Nucleoside Inhibitors of Tick-Borne Encephalitis Virus
Open Access
- 1 September 2015
- journal article
- Published by American Society for Microbiology in Antimicrobial Agents and Chemotherapy
- Vol. 59 (9), 5483-5493
- https://doi.org/10.1128/aac.00807-15
Abstract
Tick-borne encephalitis virus (TBEV) is a leading cause of human neuroinfections in Europe and Northeast Asia. There are no antiviral therapies for treating TBEV infection. A series of nucleoside analogues was tested for the ability to inhibit the replication of TBEV in porcine kidney cells and human neuroblastoma cells. The interactions of three nucleoside analogues with viral polymerase were simulated using advanced computational methods. The nucleoside analogues 7-deaza-2′- C -methyladenosine (7-deaza-2′-CMA), 2′- C -methyladenosine (2′-CMA), and 2′-C-methylcytidine (2′-CMC) inhibited TBEV replication. These compounds showed dose-dependent inhibition of TBEV-induced cytopathic effects, TBEV replication (50% effective concentrations [EC 50 ]of 5.1 ± 0.4 μM for 7-deaza-2′-CMA, 7.1 ± 1.2 μM for 2′-CMA, and 14.2 ± 1.9 μM for 2′-CMC) and viral antigen production. Notably, 2′-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC 50 ] of ∼50 μM). The anti-TBEV effect of 2′-CMA in cell culture diminished gradually after day 3 posttreatment. 7-Deaza-2′-CMA showed no detectable cellular toxicity (CC 50 > 50 μM), and the antiviral effect in culture was stable for >6 days posttreatment. Computational molecular analyses revealed that compared to the other two compounds, 7-deaza-2′-CMA formed a large cluster near the active site of the TBEV polymerase. High antiviral activity and low cytotoxicity suggest that 7-deaza-2′-CMA is a promising candidate for further investigation as a potential therapeutic agent in treating TBEV infection.Keywords
This publication has 54 references indexed in Scilit:
- PELE web server: atomistic study of biomolecular systems at your fingertipsNucleic Acids Research, 2013
- The ModFOLD4 server for the quality assessment of 3D protein modelsNucleic Acids Research, 2013
- Fiji: an open-source platform for biological-image analysisNature Methods, 2012
- Antiviral Efficacy upon Administration of a HepDirect Prodrug of 2′- C -Methylcytidine to Hepatitis C Virus-Infected ChimpanzeesAntimicrobial Agents and Chemotherapy, 2011
- Inhibition of Dengue Virus by an Ester Prodrug of an Adenosine AnalogAntimicrobial Agents and Chemotherapy, 2010
- Inhibition of Dengue Virus RNA Synthesis by an Adenosine NucleosideAntimicrobial Agents and Chemotherapy, 2010
- Efficacy of 2′-C-methylcytidine against yellow fever virus in cell culture and in a hamster modelAntiviral Research, 2010
- An adenosine nucleoside inhibitor of dengue virusProceedings of the National Academy of Sciences, 2009
- QMEAN server for protein model quality estimationNucleic Acids Research, 2009
- Comparative Protein Modelling by Satisfaction of Spatial RestraintsJournal of Molecular Biology, 1993