In vitro selection of macrocyclic peptide inhibitors containing cyclic γ2,4-amino acids targeting the SARS-CoV-2 main protease

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<jats:title>Abstract</jats:title><jats:p>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<jats:sup>2,4</jats:sup>-amino acids resulted in the discovery of very potent inhibitors of the SARS-CoV-2 main protease (M<jats:sup>pro</jats:sup>). Two kinds of cyclic γ<jats:sup>2,4</jats:sup>-amino acids, <jats:italic>cis</jats:italic>-3-aminocyclobutane carboxylic acid (γ<jats:sup>1</jats:sup>) and (1<jats:italic>R</jats:italic>,3<jats:italic>S</jats:italic>)-3-aminocyclopentane carboxylic acid (γ<jats:sup>2</jats:sup>), were ribosomally introduced into a library of thioether-macrocyclic peptides. One resultant potent M<jats:sup>pro</jats:sup> inhibitor (half-maximal inhibitory concentration = 50 nM), GM4, comprising 13 residues with γ<jats:sup>1</jats:sup> at the fourth position, manifests a 5.2 nM dissociation constant. An M<jats:sup>pro</jats:sup>:GM4 complex crystal structure reveals the intact inhibitor spans the substrate binding cleft. The γ<jats:sup>1</jats:sup> 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<jats:sup>pro</jats:sup> enabled production of a variant with a 5-fold increase in potency.</jats:p>

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  • Nature Chemistry

    Nature Chemistry 15 (7), 998-1005, 2023-05-22

    Springer Science and Business Media LLC

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