title: Nucleoside inhibitors of tick-borne encephalitis virus.
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 [EC50]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 [CC50] 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 (CC50 > 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.
authors.affiliation: Department of Virology, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Eyer
authors.affiliation: Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic.
authors.forename: James J
authors.initials: JJ
authors.lastname: Valdés
authors.affiliation: Joint BSC-CRG-IRB Research Program in Computational Biology, Barcelona Supercomputing Center, Barcelona, Spain.
authors.forename: Victor A
authors.initials: VA
authors.lastname: Gil
authors.affiliation: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
authors.affiliation: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Prague, Czech Republic.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: Department of Virology, Veterinary Research Institute, Brno, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Salát
authors.affiliation: Department of Virology, Veterinary Research Institute, Brno, Czech Republic Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Černý
authors.affiliation: Department of Virology, Veterinary Research Institute, Brno, Czech Republic Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Palus
authors.affiliation: Rega Institute for Medical Research, Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Department of Virology, Veterinary Research Institute, Brno, Czech Republic Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, České Budějovice, Czech Republic Faculty of Science, University of South Bohemia, České Budějovice, Czech Republic ruzekd@paru.cas.cz.
authors.forename: Daniel
authors.initials: D
authors.lastname: Růžek
mesh_terms: D000241:Adenosine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D003562:Cytidine / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D004669:Encephalitis Viruses, Tick-Borne / Q000187:drug effects*; D006801:Humans; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D013552:Swine; D014372:Tubercidin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology; D014779:Virus Replication / Q000187:drug effects
chemical_list: C569537:2'-C-methyladenosine; D000998:Antiviral Agents; D009705:Nucleosides; C513402:2'-C-methylcytidine; D003562:Cytidine; D000241:Adenosine; D014372:Tubercidin; C518645:7-deaza-2'-C-methyladenosine