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

• Published in: ACS omega Vol. 6; no. 25; pp. 16584 - 16591
• Main Authors: Niesor, Eric J, Boivin, Guy, Rhéaume, Eric, Shi, Rong, Lavoie, Véronique, Goyette, Nathalie, Picard, Marie-Eve, Perez, Anne, Laghrissi-Thode, Fouzia, Tardif, Jean-Claude
• Format: Journal Article
• Language: English
• Published: American Chemical Society 29.06.2021
• ISSN: 2470-1343; 2470-1343
• DOI: 10.1021/acsomega.1c01797

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.