Selected article for: "acute respiratory syndrome and clinical evaluation"
Author: Niesor, Eric J; Boivin, Guy; Rhéaume, Eric; Shi, Rong; Lavoie, Véronique; Goyette, Nathalie; Picard, Marie-Eve; Perez, Anne; Laghrissi-Thode, Fouzia; Tardif, Jean-Claude
Title: Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib
  • Cord-id: 52t0gsda
  • Document date: 2021_6_17
    • ID: 52t0gsda
    Snippet: [Image: see text] 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 S
    Document: [Image: see text] 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 IC(50) values of 14.4 ± 3.3 μM and an EC(50) 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 IC(50) 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.

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