Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir

TitleCombined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir
Publication TypeJournal Article
Year of Publication2021
AuthorsPohl M.O, Busnadiego I., Marrafino F., Wiedmer L., Hunziker A., Fernbach S., Glas I., Moroz-Omori E.V, Hale B.G, Caflisch A., Stertz S.
JournalJournal of General Virology
Volume102
Issue7
Date Published2021 07
Type of ArticleResearch Article
ISSN1465-2099
KeywordsAdenosine Monophosphate, Alanine, Animals, Antiviral Agents, Cells, Cultured, Chymases, COVID-19, Drug Evaluation, Preclinical, Humans, Molecular Docking Simulation, Phenylurea Compounds, Protein Kinase Inhibitors, Quinolines, SARS-CoV-2
Abstract

Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3 CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3 CL main protease inhibitor (IC value of 29 µM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3 CL main protease inhibitor , but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.

DOI10.1099/jgv.0.001625
pubindex

0269

Alternate JournalJ. Gen. Virol.
PubMed ID34319869