Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses

Authors

• Keivan Zandi
• Leda Bassit
• Franck Amblard
• Bryan D. Cox
• Pouya HassandarvishFollow
• Ehsan Moghaddam
• Andrew Yueh
• Gisele Olinto Libanio Rodrigues
• Ingredy Passos
• Vivian V. Costa
• Sazaly AbuBakarFollow
• Longhu Zhou
• James Kohler
• Mauro M. Teixeira
• Raymond F. Schinazi

Document Type

Article

Publication Date

1-1-2019

Abstract

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.

Keywords

Antiviral agents, Dengue virus, Japanese encephalitis virus, Nucleoside analogs

Publication Title

Antimicrobial Agents and Chemotherapy

Divisions

tidrec

Funders

NIH (grant R21-AI-129607),Emory University Center for AIDS Research (NIH grant 2P30-AI-050409 to R.F.S.),Ministry of Higher Education, Malaysia (high-impact research grant E000087-20001 and long-range scheme grant LR001/2011F),National Institute of Science and Technology in Dengue and Host-Microorganism Interaction, a program funded by the Brazilian National Science Council (Brazil),Minas Gerais Foundation for Science (Brazil),Comissao de Apoio a Pessoal de Ensino Superior (Brazil)

Volume

63

Issue

7

Publisher

American Society for Microbiology