title: Structure-activity relationships of nucleoside analogues for inhibition of tick-borne encephalitis virus.
abstract: Tick-borne encephalitis (TBE) represents one of the most serious arboviral neuro-infections in Europe and northern Asia. As no specific antiviral therapy is available at present, there is an urgent need for efficient drugs to treat patients with TBE virus (TBEV) infection. Using two standardised in vitro assay systems, we evaluated a series of 29 nucleoside derivatives for their ability to inhibit TBEV replication in cell lines of neuronal as well as extraneural origin. The series of tested compounds included 2'-C- or 2'-O-methyl substituted nucleosides, 2'-C-fluoro-2'-C-methyl substituted nucleosides, 3'-O-methyl substituted nucleosides, 3'-deoxynucleosides, derivatives with 4'-C-azido substitution, heterobase modified nucleosides and neplanocins. Our data demonstrate a relatively stringent structure-activity relationship for modifications at the 2', 3', and 4' nucleoside positions. Whereas nucleoside derivatives with the methylation at the C2' position or azido modification at the C4'position exerted a strong TBEV inhibition activity (EC50 from 0.3 to 11.1 μM) and low cytotoxicity in vitro, substitutions of the O2' and O3' positions led to a complete loss of anti-TBEV activity (EC50 > 50 μM). Moreover, some structural modifications of the heterobase moiety resulted in a high increase of cytotoxicity in vitro. High antiviral activity and low cytotoxicity of C2' methylated or C4' azido substituted pharmacophores suggest that such compounds might represent promising candidates for further development of potential therapeutic agents in treating TBEV infection.
authors.affiliation: Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic.
authors.forename: Luděk
authors.initials: L
authors.lastname: Eyer
authors.affiliation: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Fleming Sq. 2, CZ-16610 Prague, Czech Republic.
authors.forename: Markéta
authors.initials: M
authors.lastname: Šmídková
authors.affiliation: Institute of Organic Chemistry and Biochemistry, The Czech Academy of Sciences, Fleming Sq. 2, CZ-16610 Prague, Czech Republic.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
authors.affiliation: Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic.
authors.forename: Jiří
authors.initials: J
authors.lastname: Neča
authors.affiliation: Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic.
authors.forename: Tomáš
authors.initials: T
authors.lastname: Kastl
authors.affiliation: Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, and Faculty of Science, University of South Bohemia, Branišovská 31, CZ-37005 České Budějovice, Czech Republic.
authors.forename: Martin
authors.initials: M
authors.lastname: Palus
authors.affiliation: Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000 Leuven, Belgium.
authors.forename: Erik
authors.initials: E
authors.lastname: De Clercq
authors.affiliation: Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, and Faculty of Science, University of South Bohemia, Branišovská 31, CZ-37005 České Budějovice, Czech Republic. Electronic address: ruzekd@paru.cas.cz.
authors.forename: Daniel
authors.initials: D
authors.lastname: Růžek
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D004305:Dose-Response Relationship, Drug; D004669:Encephalitis Viruses, Tick-Borne / Q000187:drug effects*; D004675:Encephalitis, Tick-Borne / Q000188:drug therapy / Q000821:virology; D015394:Molecular Structure; D009705:Nucleosides / Q000737:chemistry* / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013552:Swine; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D009705:Nucleosides
keywords: Antiviral activity; Cytotoxicity; Nucleoside inhibitor; Structure-activity relationship; Tick-borne encephalitis