Atovaquone and Pibrentasvir Inhibit the SARS-CoV-2 Endoribonuclease and Restrict Infection In Vitro but Not In Vivo

• Type of Material: Article
• Authors: Troy von Beck, Emory University; Luis Mena Hernandez, Emory University; Hongyi Zhou, Georgia Institute of Technology; Katharine Floyd, Emory University; Mehul Suthar, Emory University; Jeffrey Skolnick, Georgia Institute of Technology; Joshy Jacob, Emory University
• Language: English
• Date: 2023-08-30
• Publisher: MDPI
• Publication Version: Final Published Version
• Copyright Statement: © 2023 by the authors.
• License: Creative Commons Attribution 4.0 International
• Final Published Version (URL): https://doi.org/10.3390/v15091841
• Title of Journal or Parent Work: Viruses
• Volume: 15
• Issue: 9
• Start Page: 1841
• Grant/Funding Information: This work was supported by the Emory University School of Medicine I3 Nexus award, the Georgia CTSA NIH award (UL1-TR002378), and the Division of General Medical Sciences of the National Institutes of Health (NIH R35GM118039).
• Keywords: endoribonuclease; nsp15; SARS-CoV-2; antiviral
• Research Categories: Biology, Molecular; Health Sciences, Epidemiology; Health Sciences, Public Health

Abstract

The emergence of SARS-CoV-1 in 2003 followed by MERS-CoV and now SARS-CoV-2 has proven the latent threat these viruses pose to humanity. While the SARS-CoV-2 pandemic has shifted to a stage of endemicity, the threat of new coronaviruses emerging from animal reservoirs remains. To address this issue, the global community must develop small molecule drugs targeting highly conserved structures in the coronavirus proteome. Here, we characterized existing drugs for their ability to inhibit the endoribonuclease activity of the SARS-CoV-2 non-structural protein 15 (nsp15) via in silico, in vitro, and in vivo techniques. We have identified nsp15 inhibition by the drugs pibrentasvir and atovaquone which effectively inhibit SARS-CoV-2 and HCoV-OC43 at low micromolar concentrations in cell cultures. Furthermore, atovaquone, but not pibrentasvir, is observed to modulate HCoV-OC43 dsRNA and infection in a manner consistent with nsp15 inhibition. Although neither pibrentasvir nor atovaquone translate to clinical efficacy in a murine prophylaxis model of SARS-CoV-2 infection, atovaquone may serve as a basis for the design of future nsp15 inhibitors.