Abstract
Emergent novel SARS-CoV-2 is responsible for the current pandemic outbreak of severe acute respiratory syndrome with high mortality among the symptomatic population worldwide. Given the absence of a current vaccine or specific antiviral treatment, it is urgent to search for FDA-approved drugs that can potentially inhibit essential viral enzymes. The inhibition of 3CL pro has potential medical application, due to the fact that it is required for processing of the first translated replicase polyproteins into a series of native proteins, which are essential for viral replication in the host cell. We employed an in silico approach to test if disulfiram, as well as its metabolites, and captopril could be used as potential antiviral drugs against COVID-19. We provide data on the potential covalent interaction of disulfiram and its metabolites with the substrate binding subsite of 3CL pro and propose a possible mechanism for the irreversible protease inactivation thought the reaction of the aforementioned compounds with the Cys145. Although, captopril is shown to be a potential ligand of 3CL pro , it is not recommended anti-COVID-19 therapy, due to the fact that it can induce the expression of the viral cellular receptor such as, angiotensin-converting enzyme ACE-2, and thus, making the patient potentially more susceptible to infection. On the other hand, disulfiram, an alcoholism-averting drug, has been previously proposed as an antimicrobial and anti-SARS and MERS agent, safe to use even at higher doses with low side effects, it is recommended to be tested for control of SARS-CoV-2 infection.Communicated by Ramaswamy H. Sarma.
Keywords: 3CL main protease; COVID-19; SARS-CoV-2; disulfiram; thiol-reacting drugs.
【저자키워드】 COVID-19, SARS-CoV-2, 3CL main protease, disulfiram, thiol-reacting drugs., 【초록키워드】 Vaccine, pandemic, therapy, SARS-COV-2 infection, antiviral drugs, Infection, drugs, Proteins, Antiviral treatment, 3CL pro, protease, thiol, MERS, FDA-approved drugs, antimicrobial, disulfiram, antiviral drug, ACE-2, Severe acute respiratory syndrome, Viral, outbreak, viral replication, inactivation, symptomatic, metabolites, Side effects, respiratory, Enzymes, expression, mechanism, 3CL, metabolite, binding, Angiotensin-converting enzyme, Ligand, Interaction, dose, angiotensin, Captopril, Safe, host cell, acute respiratory syndrome, in silico Approach, reaction, FDA-approved drug, Compound, high mortality, alcoholism, processing, replicase polyproteins, Cys145, cellular receptor, susceptible, thought, shown, responsible, tested, the patient, inhibit, required, absence, induce, translated, replicase polyprotein, 【제목키워드】 drug, the SARS-CoV-2,