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 EC50 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
Antivirais/farmacologia , Infecções por Coronavirus/tratamento farmacológico , Oxirredutases/antagonistas & inibidores , Pandemias , Pneumonia Viral/tratamento farmacológico , Vírus de RNA/efeitos dos fármacos , Tiazóis/farmacologia , Animais , Antivirais/uso terapêutico , Betacoronavirus/efeitos dos fármacos , Betacoronavirus/fisiologia , Sítios de Ligação/efeitos dos fármacos , COVID-19 , Linhagem Celular , Infecções por Coronavirus/virologia , Crotonatos/farmacologia , Síndrome da Liberação de Citocina/tratamento farmacológico , Di-Hidro-Orotato Desidrogenase , Avaliação Pré-Clínica de Medicamentos , Técnicas de Inativação de Genes , Humanos , Hidroxibutiratos , Vírus da Influenza A/efeitos dos fármacos , Leflunomida/farmacologia , Camundongos , Camundongos Endogâmicos BALB C , Nitrilas , Infecções por Orthomyxoviridae/tratamento farmacológico , Oseltamivir/uso terapêutico , Oxirredutases/metabolismo , Oxirredutases atuantes sobre Doadores de Grupo CH-CH , Pneumonia Viral/virologia , Ligação Proteica/efeitos dos fármacos , Pirimidinas/biossíntese , Vírus de RNA/fisiologia , SARS-CoV-2 , Relação Estrutura-Atividade , Tiazóis/uso terapêutico , Toluidinas/farmacologia , Ubiquinona/metabolismo , Replicação Viral/efeitos dos fármacosRESUMO
Starting from the lead isodaphnetin, a natural product inhibitor of DPP-4 discovered through a target fishing docking based approach, a series of novel 2-phenyl-3,4-dihydro-2H-benzo[f]chromen-3-amine derivatives as potent DPP-4 inhibitors are rationally designed utilizing highly efficient 3D molecular similarity based scaffold hopping as well as electrostatic complementary methods. Those ingenious drug design strategies bring us approximate 7400-fold boost in potency. Compounds 22a and 24a are the most potent ones (IC50 ≈ 2.0 nM) with good pharmacokinetic profiles. Compound 22a demonstrated stable pharmacological effect. A 3 mg/kg oral dose provided >80% inhibition of DPP-4 activity within 24 h, which is comparable to the performance of the long-acting control omarigliptin. Moreover, the efficacy of 22a in improving the glucose tolerance is also comparable with omarigliptin. In this study, not only promising DPP-4 inhibitors as long acting antidiabetic that are clinically on demand are identified, but the target fish docking and medicinal chemistry strategies were successfully implemented.