Počet záznamů: 1
Escape of Tick-Borne Flavivirus from 2'-C-Methylated Nucleoside Antivirals Is Mediated by a Single Conservative Mutation in NS5 That Has a Dramatic Effect on Viral Fitness
- 1.
SYSNO ASEP 0482878 Druh ASEP J - Článek v odborném periodiku Zařazení RIV J - Článek v odborném periodiku Poddruh J Článek ve WOS Název Escape of Tick-Borne Flavivirus from 2'-C-Methylated Nucleoside Antivirals Is Mediated by a Single Conservative Mutation in NS5 That Has a Dramatic Effect on Viral Fitness Tvůrce(i) Eyer, Luděk (BC-A) RID, ORCID
Kondo, H. (JP)
Zouharová, D. (CZ)
Hirano, M. (JP)
Valdés, James J. (BC-A) RID, ORCID
Muto, M. (JP)
Kastl, T. (CZ)
Kobayashi, S. (JP)
Haviernik, J. (CZ)
Igarashi, K. (JP)
Kariwa, H. (JP)
Vaculovicova, M. (CZ)
Černý, Jiří (BC-A)
Kizek, R. (CZ)
Kroeger, A. (DE)
Lienenklaus, S. (DE)
Dejmek, Milan (UOCHB-X) RID, ORCID
Nencka, Radim (UOCHB-X) RID, ORCID
Palus, Martin (BC-A) RID, ORCID
Salát, J. (CZ)
De Clercq, E. (BE)
Yoshii, K. (JP)
Růžek, Daniel (BC-A) RID, ORCIDCelkový počet autorů 23 Číslo článku e01028-17 Zdroj.dok. Journal of Virology - ISSN 0022-538X
Roč. 91, č. 21 (2017)Poč.str. 20 s. Forma vydání Online - E Jazyk dok. eng - angličtina Země vyd. US - Spojené státy americké Klíč. slova antiviral agents ; antiviral therapy ; escape mutant ; tick-borne ; encephalitis virus ; tick-borne pathogens Vědní obor RIV EE - Mikrobiologie, virologie Obor OECD Virology CEP NV16-34238A GA MZd - Ministerstvo zdravotnictví Institucionální podpora BC-A - RVO:60077344 ; UOCHB-X - RVO:61388963 UT WOS 000413195400026 EID SCOPUS 85031099670 DOI 10.1128/JVI.01028-17 Anotace Tick-borne encephalitis virus (TBEV) causes a severe and potentially fatal neuroinfection in humans. Despite its high medical relevance, no specific antiviral therapy is currently available. Here we demonstrate that treatment with a nucleoside analog, 7-deaza-2'-C-methyladenosine (7-deaza-2'-CMA), substantially improved disease outcomes, increased survival, and reduced signs of neuroinfection and viral titers in the brains of mice infected with a lethal dose of TBEV. To investigate the mechanism of action of 7-deaza-2'-CMA, two drug-resistant TBEV clones were generated and characterized. The two clones shared a signature amino acid substitution, S603T, in the viral NS5 RNA-dependent RNA polymerase (RdRp) domain. This mutation conferred resistance to various 2'-C-methylated nucleoside derivatives, but no cross-resistance was seen with other nucleoside analogs, such as 4'-C-azidocytidine and 2'-deoxy-2'-beta-hydroxy-4'-azidocytidine (RO-9187). All-atom molecular dynamics simulations revealed that the S603T RdRp mutant repels a water molecule that coordinates the position of a metal ion cofactor as 2'-C-methylated nucleoside analogs approach the active site. To investigate its phenotype, the S603T mutation was introduced into a recombinant TBEV strain (Oshima-IC) generated from an infectious cDNA clone and into a TBEV replicon that expresses a reporter luciferase gene (Oshima-REP- luc2A). The mutants were replication impaired, showing reduced growth and a small plaque size in mammalian cell culture and reduced levels of neuroinvasiveness and neurovirulence in rodent models. These results indicate that TBEV resistance to 2'-C-methylated nucleoside inhibitors is conferred by a single conservative mutation that causes a subtle atomic effect within the active site of the viral NS5 RdRp and is associated with strong attenuation of the virus. Pracoviště Biologické centrum (od r. 2006) Kontakt Dana Hypšová, eje@eje.cz, Tel.: 387 775 214 Rok sběru 2018
Počet záznamů: 1