Dengue virus (DENV) and Japanese Encephalitis virus (JEV) are two important arthropod-borne viruses from 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 US FDA approved antiviral drugs available to treat or prevent DENV and JEV leaving nearly one-third of the worldwide 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 activity 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 that recognize the same nucleotide inhibitors. Collectively, our findings provide promising compounds and structural rationale for the development of direct-acting antiviral agents with dual activity against JEV and DENV infections.
Date:
2019-07
Relation:
Antimicrobial Agents and Chemotherapy. 2019 Jul;63(7):e00397-19.
