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Inhibition of Enterovirus 71 by Adenosine Analog NITD008.
- Source :
-
Journal of Virology . 10/15/2014, Vol. 88 Issue 20, p11915-11923. 9p. - Publication Year :
- 2014
-
Abstract
- Enterovirus 71 (EV71) is a major viral pathogen in China and Southeast Asia. There is no clinically approved vaccine or antiviral therapy for EV71 infection. NITD008, an adenosine analog, is an inhibitor of flavivirus that blocks viral RNA synthesis. Here we report that NITD008 has potent antiviral activity against EV71. In cell culture, the compound inhibits EV71 at a 50% effective concentration of 0.67 μMand a 50% cytotoxic concentration of 119.97 μM. When administered at 5 mg/kg in an EV71 mouse model, the compound reduced viral loads in various organs and completely prevented clinical symptoms and death. To study the antiviral mechanism and drug resistance, we selected escape mutant viruses by culturing EV71 with increasing concentrations of NITD008. Resistance mutations were reproducibly mapped to the viral 3A and 3D polymerase regions. Resistance analysis with recombinant viruses demonstrated that either a 3A or a 3D mutation alone could lead to resistance to NITD008. A combination of both 3A and 3D mutations conferred higher resistance, suggesting a collaborative interplay between the 3A and 3D proteins during viral replication. The resistance results underline the importance of combination therapy required for EV71 treatment. [ABSTRACT FROM AUTHOR]
- Subjects :
- *ENTEROVIRUS diseases
*ADENOSINES
*ANTIVIRAL agents
*RNA synthesis
*THERAPEUTICS
Subjects
Details
- Language :
- English
- ISSN :
- 0022538X
- Volume :
- 88
- Issue :
- 20
- Database :
- Academic Search Index
- Journal :
- Journal of Virology
- Publication Type :
- Academic Journal
- Accession number :
- 103592707
- Full Text :
- https://doi.org/10.1128/JVI.01207-14