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

Result code in 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>

Alternative codes found

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

Result on the web

<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>

Result language

angličtina

Original language name

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

Original language 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 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.

Czech name

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Czech description

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Type

J_imp - Article in a specialist periodical, which is included in the Web of Science database

CEP classification

—

OECD FORD branch

10606 - Microbiology

Project

—

Continuities

I - Institucionalni podpora na dlouhodoby koncepcni rozvoj vyzkumne organizace

Publication year

2021

Confidentiality

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

Name of the periodical

Antimicrobial Agents and Chemotherapy

ISSN

0066-4804

e-ISSN

1098-6596

Volume of the periodical

65

Issue of the periodical within the volume

2

Country of publishing house

US - UNITED STATES

Number of pages

45

Pages from-to

e01522-20

UT code for WoS article

000609954100018

EID of the result in the Scopus database

2-s2.0-85099983413