Antiviral activity of the adenosine analogue BCX4430 against West Nile virus and tick-borne flaviviruses.
There are currently no approved antiviral therapies against medically important human flaviviruses. The imino-C-nucleoside BCX4430 shows broad-spectrum antiviral activity against a wide range of RNA viruses. Here, we demonstrate that BCX4430 inhibits tick-borne species of the genus Flavivirus; however, the antiviral effect varies against individual species. Micro-molar BCX4430 levels inhibited tick-borne encephalitis virus (TBEV); while, approximately 3-8-fold higher concentrations were needed to inhibit louping ill virus and Kyasanur Forest disease virus. Moreover, the compound strongly inhibited in vitro replication of West Nile virus, a typical mosquito-transmitted flavivirus. Two chemical forms of the compound, i.e. BCX4430 and BCX4430 hydrochloride, were compared and both exerted similar inhibitory profiles in our in vitro antiviral assay systems and no or negligible cytotoxicity in porcine kidney stable and Vero cells. The obtained data indicate that, in addition to mosquito-borne flaviviruses, the compound has strong antiviral activity against members of the TBEV serocomplex.
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branišovská 31, CZ-37005, České Budějovice, Czech Republic.
Luděk
L
Eyer
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.
Darina
D
Zouharová
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.
Jana
J
Širmarová
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.
Martina
M
Fojtíková
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.
Michal
M
Štefánik
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic.
Jan
J
Haviernik
Institute of Organic Chemistry and Biochemistry, Czech Academy of Sciences, Flemingovo nam. 2, CZ-16610, Prague 6, Czech Republic.
Radim
R
Nencka
Rega Institute for Medical Research, KU Leuven, Minderbroedersstraat 10, B-3000, Leuven, Belgium.
Erik
E
de Clercq
Department of Virology, Veterinary Research Institute, Hudcova 70, CZ-62100, Brno, Czech Republic; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branišovská 31, CZ-37005, České Budějovice, Czech Republic. Electronic address: ruzekd@paru.cas.cz.
Daniel
D
Růžek
D000225:Adenine / Q000031:analogs & derivatives; D000241:Adenosine / Q000031:analogs & derivatives* / Q000494:pharmacology; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D002522:Chlorocebus aethiops; D009033:Culicidae / Q000821:virology; D004305:Dose-Response Relationship, Drug; D004669:Encephalitis Viruses, Tick-Borne / Q000187:drug effects* / Q000472:pathogenicity; D004675:Encephalitis, Tick-Borne / Q000635:transmission / Q000821:virology; D005416:Flavivirus / Q000187:drug effects*; D011684:Purine Nucleosides / Q000037:antagonists & inhibitors* / Q000737:chemistry; D011759:Pyrrolidines; D013552:Swine; D017282:Tick-Borne Diseases; D013987:Ticks / Q000821:virology; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects; D014902:West Nile virus / Q000187:drug effects* / Q000472:pathogenicity
D000998:Antiviral Agents; D011684:Purine Nucleosides; D011759:Pyrrolidines; D000225:Adenine; D000241:Adenosine; C517546:galidesivir
Adenosine analogue; Antiviral activity; BCX4430; Cytotoxicity; Flavivirus; Nucleoside inhibitor