RESUMEN
The global COVID-19 coronavirus pandemic has infected over 109 million people, leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment. Here, we screened about 1.8 million small molecules against the main protease (Mpro) and papain like protease (PLpro), two major proteases in severe acute respiratory syndrome-coronavirus 2 genome, and identified 1851Mpro inhibitors and 205 PLpro inhibitors with low nmol/l activity of the best hits. Among these inhibitors, eight small molecules showed dual inhibition effects on both Mpro and PLpro, exhibiting potential as better candidates for COVID-19 treatment. The best inhibitors of each protease were tested in antiviral assay, with over 40% of Mpro inhibitors and over 20% of PLpro inhibitors showing high potency in viral inhibition with low cytotoxicity. The X-ray crystal structure of SARS-CoV-2 Mpro in complex with its potent inhibitor 4a was determined at 1.8 Å resolution. Together with docking assays, our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
Asunto(s)
Humanos , Antivirales/química , COVID-19 , Tratamiento Farmacológico de COVID-19 , Ensayos Analíticos de Alto Rendimiento , Simulación del Acoplamiento Molecular , Inhibidores de Proteasas/química , SARS-CoV-2/enzimología , Proteínas no Estructurales ViralesRESUMEN
A new coronavirus (SARS-CoV-2) has been identified as the etiologic agent for the COVID-19 outbreak. Currently, effective treatment options remain very limited for this disease; therefore, there is an urgent need to identify new anti-COVID-19 agents. In this study, we screened over 6,000 compounds that included approved drugs, drug candidates in clinical trials, and pharmacologically active compounds to identify leads that target the SARS-CoV-2 papain-like protease (PLpro). Together with main protease (M
Asunto(s)
Humanos , Antivirales/uso terapéutico , Sitios de Unión , COVID-19/virología , Proteasas Similares a la Papaína de Coronavirus/metabolismo , Cristalografía por Rayos X , Evaluación Preclínica de Medicamentos , Reposicionamiento de Medicamentos , Ensayos Analíticos de Alto Rendimiento/métodos , Imidazoles/uso terapéutico , Concentración 50 Inhibidora , Simulación de Dinámica Molecular , Mutagénesis Sitio-Dirigida , Naftoquinonas/uso terapéutico , Inhibidores de Proteasas/uso terapéutico , Estructura Terciaria de Proteína , Proteínas Recombinantes/aislamiento & purificación , SARS-CoV-2/aislamiento & purificaciónRESUMEN
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Asunto(s)
Animales , Humanos , Ratones , Antivirales , Farmacología , Usos Terapéuticos , Betacoronavirus , Fisiología , Sitios de Unión , Línea Celular , Infecciones por Coronavirus , Quimioterapia , Virología , Crotonatos , Farmacología , Síndrome de Liberación de Citoquinas , Quimioterapia , Evaluación Preclínica de Medicamentos , Técnicas de Inactivación de Genes , Virus de la Influenza A , Leflunamida , Farmacología , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae , Quimioterapia , Oseltamivir , Usos Terapéuticos , Oxidorreductasas , Metabolismo , Pandemias , Neumonía Viral , Quimioterapia , Virología , Unión Proteica , Pirimidinas , Virus ARN , Fisiología , Relación Estructura-Actividad , Toluidinas , Farmacología , Ubiquinona , Metabolismo , Replicación ViralRESUMEN
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.
Asunto(s)
Animales , Humanos , Ratones , Antivirales , Farmacología , Usos Terapéuticos , Betacoronavirus , Fisiología , Sitios de Unión , Línea Celular , Infecciones por Coronavirus , Quimioterapia , Virología , Crotonatos , Farmacología , Síndrome de Liberación de Citoquinas , Quimioterapia , Evaluación Preclínica de Medicamentos , Técnicas de Inactivación de Genes , Virus de la Influenza A , Leflunamida , Farmacología , Ratones Endogámicos BALB C , Infecciones por Orthomyxoviridae , Quimioterapia , Oseltamivir , Usos Terapéuticos , Oxidorreductasas , Metabolismo , Pandemias , Neumonía Viral , Quimioterapia , Virología , Unión Proteica , Pirimidinas , Virus ARN , Fisiología , Relación Estructura-Actividad , Toluidinas , Farmacología , Ubiquinona , Metabolismo , Replicación ViralRESUMEN
Emerging and re-emerging RNA viruses occasionally cause epidemics and pandemics worldwide, such as the on-going outbreak of the novel coronavirus SARS-CoV-2. Herein, we identified two potent inhibitors of human DHODH, S312 and S416, with favorable drug-likeness and pharmacokinetic profiles, which all showed broad-spectrum antiviral effects against various RNA viruses, including influenza A virus, Zika virus, Ebola virus, and particularly against SARS-CoV-2. Notably, S416 is reported to be the most potent inhibitor so far with an EC of 17 nmol/L and an SI value of 10,505.88 in infected cells. Our results are the first to validate that DHODH is an attractive host target through high antiviral efficacy in vivo and low virus replication in DHODH knock-out cells. This work demonstrates that both S312/S416 and old drugs (Leflunomide/Teriflunomide) with dual actions of antiviral and immuno-regulation may have clinical potentials to cure SARS-CoV-2 or other RNA viruses circulating worldwide, no matter such viruses are mutated or not.