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• W3196622003 endingPage "3617" @default.
• W3196622003 startingPage "3604" @default.
• W3196622003 abstract "ConspectusAlthough macrocyclic peptides bearing exotic building blocks have proven their utility as pharmaceuticals, the sources of macrocyclic peptide drugs have been largely limited to mimetics of native peptides or natural product peptides. However, the recent emergence of technologies for discovering de novo bioactive peptides has led to their reconceptualization as a promising therapeutic modality. For the construction and screening of libraries of such macrocyclic peptides, our group has devised a platform to conduct affinity-based selection of massive libraries (>1012 unique sequences) of in vitro expressed macrocyclic peptides, which is referred to as the random nonstandard peptides integrated discovery (RaPID) system. The RaPID system integrates genetic code reprogramming using the FIT (flexible in vitro translation) system, which is largely facilitated by flexizymes (flexible tRNA-aminoacylating ribozymes), with mRNA display technology.We have demonstrated that the RaPID system enables rapid discovery of various de novo pseudo-natural peptide ligands for protein targets of interest. Many examples discussed in this Account prove that thioether-closed macrocyclic peptides (teMPs) obtained by the RaPID system generally exhibit remarkably high affinity and specificity, thereby potently inhibiting or activating a specific function(s) of the target. Moreover, such teMPs are used for a wide range of biochemical applications, for example, as crystallization chaperones for intractable transmembrane proteins and for in vivo recognition of specific cell types. Furthermore, recent studies demonstrate that some teMPs exhibit pharmacological activities in animal models and that even intracellular proteins can be inhibited by teMPs, illustrating the potential of this class of peptides as drug leads.Besides the ring-closing thioether linkage in the teMPs, genetic code reprogramming by the FIT system allows for incorporation of a variety of other exotic building blocks. For instance, diverse nonproteinogenic amino acids, hydroxy acids (ester linkage), amino carbothioic acid (thioamide linkage), and abiotic foldamer units have been successfully incorporated into ribosomally synthesized peptides. Despite such enormous successes in the conventional FIT system, multiple or consecutive incorporation of highly exotic amino acids, such as d- and β-amino acids, is yet challenging, and particularly the synthesis of peptides bearing non-carbonyl backbone structures remains a demanding task. To upgrade the RaPID system to the next generation, we have engaged in intensive manipulation of the FIT system to expand the structural diversity of peptides accessible by our in vitro biosynthesis strategy. Semilogical engineering of tRNA body sequences led to a new suppressor tRNA (tRNAPro1E2) capable of effectively recruiting translation factors, particularly EF-Tu and EF-P. The use of tRNAPro1E2 in the FIT system allows for not only single but also consecutive and multiple elongation of exotic amino acids, such as d-, β-, and γ-amino acids as well as aminobenzoic acids. Moreover, the integration of the FIT system with various chemical or enzymatic posttranslational modifications enables us to expand the range of accessible backbone structures to non-carbonyl moieties prominent in natural products and peptidomimetics. In such systems, FIT-expressed peptides undergo multistep backbone conversions in a one-pot manner to yield designer peptides composed of modified backbones such as azolines, azoles, and ring-closing pyridines. Our current research endeavors focus on applying such in vitro biosynthesis systems for the discovery of bioactive de novo pseudo-natural products." @default.
• W3196622003 created "2021-09-13" @default.
• W3196622003 creator A5017224243 @default.
• W3196622003 creator A5058688721 @default.
• W3196622003 date "2021-09-10" @default.
• W3196622003 modified "2023-10-18" @default.
• W3196622003 title "The RaPID Platform for the Discovery of Pseudo-Natural Macrocyclic Peptides" @default.
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• W3196622003 doi "https://doi.org/10.1021/acs.accounts.1c00391" @default.
• W3196622003 hasPubMedId "https://pubmed.ncbi.nlm.nih.gov/34505781" @default.

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