Dalcetrapib
The same cysteine-binding chemistry that makes dalcetrapib a CETP inhibitor also lets it block the SARS-CoV-2 3CL protease (ACS Omega 2021)
Original title: Inhibition of the 3CL Protease and SARS-CoV-2 Replication by Dalcetrapib
Dalcetrapib exerts its lipid-modulating effect by binding covalently to cysteine 13 of CETP, and the SARS-CoV-2 3CL protease is a promising antiviral target reliant on a catalytic cysteine residue (Cys145) among 12 free cysteines. Reasoning from this shared covalent-cysteine chemistry, the authors tested whether dalcetrapib could inhibit the 3CL protease and viral replication. Molecular docking suggested dalcetrapib-thiol binds the protease catalytic site with a delta G of -8.5 kcal/mol, and dalcetrapib inhibited 3CL protease activity in vitro (IC50 14.4 plus or minus 3.3 microM) and SARS-CoV-2 replication in Vero E6 cells (EC50 17.5 plus or minus 3.5 microM). Near-complete protease inhibition persisted despite 1000-fold dilution after ultrafiltration at a dalcetrapib-thiol concentration roughly 100-fold below the IC50, indicating a stable protease-drug interaction and supporting clinical evaluation of dalcetrapib for COVID-19.
Original 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.
Summary written by cetpinhibition.org from the published abstract; figures as published. Page updated 18 August 2026. Methods.