期刊
ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
卷 59, 期 9, 页码 5483-5493出版社
AMER SOC MICROBIOLOGY
DOI: 10.1128/AAC.00807-15
关键词
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资金
- Czech Science Foundation [P502/11/2116, GA14-29256S]
- Ministry of Education, Youth and Sports of the Czech Republic under the NPU I program [LO1218]
- AdmireVet project [CZ1.05/2.1.00/01.0006-ED 0006/01/01]
- European Social Fund
- state budget of the Czech Republic
- European project PELE [ERC-2009-Adg 25027]
- [RVO: 61388963]
- [CZ.1.07/2.3.00/30.0032]
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 [EC50] of 5.1 +/- 0.4 mu M for 7-deaza-2'-CMA, 7.1 +/- 1.2 mu M for 2'-CMA, and 14.2 +/- 1.9 mu M for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of similar to 50 mu M). 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 (CC50 > 50 mu M), 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.
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