title: Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase.
abstract: We describe the expression and purification of an active recombinant Zika virus RNA-dependent RNA polymerase (RdRp). Next, we present the development and optimization of an in vitro assay to measure its activity. We then applied the assay to selected triphosphate analogs and discovered that 2'-C-methylated nucleosides exhibit strong inhibitory activity. Surprisingly, also carbocyclic derivatives with the carbohydrate locked in a North-like conformation as well as a ribonucleotide with a South conformation exhibited strong activity. Our results suggest that the traditional 2'-C-methylated nucleosides pursued in the race for anti-HCV treatment can be superseded by brand new scaffolds in the case of the Zika virus.
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Kamil
authors.initials: K
authors.lastname: Hercík
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Kozak
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Michal
authors.initials: M
authors.lastname: Šála
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Milan
authors.initials: M
authors.lastname: Dejmek
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Hubert
authors.initials: H
authors.lastname: Hřebabecký
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Eva
authors.initials: E
authors.lastname: Zborníková
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia.
authors.forename: Miroslav
authors.initials: M
authors.lastname: Smola
authors.affiliation: Veterinary Research Institute, Hudcova 70, CZ-62100 Brno, Czechia; Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Branisovska 31, CZ-37005 Ceske Budejovice, Czechia.
authors.forename: Daniel
authors.initials: D
authors.lastname: Ruzek
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia. Electronic address: nencka@uochb.cas.cz.
authors.forename: Radim
authors.initials: R
authors.lastname: Nencka
authors.affiliation: Institute of Organic Chemistry and Biochemistry AS CR, v.v.i., Flemingovo nam. 2, 166 10 Prague 6, Czechia. Electronic address: boura@uochb.cas.cz.
authors.forename: Evzen
authors.initials: E
authors.lastname: Boura
mesh_terms: D000255:Adenosine Triphosphate / Q000031:analogs & derivatives* / Q000737:chemistry; D000998:Antiviral Agents / Q000494:pharmacology*; D055808:Drug Discovery; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D006801:Humans; D008968:Molecular Conformation; D009705:Nucleosides / Q000737:chemistry / Q000494:pharmacology*; D012324:RNA-Dependent RNA Polymerase / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000302:isolation & purification; D000071244:Zika Virus / Q000187:drug effects* / Q000201:enzymology
chemical_list: D000998:Antiviral Agents; D004791:Enzyme Inhibitors; D009705:Nucleosides; D000255:Adenosine Triphosphate; D012324:RNA-Dependent RNA Polymerase