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Broad-spectrum antiviral activity of 3′-deoxy-3′-fluoroadenosine against emerging flaviviruses
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SYSNO ASEP 0541187 Document Type J - Journal Article R&D Document Type Journal Article Subsidiary J Článek ve WOS Title Broad-spectrum antiviral activity of 3′-deoxy-3′-fluoroadenosine against emerging flaviviruses Author(s) Eyer, Luděk (BC-A) RID, ORCID
Svoboda, P. (CZ)
Balvan, J. (CZ)
Vicar, T. (CZ)
Raudenská, M. (CZ)
Štefánik, M. (CZ)
Haviernik, J. (CZ)
Huvarová, I. (CZ)
Straková, P. (CZ)
Rudolf, Ivo (UBO-W) RID, ORCID, SAI
Hubálek, Zdeněk (UBO-W) RID, SAI, ORCID
Seley-Radtke, K. (US)
De Clercq, E. (BE)
Růžek, Daniel (BC-A) RID, ORCIDNumber of authors 14 Article number e01522-20 Source Title Antimicrobial Agents and Chemotherapy. - : American Society for Microbiology - ISSN 0066-4804
Roč. 65, č. 2 (2021)Number of pages 45 s. Publication form Online - E Language eng - English Country US - United States Keywords west nile virus ; selective-inhibition ; error catastrophe ; in-vitro ; borne ; sofosbuvir ; analogs ; targets ; future ; agents ; nucleoside analogue ; 3'-deoxy-3'-fluoroadenosine ; flavivirus ; tick-borne encephalitis virus ; antiviral activity ; cytotoxicity ; mouse model Subject RIV EE - Microbiology, Virology OECD category Microbiology Subject RIV - cooperation Institute of Vertebrate Biology - Microbiology, Virology R&D Projects LTAUSA18016 GA MŠMT - Ministry of Education, Youth and Sports (MEYS) Method of publishing Open access Institutional support BC-A - RVO:60077344 ; UBO-W - RVO:68081766 UT WOS 000609954100018 EID SCOPUS 85099983413 DOI 10.1128/AAC.01522-20 Annotation 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. Workplace Biology Centre (since 2006) Contact Dana Hypšová, eje@eje.cz, Tel.: 387 775 214 Year of Publishing 2022 Electronic address https://aac.asm.org/content/65/2/e01522-20
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