Broad-spectrum antiviral activity of 3′-deoxy-3′-fluoroadenosine against emerging flaviviruses

0541187 - BC 2022 RIV US eng J - Journal Article
Eyer, Luděk - Svoboda, P. - Balvan, J. - Vicar, T. - Raudenská, M. - Štefánik, M. - Haviernik, J. - Huvarová, I. - Straková, P. - Rudolf, Ivo - Hubálek, Zdeněk - Seley-Radtke, K. - De Clercq, E. - Růžek, Daniel
Broad-spectrum antiviral activity of 3′-deoxy-3′-fluoroadenosine against emerging flaviviruses.
Antimicrobial Agents and Chemotherapy. Roč. 65, č. 2 (2021), č. článku e01522-20. ISSN 0066-4804. E-ISSN 1098-6596
R&D Projects: GA MŠMT(CZ) LTAUSA18016
Institutional support: RVO:60077344 ; RVO:68081766
Keywords : west nile virus * selective-inhibition * error catastrophe * in-vitro * borne * sofosbuvir * analogs * targets * future * agents * nucleoside analogue * 3'-deoxy-3'-fluoroadenosine * flavivirus * tick-borne encephalitis virus * antiviral activity * cytotoxicity * mouse model
OECD category: Microbiology; Microbiology (UBO-W)
Impact factor: 5.938, year: 2021
Method of publishing: Open access
https://aac.asm.org/content/65/2/e01522-20

Emerging flaviviruses are causative agents of severe and life-threatening diseases, against which no approved therapies are available. Among the nucleoside analogues, which represent a promising group of potentially therapeutic compounds, fluorine-substituted nucleosides are characterized by unique structural and functional properties. Despite having first been synthesized almost 5 decades ago, they still offer new therapeutic opportunities as inhibitors of essential viral or cellular enzymes active in nucleic acid replication/transcription or nucleoside/nucleotide metabolism. Here, we report evaluation of the antiflaviviral activity of 28 nucleoside analogues, each modified with a fluoro substituent at different positions of the ribose ring and/or heterocyclic nucleobase. Our antiviral screening revealed that 39deoxy-39-fluoroadenosine exerted a low-micromolar antiviral effect against tick-borne encephalitis virus (TBEV), Zika virus, and West Nile virus (WNV) (EC50 values from 1.1 +/- 0.1 mu M to 4.7 +/- 1.5 mu M), which was manifested in host cell lines of neural and extraneural origin. The compound did not display any measurable cytotoxicity up to concentrations of 25 mu M but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of > 12.5 mu M. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of antiviral and cytotoxic profiles of 39-deoxy-39-fluoroadenosine in vitro. In addition to its antiviral activity in cell cultures, 39-deoxy-39-fluoroadenosine was active in vivo in mouse models of TBEV and WNV infection. Our results demonstrate that fluoro-modified nucleosides represent a group of bioactive molecules with excellent potential to serve as prospective broad-spectrum antivirals in antiviral research and drug development.
Permanent Link: http://hdl.handle.net/11104/0318790