Viral RNA-Dependent RNA Polymerase Inhibitor 7-Deaza-2 '-C-Methyladenosine Prevents Death in a Mouse Model of West Nile Virus Infection

0511116 - BC 2020 RIV US eng J - Článek v odborném periodiku
Eyer, Luděk - Fojtiková, M. - Nencka, Radim - Rudolf, Ivo - Hubálek, Zdeněk - Růžek, Daniel
Viral RNA-Dependent RNA Polymerase Inhibitor 7-Deaza-2 '-C-Methyladenosine Prevents Death in a Mouse Model of West Nile Virus Infection.
Antimicrobial Agents and Chemotherapy. Roč. 63, č. 3 (2019), č. článku e02093-18. ISSN 0066-4804. E-ISSN 1098-6596
Grant CEP: GA ČR(CZ) GA16-20054S
Institucionální podpora: RVO:60077344 ; RVO:68081766 ; RVO:61388963
Klíčová slova: adenosine nucleoside inhibitor * hepatitis-c * tick-borne * dengue virus * uridine phosphorylase * antiviral activity * zika virus * new-york * replication * encephalitis * West Nile virus * antiviral agents * flavivirus * nucleoside analogs
Obor OECD: Microbiology; Microbiology (UBO-W); Virology (UOCHB-X)
Impakt faktor: 4.904, rok: 2019
Způsob publikování: Open access
https://aac.asm.org/content/aac/63/3/e02093-18.full.pdf

West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans and against which no approved antiviral therapy is currently available. In this study, we demonstrate that 2'-C-methyl- or 4'-azido-modified nucleosides are highly effective inhibitors of WNV replication, showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. One representative of C2'-methylated nucleosides, 7-deaza-2'-C-methyladenosine, significantly protected WNV-infected mice from disease progression and mortality. Twice daily treatment at 25 mg/kg starting at the time of infection resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days postinfection, at the time of a peak of viremia, which resulted in a 90% survival rate. However, the antiviral effect of 7-deaza-2'-C-methyladenosine was absent or negligible when the treatment was started 8 days postinfection (i.e., at the time of extensive brain infection). The 4'-azido moiety appears to be another important determinant for highly efficient inhibition of WNV replication in vitro. However, the strong anti-WNV effect of 4'-azidocytidine and 4'-azido-aracytidine was cell type dependent and observed predominantly in porcine kidney stable (PS) cells. The effect was much less pronounced in Vero cells. Our results indicate that 2'-C-methylated or 4'-azidated nucleosides merit further investigation as potential therapeutic agents for treating WNV infections as well as infections caused by other medically important flaviviruses.
Trvalý link: http://hdl.handle.net/11104/0301436