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Artículo en Inglés | MEDLINE | ID: mdl-31061163

RESUMEN

Dengue virus (DENV) and Japanese encephalitis virus (JEV) are important arthropod-borne viruses from the Flaviviridae family. DENV is a global public health problem with significant social and economic impacts, especially in tropical and subtropical areas. JEV is a neurotropic arbovirus endemic to east and southeast Asia. There are no U.S. FDA-approved antiviral drugs available to treat or to prevent DENV and JEV infections, leaving nearly one-third of the world's population at risk for infection. Therefore, it is crucial to discover potent antiviral agents against these viruses. Nucleoside analogs, as a class, are widely used for the treatment of viral infections. In this study, we discovered nucleoside analogs that possess potent and selective anti-JEV and anti-DENV activities across all serotypes in cell-based assay systems. Both viruses were susceptible to sugar-substituted 2'-C-methyl analogs with either cytosine or 7-deaza-7-fluoro-adenine nucleobases. Mouse studies confirmed the anti-DENV activity of these nucleoside analogs. Molecular models were assembled for DENV serotype 2 (DENV-2) and JEV RNA-dependent RNA polymerase replication complexes bound to nucleotide inhibitors. These models show similarities between JEV and DENV-2, which recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and a structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.


Asunto(s)
Antivirales/farmacología , Virus del Dengue/efectos de los fármacos , Dengue/tratamiento farmacológico , Virus de la Encefalitis Japonesa (Subgrupo)/efectos de los fármacos , Nucleósidos/análogos & derivados , Animales , Antivirales/química , Chlorocebus aethiops , Dengue/sangre , Dengue/patología , Virus del Dengue/genética , Virus del Dengue/fisiología , Evaluación Preclínica de Medicamentos/métodos , Virus de la Encefalitis Japonesa (Subgrupo)/genética , Virus de la Encefalitis Japonesa (Subgrupo)/fisiología , Encefalitis por Arbovirus/tratamiento farmacológico , Ratones , Modelos Moleculares , Nucleósidos/química , Nucleósidos/farmacología , ARN Polimerasa Dependiente del ARN/química , ARN Polimerasa Dependiente del ARN/metabolismo , Células Vero , Proteínas Virales/química , Proteínas Virales/metabolismo , Replicación Viral/efectos de los fármacos
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