Publication details
Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses
| Authors | |
|---|---|
| Year of publication | 2021 |
| Type | Article in Periodical |
| Magazine / Source | Antimicrobial Agents and Chemotherapy |
| MU Faculty or unit | |
| Citation | |
| Web | https://aac.asm.org/content/65/2/e01522-20 |
| Doi | http://dx.doi.org/10.1128/AAC.01522-20 |
| Keywords | nucleoside analogue; 39-deoxy-39-fluoroadenosine; flavivirus; tick-borne encephalitis virus; antiviral activity; cytotoxicity; mouse model |
| Description | 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 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 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. |