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An E460D Substitution in the NS5 Protein of Tick-Borne Encephalitis Virus Confers Resistance to the Inhibitor Galidesivir (BCX4430) and Also Attenuates the Virus for Mice
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SYSNO ASEP 0519417 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název An E460D Substitution in the NS5 Protein of Tick-Borne Encephalitis Virus Confers Resistance to the Inhibitor Galidesivir (BCX4430) and Also Attenuates the Virus for Mice Tvůrce(i) Eyer, Luděk (BC-A) RID, ORCID
Nougairede, A. (FR)
Uhlířová, M. (DE)
Driouich, J.-S. (FR)
Zouharová, D. (CZ)
Valdés, James J. (BC-A) RID, ORCID
Haviernik, J. (CZ)
Gould, E. A. (FR)
De Clercq, E. (BE)
de Lamballerie, X. (FR)
Růžek, Daniel (BC-A) RID, ORCIDCelkový počet autorů 11 Číslo článku e00367-19 Zdroj.dok. Journal of Virology - ISSN 0022-538X
Roč. 93, č. 16 (2019)Poč.str. 28 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova zika virus ; nucleoside analog ; polymerase ; culture ; fever ; dna ; bcx4430 ; galidesivir ; attenuation ; drug resistance ; mutation ; tick-borne encephalitis virus Vědní obor RIV EE - Mikrobiologie, virologie Obor OECD Microbiology CEP NV16-34238A GA MZd - Ministerstvo zdravotnictví Způsob publikování Open access Institucionální podpora BC-A - RVO:60077344 UT WOS 000480711400011 EID SCOPUS 85070760036 DOI 10.1128/JVI.00367-19 Anotace The adenosine analogue galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, has entered a phase 1 clinical safety and pharmacokinetics study in healthy subjects and is under clinical development for treatment of Ebola and yellow fever virus infections. Moreover, galidesivir also inhibits the reproduction of tick-borne encephalitis virus (TBEV) and numerous other medically important flaviviruses. Until now, studies of this antiviral agent have not yielded resistant viruses. Here, we demonstrate that an E460D substitution in the active site of TBEV RNA-dependent RNA polymerase (RdRp) confers resistance to galidesivir in cell culture. Galidesivir-resistant TBEV exhibited no cross-resistance to structurally different antiviral nucleoside analogues, such as 7-deaza-2'-C-methyladenosine, 2'-C-methyladenosine, and 4'-azido-aracytidine. Although the E460D substitution led to only a subtle decrease in viral fitness in cell culture, galidesivir-resistant TBEV was highly attenuated in vivo, with a 100% survival rate and no clinical signs observed in infected mice. Furthermore, no virus was detected in the sera, spleen, or brain of mice inoculated with the galidesivir-resistant TBEV. Our results contribute to understanding the molecular basis of galidesivir antiviral activity, flavivirus resistance to nucleoside inhibitors, and the potential contribution of viral RdRp to flavivirus neurovirulence. Pracoviště Biologické centrum (od r. 2006) Kontakt Dana Hypšová, eje@eje.cz, Tel.: 387 775 214 Rok sběru 2020 Elektronická adresa https://jvi.asm.org/content/jvi/early/2019/05/23/JVI.00367-19.full.pdf
Počet záznamů: 1