RESUMO
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.
Assuntos
Dissuasores de Álcool/química , Antivirais/química , Proteases 3C de Coronavírus/antagonistas & inibidores , Proteases Semelhantes à Papaína de Coronavírus/antagonistas & inibidores , Dissulfiram/química , Inibidores de Proteases/química , SARS-CoV-2/química , Dissuasores de Álcool/farmacologia , Antivirais/farmacologia , Domínio Catalítico , Proteases 3C de Coronavírus/química , Proteases 3C de Coronavírus/genética , Proteases 3C de Coronavírus/metabolismo , Proteases Semelhantes à Papaína de Coronavírus/química , Proteases Semelhantes à Papaína de Coronavírus/genética , Proteases Semelhantes à Papaína de Coronavírus/metabolismo , Dissulfiram/farmacologia , Reposicionamento de Medicamentos , Expressão Gênica , Humanos , Cinética , Simulação de Acoplamento Molecular , Oxirredução , Inibidores de Proteases/farmacologia , Ligação Proteica , Domínios e Motivos de Interação entre Proteínas , Estrutura Secundária de Proteína , Teoria Quântica , SARS-CoV-2/enzimologia , Especificidade por Substrato , Termodinâmica , Tratamento Farmacológico da COVID-19RESUMO
The spike protein is a focused target of COVID-19, a pandemic caused by SARS-CoV-2. A 12-nt insertion at S1/S2 in the spike coding sequence yields a furin cleavage site, which raised controversy views on origin of the virus. Here we analyzed the phylogenetic relationships of coronavirus spike proteins and mapped furin recognition motif on the tree. Furin cleavage sites occurred independently for multiple times in the evolution of the coronavirus family, supporting the natural occurring hypothesis of SARS-CoV-2.