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
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Czech description
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Classification
Type
J<sub>imp</sub> - Article in a specialist periodical, which is included in the Web of Science database
CEP classification
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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
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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