Blacklow
mesh_terms: D001483:Base Sequence; D005815:Genetic Code; D018716:Molecular Mimicry; D008969:Molecular Sequence Data; D009690:Nucleic Acid Conformation; D010455:Peptides / Q000737:chemistry* / Q000235:genetics; D014176:Protein Biosynthesis; D012333:RNA, Messenger / Q000737:chemistry / Q000235:genetics
chemical_list: D010455:Peptides; D012333:RNA, Messenger