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

J 2021

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

EYER, Luděk, Pavel SVOBODA, Jan BALVAN, Tomáš VIČAR, Martina RAUDENSKÁ et. al.

Basic information

Original name

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

Authors

EYER, Luděk (203 Czech Republic, guarantor), Pavel SVOBODA (203 Czech Republic), Jan BALVAN (203 Czech Republic, belonging to the institution), Tomáš VIČAR (203 Czech Republic, belonging to the institution), Martina RAUDENSKÁ (203 Czech Republic, belonging to the institution), Michal ŠTEFÁNIK (203 Czech Republic), Jan HAVIERNIK (203 Czech Republic, belonging to the institution), Ivana HUVAROVÁ (203 Czech Republic), Petra STRAKOVÁ (203 Czech Republic), Ivo RUDOLF (203 Czech Republic, belonging to the institution), Zdeněk HUBÁLEK (203 Czech Republic), Katherine SELEY-RADTKE (840 United States of America), Erik DE CLERCQ (56 Belgium) and Daniel RŮŽEK (203 Czech Republic)

Edition

Antimicrobial Agents and Chemotherapy, Washington, AMER SOC MICROBIOLOG, 2021, 0066-4804

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10606 Microbiology

Country of publisher

United States of America

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 5.938

RIV identification code

RIV/00216224:14110/21:00121049

Organization unit

Faculty of Medicine

DOI

http://dx.doi.org/10.1128/AAC.01522-20

UT WoS

000609954100018

Keywords in English

nucleoside analogue; 39-deoxy-39-fluoroadenosine; flavivirus; tick-borne encephalitis virus; antiviral activity; cytotoxicity; mouse model

Abstract

V originále

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.

Citovat

EYER, Luděk, Pavel SVOBODA, Jan BALVAN, Tomáš VIČAR, Martina RAUDENSKÁ, Michal ŠTEFÁNIK, Jan HAVIERNIK, Ivana HUVAROVÁ, Petra STRAKOVÁ, Ivo RUDOLF, Zdeněk HUBÁLEK, Katherine SELEY-RADTKE, Erik DE CLERCQ and Daniel RŮŽEK. Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses. Antimicrobial Agents and Chemotherapy. Washington: AMER SOC MICROBIOLOG, 2021, vol. 65, No 2, p. 1-19. ISSN 0066-4804. Available from: https://dx.doi.org/10.1128/AAC.01522-20.

@article{1735136,
   author = {Eyer, Luděk and Svoboda, Pavel and Balvan, Jan and Vičar, Tomáš and Raudenská, Martina and Štefánik, Michal and Haviernik, Jan and Huvarová, Ivana and Straková, Petra and Rudolf, Ivo and Hubálek, Zdeněk and SeleyandRadtke, Katherine and de Clercq, Erik and Růžek, Daniel},
   article_location = {Washington},
   article_number = {2},
   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},
   language = {eng},
   issn = {0066-4804},
   journal = {Antimicrobial Agents and Chemotherapy},
   title = {Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses},
   url = {https://aac.asm.org/content/65/2/e01522-20},
   volume = {65},
   year = {2021}
}

TY  - JOUR
ID  - 1735136
AU  - Eyer, Luděk - Svoboda, Pavel - Balvan, Jan - Vičar, Tomáš - Raudenská, Martina - Štefánik, Michal - Haviernik, Jan - Huvarová, Ivana - Straková, Petra - Rudolf, Ivo - Hubálek, Zdeněk - Seley-Radtke, Katherine - de Clercq, Erik - Růžek, Daniel
PY  - 2021
TI  - Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses
JF  - Antimicrobial Agents and Chemotherapy
VL  - 65
IS  - 2
SP  - 1-19
EP  - 1-19
PB  - AMER SOC MICROBIOLOG
SN  - 00664804
KW  - nucleoside analogue
KW  - 39-deoxy-39-fluoroadenosine
KW  - flavivirus
KW  - tick-borne encephalitis virus
KW  - antiviral activity
KW  - cytotoxicity
KW  - mouse model
UR  - https://aac.asm.org/content/65/2/e01522-20
L2  - https://aac.asm.org/content/65/2/e01522-20
N2  - 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.
ER  -

EYER, Luděk, Pavel SVOBODA, Jan BALVAN, Tomáš VIČAR, Martina RAUDENSKÁ, Michal ŠTEFÁNIK, Jan HAVIERNIK, Ivana HUVAROVÁ, Petra STRAKOVÁ, Ivo RUDOLF, Zdeněk HUBÁLEK, Katherine SELEY-RADTKE, Erik DE CLERCQ and Daniel RŮŽEK. Broad-Spectrum Antiviral Activity of 3'-Deoxy-3'Fluoroadenosine against Emerging Flaviviruses. \textit{Antimicrobial Agents and Chemotherapy}. Washington: AMER SOC MICROBIOLOG, 2021, vol.~65, No~2, p.~1-19. ISSN~0066-4804. Available from: https://dx.doi.org/10.1128/AAC.01522-20.

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