In vitro selection of macrocyclic peptide inhibitors containing cyclic γ 2,4 -amino acids targeting the SARS-CoV-2 main protease.

Autor: Miura T; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan., Malla TR; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., Owen CD; Diamond Light Source, Harwell Science & Innovation Campus, Didcot, UK.; Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK., Tumber A; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., Brewitz L; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., McDonough MA; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., Salah E; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., Terasaka N; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan., Katoh T; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan., Lukacik P; Diamond Light Source, Harwell Science & Innovation Campus, Didcot, UK.; Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK., Strain-Damerell C; Diamond Light Source, Harwell Science & Innovation Campus, Didcot, UK.; Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK., Mikolajek H; Diamond Light Source, Harwell Science & Innovation Campus, Didcot, UK.; Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK., Walsh MA; Diamond Light Source, Harwell Science & Innovation Campus, Didcot, UK.; Research Complex at Harwell, Harwell Science & Innovation Campus, Didcot, UK., Kawamura A; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK.; Chemistry - School of Natural and Environmental Sciences, Newcastle University, Newcastle upon Tyne, UK., Schofield CJ; Department of Chemistry and the Ineos Oxford Institute for Antimicrobial Research, Chemistry Research Laboratory, University of Oxford, Oxford, UK., Suga H; Department of Chemistry, Graduate School of Science, The University of Tokyo, Tokyo, Japan. hsuga@chem.s.u-tokyo.ac.jp.
Jazyk: angličtina
Zdroj: Nature chemistry [Nat Chem] 2023 Jul; Vol. 15 (7), pp. 998-1005. Date of Electronic Publication: 2023 May 22.
DOI: 10.1038/s41557-023-01205-1
Abstrakt: γ-Amino acids can play important roles in the biological activities of natural products; however, the ribosomal incorporation of γ-amino acids into peptides is challenging. Here we report how a selection campaign employing a non-canonical peptide library containing cyclic γ 2,4 -amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M pro ). Two kinds of cyclic γ 2,4 -amino acids, cis-3-aminocyclobutane carboxylic acid (γ 1 ) and (1R,3S)-3-aminocyclopentane carboxylic acid (γ 2 ), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M pro inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ 1 at the fourth position, manifests a 5.2 nM dissociation constant. An M pro :GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ 1 interacts with the S1' catalytic subsite and contributes to a 12-fold increase in proteolytic stability compared to its alanine-substituted variant. Knowledge of interactions between GM4 and M pro enabled production of a variant with a 5-fold increase in potency.
(© 2023. The Author(s).)
Databáze: MEDLINE
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