ABSTRACT
In the new millennium, the outbreak of new coronavirus has happened three times: SARS-CoV, MERS-CoV, and SARS-CoV-2. Unfortunately, we still have no pharmaceutical weapons against the diseases caused by these viruses. The pandemic of SARS-CoV-2 reminds us the urgency to search new drugs with totally different mechanism that may target the weaknesses specific to coronaviruses. Herein, we disclose a computational evaluation of targeted oxidation strategy (TOS) for potential inhibition of SARS-CoV-2 by disulfiram, a 70-year-old anti-alcoholism drug, and predict a multiple-target mechanism. A preliminary list of promising TOS drug candidates targeting the two thiol proteases of SARS-CoV-2 are proposed upon virtual screening of 32,143 disulfides.
Subject(s)
Alcohol Deterrents/chemistry , Antiviral Agents/chemistry , Coronavirus 3C Proteases/antagonists & inhibitors , Coronavirus Papain-Like Proteases/antagonists & inhibitors , Disulfiram/chemistry , Protease Inhibitors/chemistry , SARS-CoV-2/chemistry , Alcohol Deterrents/pharmacology , Antiviral Agents/pharmacology , Catalytic Domain , Coronavirus 3C Proteases/chemistry , Coronavirus 3C Proteases/genetics , Coronavirus 3C Proteases/metabolism , Coronavirus Papain-Like Proteases/chemistry , Coronavirus Papain-Like Proteases/genetics , Coronavirus Papain-Like Proteases/metabolism , Disulfiram/pharmacology , Drug Repositioning , Gene Expression , Humans , Kinetics , Molecular Docking Simulation , Oxidation-Reduction , Protease Inhibitors/pharmacology , Protein Binding , Protein Interaction Domains and Motifs , Protein Structure, Secondary , Quantum Theory , SARS-CoV-2/enzymology , Substrate Specificity , Thermodynamics , COVID-19 Drug TreatmentABSTRACT
AIM: In view of the increase in the use of ethanol-containing hand sanitizers throughout the world due to the current COVID-19 pandemic, we wished to review the possible risks to patients treated with disulfiram, following a case report in which an apparent DER (disulfiram-ethanol reaction) was attributed to the cutaneous absorption of alcohol from hand sanitizers as well as by inhalation of vapour. METHOD: Simple experiments to assess the levels of absorption by each route separately. RESULTS: Our results strongly suggest that while amounts of alcohol sufficient to cause a DER may be inhaled when hand sanitizers are used in confined spaces, absorption can be avoided by dispersal of the fumes, and absorption from the skin alone does not occur in pharmacologically significant quantities. CONCLUSION: Warnings about absorption of alcohol through the skin from hand sanitizers and products such as perfumes, deodorants and after-shave (whose use is often warned against when disulfiram is prescribed) should be modified accordingly.