Nucleoside Inhibitors of Tick-Borne Encephalitis Virus

0448138 - BC 2016 RIV US eng J - Článek v odborném periodiku
Eyer, L. - Valdés, James J. - Gil, V.A. - Nencka, Radim - Hřebabecký, Hubert - Šála, Michal - Salát, J. - Černý, Jiří - Palus, Martin - De Clercq, E. - Růžek, Daniel
Nucleoside Inhibitors of Tick-Borne Encephalitis Virus.
Antimicrobial Agents and Chemotherapy. Roč. 59, č. 9 (2015), s. 5483-5493. ISSN 0066-4804. E-ISSN 1098-6596
Grant CEP: GA ČR GAP502/11/2116; GA MŠMT(CZ) EE2.3.30.0032
Institucionální podpora: RVO:60077344 ; RVO:61388963
Klíčová slova: tick-borne encephalitis virus * infection * molecular analyses
Kód oboru RIV: EE - Mikrobiologie, virologie; CC - Organická chemie (UOCHB-X)
Impakt faktor: 4.415, rok: 2015

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 muM for 7-deaza-2'-CMA, 7.1 ± 1.2 muM for 2'-CMA, and 14.2 ± 1.9 muM for 2'-CMC) and viral antigen production. Notably, 2'-CMC was relatively cytotoxic to porcine kidney cells (50% cytotoxic concentration [CC50] of 50 muM). 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 muM), 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.
Trvalý link: http://hdl.handle.net/11104/0249864