A cyclic peptide inhibitor of the SARS-CoV-2 main protease.
Kreutzer AG, Krumberger M, Diessner EM, Parrocha CMT, Morris MA, Guaglianone G, Butts CT, Nowick JS.
This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (M<sup>pro</sup>). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at a C-terminal autolytic cleavage site of M<sup>pro</sup>. The cyclic peptide contains a [4-(2-aminoethyl)phenyl]-acetic acid (AEPA) linker that is designed to enforce a conformation that mimics a peptide substrate of M<sup>pro</sup>. In vitro evaluation of the cyclic peptide inhibitor reveals that the inhibitor exhibits modest activity against M<sup>pro</sup> and does not appear to be cleaved by the enzyme. Conformational searching predicts that the cyclic peptide inhibitor is fairly rigid, adopting a favorable conformation for binding to the active site of M<sup>pro</sup>. Computational docking to the SARS-CoV-2 M<sup>pro</sup> suggests that the cyclic peptide inhibitor can bind the active site of M<sup>pro</sup> in the predicted manner. Molecular dynamics simulations provide further insights into how the cyclic peptide inhibitor may bind the active site of M<sup>pro</sup>. Although the activity of the cyclic peptide inhibitor is modest, its design and study lays the groundwork for the development of additional cyclic peptide inhibitors against M<sup>pro</sup> with improved activities.