Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2´-C-methyladenosine prevents death in a mouse model of West Nile virus infection

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F00027162%3A_____%2F19%3AN0000250" target="_blank" >RIV/00027162:_____/19:N0000250 - isvavai.cz</a>

Výsledek na webu

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DOI - Digital Object Identifier

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Jazyk výsledku

angličtina

Název v původním jazyce

Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2´-C-methyladenosine prevents death in a mouse model of West Nile virus infection

Popis výsledku v původním jazyce

32nd International Conference on Antiviral Research (ICAR), Baltimore, 12.-15.5.2019 - Poster. West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans. No approved antiviral therapy is currently available against WNV infection. In this study, we have evaluated the antiviral activity and cytotoxicity of 2´-C-methyl-, 2´-O-methyl-, 3´-O-methyl-, 3´-deoxy-, and 4´-azido-modified nucleosides in vitro. Our results demonstrate that 2´-C-methyl- or 4´-azido-modified nucleosides are highly effective inhibitors of WNV replication (strains Eg-101 and 13-104), showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. 7-Deaza-2´-C-methyladenosine, a representative of C2´-methylated nucleosides, significantly protected WNV-infected mice from disease progression and mortality. Treatment at 25 mg/kg (twice daily) starting at the time of infection (day 0) resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days post-infection, 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 post-infection (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 and 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.

Název v anglickém jazyce

Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2´-C-methyladenosine prevents death in a mouse model of West Nile virus infection

Popis výsledku anglicky

32nd International Conference on Antiviral Research (ICAR), Baltimore, 12.-15.5.2019 - Poster. West Nile virus (WNV) is a medically important emerging arbovirus causing serious neuroinfections in humans. No approved antiviral therapy is currently available against WNV infection. In this study, we have evaluated the antiviral activity and cytotoxicity of 2´-C-methyl-, 2´-O-methyl-, 3´-O-methyl-, 3´-deoxy-, and 4´-azido-modified nucleosides in vitro. Our results demonstrate that 2´-C-methyl- or 4´-azido-modified nucleosides are highly effective inhibitors of WNV replication (strains Eg-101 and 13-104), showing nanomolar or low micromolar anti-WNV activity and negligible cytotoxicity in cell culture. 7-Deaza-2´-C-methyladenosine, a representative of C2´-methylated nucleosides, significantly protected WNV-infected mice from disease progression and mortality. Treatment at 25 mg/kg (twice daily) starting at the time of infection (day 0) resulted in 100% survival of the mice. This compound was highly effective, even if the treatment was initiated 3 days post-infection, 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 post-infection (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 and 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.

Druh

O - Ostatní výsledky

CEP obor

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OECD FORD obor

10607 - Virology

Projekt

<a href="/cs/project/GA16-20054S" target="_blank" >GA16-20054S: Pokročilé studie patogeneze západonilské virové horečky směřující k novým terapeutickým strategiím</a><br>

Návaznosti

P - Projekt vyzkumu a vyvoje financovany z verejnych zdroju (s odkazem do CEP)

Rok uplatnění

2019

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů