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  3. A cyclic peptide inhibitor of the SARS-CoV-2 main protease

A cyclic peptide inhibitor of the SARS-CoV-2 main protease

  • Eur J Med Chem. 2021 Oct 5:221:113530. doi: 10.1016/j.ejmech.2021.113530.
Adam G Kreutzer 1,  Maj Krumberger 1,  Elizabeth M Diessner 2,  Chelsea Marie T Parrocha 3,  Michael A Morris 1,  Gretchen Guaglianone 1,  Carter T Butts 4,  James S Nowick 5
Affiliations

Affiliations

  • 1 Department of Chemistry, University of California, Irvine, CA, 92697-2025, United States.
  • 2 Department of Chemistry, University of California, Irvine, CA, 92697-2025, United States; California Institute for Telecommunications and Information Technology, University of California, Irvine, CA, 92697-2025, United States.
  • 3 Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697-2025, United States.
  • 4 California Institute for Telecommunications and Information Technology, University of California, Irvine, CA, 92697-2025, United States; Departments of Sociology, Statistics, Computer Science, and Electrical Engineering and Computer Science, University of California, Irvine, CA, 92697-2025, United States.
  • 5 Department of Chemistry, University of California, Irvine, CA, 92697-2025, United States; Department of Pharmaceutical Sciences, University of California, Irvine, CA, 92697-2025, United States. Electronic address: jsnowick@uci.edu.
PMID: 34023738 DOI: 10.1016/j.ejmech.2021.113530
Abstract

This paper presents the design and study of a first-in-class cyclic peptide inhibitor against the SARS-CoV-2 main protease (Mpro). The cyclic peptide inhibitor is designed to mimic the conformation of a substrate at a C-terminal autolytic cleavage site of Mpro. 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 Mpro. In vitro evaluation of the cyclic peptide inhibitor reveals that the inhibitor exhibits modest activity against Mpro 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 Mpro. Computational docking to the SARS-CoV-2 Mpro suggests that the cyclic peptide inhibitor can bind the active site of Mpro in the predicted manner. Molecular dynamics simulations provide further insights into how the cyclic peptide inhibitor may bind the active site of Mpro. 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 Mpro with improved activities.

Keywords

COVID-19; Cyclic peptide inhibitor; Cyclophane; Main protease; SARS-CoV-2.

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