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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

The result's identifiers

  • Result code in IS VaVaI

    <a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F19%3A00519417" target="_blank" >RIV/60077344:_____/19:00519417 - isvavai.cz</a>

  • Result on the web

    <a href="https://jvi.asm.org/content/jvi/early/2019/05/23/JVI.00367-19.full.pdf" target="_blank" >https://jvi.asm.org/content/jvi/early/2019/05/23/JVI.00367-19.full.pdf</a>

  • DOI - Digital Object Identifier

    <a href="http://dx.doi.org/10.1128/JVI.00367-19" target="_blank" >10.1128/JVI.00367-19</a>

Alternative languages

  • Result language

    angličtina

  • Original language name

    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

  • Original language description

    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.

  • Czech name

  • Czech description

Classification

  • Type

    J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database

  • CEP classification

  • OECD FORD branch

    10606 - Microbiology

Result continuities

  • Project

    <a href="/en/project/NV16-34238A" target="_blank" >NV16-34238A: Development and testing of novel perspective antivirals and their prodrug forms active against tick-borne encephalitis virus</a><br>

  • Continuities

    I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Others

  • Publication year

    2019

  • Confidentiality

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

Data specific for result type

  • Name of the periodical

    Journal of Virology

  • ISSN

    1098-5514

  • e-ISSN

  • Volume of the periodical

    93

  • Issue of the periodical within the volume

    16

  • Country of publishing house

    US - UNITED STATES

  • Number of pages

    28

  • Pages from-to

    e00367-19

  • UT code for WoS article

    000480711400011

  • EID of the result in the Scopus database

    2-s2.0-85070760036