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

J 2019

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

EYER, Luděk; Martina FOJTÍKOVÁ; Radim NENCKA; Ivo RUDOLF; Zdeněk HUBÁLEK et al.

Základní údaje

Originální název

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

Autoři

EYER, Luděk; Martina FOJTÍKOVÁ; Radim NENCKA; Ivo RUDOLF; Zdeněk HUBÁLEK a Daniel RŮŽEK

Vydání

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY, Washington, D.C. AMER SOC MICROBIOLOGY, 2019, 0066-4804

Další údaje

Jazyk

angličtina

Typ výsledku

Článek v odborném periodiku

Obor

10606 Microbiology

Stát vydavatele

Spojené státy

Utajení

není předmětem státního či obchodního tajemství

Odkazy

Full Text

Impakt faktor

Impact factor: 4.904

Označené pro přenos do RIV

Ano

Kód RIV

RIV/00216224:14310/19:00109098

Organizační jednotka

Přírodovědecká fakulta

Klíčová slova anglicky

West Nile virus; antiviral agents; flavivirus; nucleoside analogs

Štítky

rivok

Příznaky

Mezinárodní význam, Recenzováno

Změněno: 16. 3. 2020 12:03, Mgr. Marie Novosadová Šípková, DiS.

Anotace

V originále

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=-Cmethyladenosine, 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=-Cmethyladenosine 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.

Citovat

EYER, Luděk; Martina FOJTÍKOVÁ; Radim NENCKA; Ivo RUDOLF; Zdeněk HUBÁLEK a Daniel RŮŽEK. 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. Washington, D.C.: AMER SOC MICROBIOLOGY, 2019, roč. 63, č. 3, s. 1-14. ISSN 0066-4804. Dostupné z: https://doi.org/10.1128/AAC.02093-18.

@article{1494116,
   author = {Eyer, Luděk and Fojtíková, Martina and Nencka, Radim and Rudolf, Ivo and Hubálek, Zdeněk and Růžek, Daniel},
   article_location = {Washington, D.C.},
   article_number = {3},
   doi = {https://doi.org/10.1128/AAC.02093-18},
   keywords = {West Nile virus; antiviral agents; flavivirus; nucleoside analogs},
   language = {eng},
   issn = {0066-4804},
   journal = {ANTIMICROBIAL AGENTS AND CHEMOTHERAPY},
   title = {Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2'-C-methyladenosine prevents death in a mouse model of West Nile virus infection},
   url = {https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395895/},
   volume = {63},
   year = {2019}
}

TY  - JOUR
ID  - 1494116
AU  - Eyer, Luděk - Fojtíková, Martina - Nencka, Radim - Rudolf, Ivo - Hubálek, Zdeněk - Růžek, Daniel
PY  - 2019
TI  - Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2'-C-methyladenosine prevents death in a mouse model of West Nile virus infection
JF  - ANTIMICROBIAL AGENTS AND CHEMOTHERAPY
VL  - 63
IS  - 3
SP  - 1-14
EP  - 1-14
PB  - AMER SOC MICROBIOLOGY
SN  - 00664804
KW  - West Nile virus
KW  - antiviral agents
KW  - flavivirus
KW  - nucleoside analogs
UR  - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395895/
L2  - https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6395895/
N2  - 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=-Cmethyladenosine, 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=-Cmethyladenosine 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.
ER  -

EYER, Luděk; Martina FOJTÍKOVÁ; Radim NENCKA; Ivo RUDOLF; Zdeněk HUBÁLEK a Daniel RŮŽEK. Viral RNA-dependent RNA polymerase inhibitor 7-deaza-2'-C-methyladenosine prevents death in a mouse model of West Nile virus infection. \textit{ANTIMICROBIAL AGENTS AND CHEMOTHERAPY}. Washington, D.C.: AMER SOC MICROBIOLOGY, 2019, roč.~63, č.~3, s.~1-14. ISSN~0066-4804. Dostupné z: https://doi.org/10.1128/AAC.02093-18.

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