RESUMO
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.
Assuntos
Animais , Humanos , Camundongos , Antivirais , Farmacologia , Usos Terapêuticos , Betacoronavirus , Fisiologia , Sítios de Ligação , Linhagem Celular , Infecções por Coronavirus , Tratamento Farmacológico , Virologia , Crotonatos , Farmacologia , Síndrome da Liberação de Citocina , Tratamento Farmacológico , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Vírus da Influenza A , Leflunomida , Farmacologia , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae , Tratamento Farmacológico , Oseltamivir , Usos Terapêuticos , Oxirredutases , Metabolismo , Pandemias , Pneumonia Viral , Tratamento Farmacológico , Virologia , Ligação Proteica , Pirimidinas , Vírus de RNA , Fisiologia , Relação Estrutura-Atividade , Toluidinas , Farmacologia , Ubiquinona , Metabolismo , Replicação ViralRESUMO
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.
Assuntos
Animais , Humanos , Camundongos , Antivirais , Farmacologia , Usos Terapêuticos , Betacoronavirus , Fisiologia , Sítios de Ligação , Linhagem Celular , Infecções por Coronavirus , Tratamento Farmacológico , Virologia , Crotonatos , Farmacologia , Síndrome da Liberação de Citocina , Tratamento Farmacológico , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Vírus da Influenza A , Leflunomida , Farmacologia , Camundongos Endogâmicos BALB C , Infecções por Orthomyxoviridae , Tratamento Farmacológico , Oseltamivir , Usos Terapêuticos , Oxirredutases , Metabolismo , Pandemias , Pneumonia Viral , Tratamento Farmacológico , Virologia , Ligação Proteica , Pirimidinas , Vírus de RNA , Fisiologia , Relação Estrutura-Atividade , Toluidinas , Farmacologia , Ubiquinona , Metabolismo , Replicação ViralRESUMO
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.