Publication detail

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

EYER, L. SVOBODA, P. BALVAN, J. VIČAR, T. RAUDENSKÁ, M. ŠTEFÁNIK, M. HAVIERNIK, J. HUVAROVÁ, I. STRAKOVÁ, P. RUDOLF, I. HUBÁLEK, Z. SELEY-RADTKE, K. DE CLERCQ, E. RŮŽEK, D.

Original Title

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

Type

journal article in Web of Science

Language

English

Original 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 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.

Keywords

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

Authors

EYER, L.; SVOBODA, P.; BALVAN, J.; VIČAR, T.; RAUDENSKÁ, M.; ŠTEFÁNIK, M.; HAVIERNIK, J.; HUVAROVÁ, I.; STRAKOVÁ, P.; RUDOLF, I.; HUBÁLEK, Z.; SELEY-RADTKE, K.; DE CLERCQ, E.; RŮŽEK, D.

Released

20. 1. 2021

Publisher

AMER SOC MICROBIOLOGY

Location

WASHINGTON

ISBN

0066-4804

Periodical

ANTIMICROBIAL AGENTS AND CHEMOTHERAPY

Year of study

65

Number

2

State

United States of America

Pages from

1

Pages to

19

Pages count

19

URL

https://journals.asm.org/doi/full/10.1128/AAC.01522-20

BibTex

@article{BUT173251,
  author="Luděk {Eyer} and Pavel {Svoboda} and Jan {Balvan} and Tomáš {Vičar} and Martina {Raudenská} and Michal {Štefánik} and Jan {Haviernik} and Ivana {Huvarová} and Petra {Straková} and Ivo {Rudolf} and Zdeněk {Hubálek} and Katherine {Seley-Radtke} and Erik {de Clercq} and Daniel {Růžek}",
  title="Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses",
  journal="ANTIMICROBIAL AGENTS AND CHEMOTHERAPY",
  year="2021",
  volume="65",
  number="2",
  pages="1--19",
  doi="10.1128/AAC.01522-20",
  issn="0066-4804",
  url="https://journals.asm.org/doi/full/10.1128/AAC.01522-20"
}