2. Academic Validation
  3. Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'-Fluoroadenosine against Emerging Flaviviruses

Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'-Fluoroadenosine against Emerging Flaviviruses

  • Antimicrob Agents Chemother. 2021 Jan 20;65(2):e01522-20. doi: 10.1128/AAC.01522-20.
Luděk Eyer # 1 2,  Pavel Svoboda # 3 4,  Jan Balvan 5 6,  Tomáš Vičar 5 7,  Matina Raudenská 6 8,  Michal Štefánik 3 6,  Jan Haviernik 3 9,  Ivana Huvarová 3,  Petra Straková 3,  Ivo Rudolf 10 9,  Zdeněk Hubálek 10,  Katherine Seley-Radtke 11,  Erik de Clercq 12,  Daniel Růžek 3 2
Affiliations

Affiliations

  • 1 Department of Virology, Veterinary Research Institute, Brno, Czech Republic eyer@vri.cz.
  • 2 Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, Ceske Budejovice, Czech Republic.
  • 3 Department of Virology, Veterinary Research Institute, Brno, Czech Republic.
  • 4 Department of Pharmacology and Pharmacy, Faculty of Veterinary Medicine, University of Verterinary and Pharmaceutical Sciences Brno, Brno, Czech Republic.
  • 5 Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 6 Department of Chemistry and Biochemistry, Mendel University in Brno, Brno, Czech Republic.
  • 7 Department of Biomedical Engineering, Faculty of Electrical Engineering and Communication, Brno University of Technology, Brno, Czech Republic.
  • 8 Department of Physiology, Faculty of Medicine, Masaryk University, Brno, Czech Republic.
  • 9 Department of Experimental Biology, Masaryk University, Brno, Czech Republic.
  • 10 Institute of Vertebrate Biology, Czech Academy of Sciences, Brno, Czech Republic.
  • 11 Department of Chemistry and Biochemistry, University of Maryland, Baltimore County, Baltimore, Maryland, USA.
  • 12 Rega Institute for Medical Research, KU Leuven, Leuven, Belgium.
  • # Contributed equally.
PMID: 33229424 DOI: 10.1128/AAC.01522-20
Abstract

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 3'-deoxy-3'-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 μM to 4.7 ± 1.5 μM), 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 μM but had an observable cytostatic effect, resulting in suppression of cell proliferation at concentrations of >12.5 μM. Novel approaches based on quantitative phase imaging using holographic microscopy were developed for advanced characterization of Antiviral and cytotoxic profiles of 3'-deoxy-3'-fluoroadenosine in vitro In addition to its Antiviral activity in cell cultures, 3'-deoxy-3'-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.

Keywords

3′-deoxy-3′-fluoroadenosine; antiviral activity; cytotoxicity; flavivirus; mouse model; nucleoside analogue; tick-borne encephalitis virus.

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