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

• Published in: Viruses Vol. 15; no. 9; p. 1841
• Main Authors: von Beck, Troy, Mena Hernandez, Luis, Zhou, Hongyi, Floyd, Katharine, Suthar, Mehul S, Skolnick, Jeffrey, Jacob, Joshy
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 30-08-2023; MDPI
• Subjects: Animals; Antibodies; antiviral; Atovaquone; Atovaquone - pharmacology; Coronavirus OC43, Human; Coronaviruses; COVID-19; Dosage and administration; Double-stranded RNA; Drug delivery; Drugs; endoribonuclease; Endoribonucleases - metabolism; Experiments; FDA approval; Glycerol; Infections; Libraries; Ligands; Mice; Mutation; nsp15; Nucleases; Pharmacology, Experimental; Physiological aspects; Prophylaxis; Proteins; Proteomes; SARS-CoV-2; SARS-CoV-2 - metabolism; Severe acute respiratory syndrome coronavirus 2; Testing; Viral infections; Viral proteins; Viruses; United States; United States > US; SARS-CoV-2; endoribonuclease; nsp15; antiviral
• ISSN: 1999-4915; 1999-4915
• DOI: 10.3390/v15091841

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.