Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib.

Abstract

The severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) 3CL protease is a promising target for inhibition of viral replication by interaction with a cysteine residue (Cys145) at its catalytic site. Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of a cholesteryl ester transfer protein. Because 12 free cysteine residues are present in the 3CL protease, we investigated the potential of dalcetrapib to inhibit 3CL protease activity and SARS-CoV-2 replication. Molecular docking investigations suggested that dalcetrapib-thiol binds to the catalytic site of the 3CL protease with a delta G value of -8.5 kcal/mol. Dalcetrapib inhibited both 3CL protease activity in vitro and viral replication in Vero E6 cells with IC50 values of 14.4 ± 3.3 μM and an EC50 of 17.5 ± 3.5 μM (mean ± SD). Near-complete inhibition of protease activity persisted despite 1000-fold dilution after ultrafiltration with a nominal dalcetrapib-thiol concentration of approximately 100 times below the IC50 of 14.4 μM, suggesting stable protease-drug interaction. The inhibitory effect of dalcetrapib on the SARS-CoV-2 3CL protease and viral replication warrants its clinical evaluation for the treatment of COVID-19.

• Authors: Eric J Niesor, Guy Boivin, Eric Rhéaume, Rong Shi, Véronique Lavoie, Nathalie Goyette, Marie-Eve Picard, Anne Perez, Fouzia Laghrissi-Thode, Jean-Claude Tardif
• Journal: ACS omega (ACS Omega) Vol. 6 Issue 25 Pg. 16584-16591 (Jun 29 2021) ISSN: 2470-1343 [Electronic] United States
• PMID: 34235330 (Publication Type: Journal Article)
• Copyright: © 2021 The Authors. Published by American Chemical Society.