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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
L. Eyer, A. Nougairède, M. Uhlířová, JS. Driouich, D. Zouharová, JJ. Valdés, J. Haviernik, EA. Gould, E. De Clercq, X. de Lamballerie, D. Ruzek,
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
NV16-34238A
MZ0
CEP - Centrální evidence projektů
Digitální knihovna NLK
Plný text - Článek
Freely Accessible Science Journals od 1967 do Před 6 měsíci
PubMed Central od 1967 do Před 6 měsíci
Europe PubMed Central od 1967 do Před 6 měsíci
Open Access Digital Library od 1967-02-01
Open Access Digital Library od 1967-02-01
Odkazy
PubMed
31142664
DOI
10.1128/jvi.00367-19
Knihovny.cz E-zdroje
- MeSH
- adenin analogy a deriváty chemie farmakologie MeSH
- alely MeSH
- antibiotická rezistence MeSH
- antivirové látky chemie farmakologie MeSH
- buněčné linie MeSH
- genotyp MeSH
- klíšťová encefalitida farmakoterapie virologie MeSH
- modely nemocí na zvířatech MeSH
- mutace * MeSH
- myši MeSH
- pyrrolidiny chemie farmakologie MeSH
- substituce aminokyselin * MeSH
- virová léková rezistence * MeSH
- virové nestrukturální proteiny genetika MeSH
- viry klíšťové encefalitidy účinky léků fyziologie MeSH
- zvířata MeSH
- Check Tag
- myši MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
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.IMPORTANCE Tick-borne encephalitis virus (TBEV) is a pathogen that causes severe human neuroinfections in Europe and Asia and for which there is currently no specific therapy. We have previously found that galidesivir (BCX4430), a broad-spectrum RNA virus inhibitor, which is under clinical development for treatment of Ebola and yellow fever virus infections, has a strong antiviral effect against TBEV. For any antiviral drug, it is important to generate drug-resistant mutants to understand how the drug works. Here, we produced TBEV mutants resistant to galidesivir and found that the resistance is caused by a single amino acid substitution in an active site of the viral RNA-dependent RNA polymerase, an enzyme which is crucial for replication of the viral RNA genome. Although this substitution led only to a subtle decrease in viral fitness in cell culture, galidesivir-resistant TBEV was highly attenuated in a mouse model. Our results contribute to understanding the molecular basis of galidesivir antiviral activity.
Department of Virology Veterinary Research Institute Brno Czech Republic
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