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

Kód výsledku v IS VaVaI

<a href="https://www.isvavai.cz/riv?ss=detail&h=RIV%2F60077344%3A_____%2F21%3A00541187" target="_blank" >RIV/60077344:_____/21:00541187 - isvavai.cz</a>

Nalezeny alternativní kódy

RIV/68081766:_____/21:00541187 RIV/62156489:43210/21:43919222 RIV/00216305:26220/21:PU142174 RIV/00216224:14110/21:00121049

Výsledek na webu

<a href="https://aac.asm.org/content/65/2/e01522-20" target="_blank" >https://aac.asm.org/content/65/2/e01522-20</a>

DOI - Digital Object Identifier

<a href="http://dx.doi.org/10.1128/AAC.01522-20" target="_blank" >10.1128/AAC.01522-20</a>

Jazyk výsledku

angličtina

Název v původním jazyce

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

Popis výsledku v původním jazyce

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.

Název v anglickém jazyce

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

Popis výsledku anglicky

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.

Druh

J_imp - Článek v periodiku v databázi Web of Science

CEP obor

—

OECD FORD obor

10606 - Microbiology

Projekt

—

Návaznosti

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Rok uplatnění

2021

Kód důvěrnosti údajů

S - Úplné a pravdivé údaje o projektu nepodléhají ochraně podle zvláštních právních předpisů

Název periodika

Antimicrobial Agents and Chemotherapy

ISSN

0066-4804

e-ISSN

1098-6596

Svazek periodika

65

Číslo periodika v rámci svazku

2

Stát vydavatele periodika

US - Spojené státy americké

Počet stran výsledku

45

Strana od-do

e01522-20

Kód UT WoS článku

000609954100018

EID výsledku v databázi Scopus

2-s2.0-85099983413