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.
Subject(s)
Coronavirus 3C Proteases/antagonists & inhibitors , Peptides, Cyclic/chemistry , Peptides, Cyclic/pharmacology , Protease Inhibitors/pharmacology , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/metabolism , Drug Design , HEK293 Cells , Humans , Molecular Docking Simulation , Molecular Dynamics Simulation , Peptides, Cyclic/chemical synthesis , Protease Inhibitors/chemistry , Protease Inhibitors/toxicity , Protein ConformationABSTRACT
As the SARS-CoV-2 pandemic spread throughout the world, universities were faced with extraordinary challenges. Shelter-in-place orders were given, in-person classes were canceled, and at the University of California Irvine, instructors had less than 2 weeks to convert spring quarter classes from a face-to-face to an online format. A team-based approach was essential to making this transition. The insights gained during the design and implementation of the final quarter of a large-enrollment online organic chemistry class are shared here, as well as student perspectives on the efficacy of key components of the course. The lessons learned during this process will be instrumental when converting other face-to-face courses into effective online formats, as online classes continue in the fall.