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%2F60077344%3A_____%2F19%3A00511116" target="_blank" >RIV/60077344:_____/19:00511116 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68081766:_____/19:00511116 RIV/61388963:_____/19:00511116 RIV/00027162:_____/19:N0000248 RIV/00216224:14310/19:00109098

Výsledek na webu

<a href="https://aac.asm.org/content/aac/63/3/e02093-18.full.pdf" target="_blank" >https://aac.asm.org/content/aac/63/3/e02093-18.full.pdf</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1128/AAC.02093-18" target="_blank" >10.1128/AAC.02093-18</a>

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

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.

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

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

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

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2019

Kód důvěrnosti údajů

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

Název periodika

Antimicrobial Agents and Chemotherapy

ISSN

0066-4804

e-ISSN

—

Svazek periodika

63

Číslo periodika v rámci svazku

3

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

14

Strana od-do

e02093-18

Kód UT WoS článku

000459683500026

EID výsledku v databázi Scopus

2-s2.0-85062297115