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

0519417 - BC 2020 RIV US eng J - Journal Article
Eyer, Luděk - Nougairede, A. - Uhlířová, M. - Driouich, J.-S. - Zouharová, D. - Valdés, James J. - Haviernik, J. - Gould, E. A. - De Clercq, E. - de Lamballerie, X. - Růžek, Daniel
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.
Journal of Virology. Roč. 93, č. 16 (2019), č. článku e00367-19. ISSN 0022-538X. E-ISSN 1098-5514
R&D Projects: GA MZd(CZ) NV16-34238A
Institutional support: RVO:60077344
Keywords : zika virus * nucleoside analog * polymerase * culture * fever * dna * bcx4430 * galidesivir * attenuation * drug resistance * mutation * tick-borne encephalitis virus
OECD category: Microbiology
Impact factor: 4.501, year: 2019
Method of publishing: Open access
https://jvi.asm.org/content/jvi/early/2019/05/23/JVI.00367-19.full.pdf

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.
Permanent Link: http://hdl.handle.net/11104/0304389