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 (203 Česká republika), Martina FOJTÍKOVÁ (203 Česká republika), Radim NENCKA, Ivo RUDOLF (203 Česká republika, domácí), Zdeněk HUBÁLEK (203 Česká republika, domácí) a Daniel RŮŽEK (203 Česká republika, garant)

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

Kód RIV

RIV/00216224:14310/19:00109098

Organizační jednotka

Přírodovědecká fakulta

DOI

http://dx.doi.org/10.1128/AAC.02093-18

UT WoS

000459683500026

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 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://dx.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 = {http://dx.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://dx.doi.org/10.1128/AAC.02093-18.

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