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

Zandi, Keivan and Bassit, Leda and Amblard, Franck and Cox, Bryan D. and Hassandarvish, Pouya and Moghaddam, Ehsan and Yueh, Andrew and Libanio Rodrigues, Gisele Olinto and Passos, Ingredy and Costa, Vivian V. and AbuBakar, Sazaly and Zhou, Longhu and Kohler, James and Teixeira, Mauro M. and Schinazi, Raymond F. (2019) Nucleoside Analogs with Selective Antiviral Activity against Dengue Fever and Japanese Encephalitis Viruses. Antimicrobial Agents and Chemotherapy, 63 (7). e00397-19. ISSN 0066-4804, DOI

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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.

Item Type: Article
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)
Uncontrolled Keywords: Antiviral agents; Dengue virus; Japanese encephalitis virus; Nucleoside analogs
Subjects: R Medicine
Divisions: Deputy Vice Chancellor (Research & Innovation) Office > Tropical Infectious Diseases Research and Education Centre
Depositing User: Ms. Juhaida Abd Rahim
Date Deposited: 01 Nov 2019 05:57
Last Modified: 01 Nov 2019 05:57

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