Guanine quadruplexes in the RNA genome of the tick-borne
encephalitis virus: their role as a new antiviral target and in
virus biology

J 2022

Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology

HOLOUBEK, Jiří, Klára BEDNÁŘOVÁ, Jan HAVIERNIK, Ivana HUVAROVÁ, Zuzana DVOŘÁKOVÁ et. al.

Basic information

Original name

Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology

Authors

HOLOUBEK, Jiří (203 Czech Republic, guarantor, belonging to the institution), Klára BEDNÁŘOVÁ (203 Czech Republic), Jan HAVIERNIK (203 Czech Republic), Ivana HUVAROVÁ, Zuzana DVOŘÁKOVÁ, Jiří ČERNÝ, Martina OUTLÁ (203 Czech Republic, belonging to the institution), Jiří SALÁT (203 Czech Republic), Eva KONKOLOVA, Evzen BOURA, Daniel RŮŽEK (203 Czech Republic, belonging to the institution), Michaela VORLÍČKOVÁ (203 Czech Republic), Luděk EYER (203 Czech Republic) and Daniel RENČIUK (203 Czech Republic)

Edition

Nucleic Acids Research, Oxford University Press, 2022, 0305-1048

Other information

Language

English

Type of outcome

Článek v odborném periodiku

Field of Study

10607 Virology

Country of publisher

United Kingdom of Great Britain and Northern Ireland

Confidentiality degree

není předmětem státního či obchodního tajemství

References:

URL

Impact factor

Impact factor: 14.900

RIV identification code

RIV/00216224:14310/22:00125682

Organization unit

Faculty of Science

DOI

http://dx.doi.org/10.1093/nar/gkac225

UT WoS

000785763900001

Keywords (in Czech)

guaninový kvadruplex; kvadruplex; sekundární struktura; RNA; virus klíšťové encefalitidy; TBEV; antivirotika

Keywords in English

guanine quadruplex; quadruplex; secondary structure; RNA; tick-borne encephalitis virus; antivirotics; TBEV

Abstract

V originále

We have identified seven putative guanine quadruplexes (G4) in the RNA genome of tick-borne encephalitis virus (TBEV), a flavivirus causing thousands of human infections and numerous deaths every year. The formation of G4s was confirmed by biophysical methods on synthetic oligonucleotides derived from the predicted TBEV sequences. TBEV-5, located at the NS4b/NS5 boundary and conserved among all known flaviviruses, was tested along with its mutated variants for interactions with a panel of known G4 ligands, for the ability to affect RNA synthesis by the flaviviral RNA-dependent RNA polymerase (RdRp) and for effects on TBEV replication fitness in cells. G4-stabilizing TBEV-5 mutations strongly inhibited RdRp RNA synthesis and exhibited substantially reduced replication fitness, different plaque morphology and increased sensitivity to G4-binding ligands in cell-based systems. In contrast, strongly destabilizing TBEV-5 G4 mutations caused rapid reversion to the wild-type genotype. Our results suggest that there is a threshold of stability for G4 sequences in the TBEV genome, with any deviation resulting in either dramatic changes in viral phenotype or a rapid return to this optimal level of G4 stability. The data indicate that G4s are critical elements for efficient TBEV replication and are suitable targets to tackle TBEV infection.

Citovat

HOLOUBEK, Jiří, Klára BEDNÁŘOVÁ, Jan HAVIERNIK, Ivana HUVAROVÁ, Zuzana DVOŘÁKOVÁ, Jiří ČERNÝ, Martina OUTLÁ, Jiří SALÁT, Eva KONKOLOVA, Evzen BOURA, Daniel RŮŽEK, Michaela VORLÍČKOVÁ, Luděk EYER and Daniel RENČIUK. Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology. Nucleic Acids Research. Oxford University Press, 2022, vol. 50, No 8, p. 4574-4600. ISSN 0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkac225.

@article{1848065,
   author = {Holoubek, Jiří and Bednářová, Klára and Haviernik, Jan and Huvarová, Ivana and Dvořáková, Zuzana and Černý, Jiří and Outlá, Martina and Salát, Jiří and Konkolova, Eva and Boura, Evzen and Růžek, Daniel and Vorlíčková, Michaela and Eyer, Luděk and Renčiuk, Daniel},
   article_number = {8},
   doi = {http://dx.doi.org/10.1093/nar/gkac225},
   keywords = {guanine quadruplex; quadruplex; secondary structure; RNA; tick-borne encephalitis virus; antivirotics; TBEV},
   language = {eng},
   issn = {0305-1048},
   journal = {Nucleic Acids Research},
   title = {Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology},
   url = {https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac225/6568495?searchresult=1},
   volume = {50},
   year = {2022}
}

TY  - JOUR
ID  - 1848065
AU  - Holoubek, Jiří - Bednářová, Klára - Haviernik, Jan - Huvarová, Ivana - Dvořáková, Zuzana - Černý, Jiří - Outlá, Martina - Salát, Jiří - Konkolova, Eva - Boura, Evzen - Růžek, Daniel - Vorlíčková, Michaela - Eyer, Luděk - Renčiuk, Daniel
PY  - 2022
TI  - Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology
JF  - Nucleic Acids Research
VL  - 50
IS  - 8
SP  - 4574-4600
EP  - 4574-4600
PB  - Oxford University Press
SN  - 03051048
KW  - guanine quadruplex
KW  - quadruplex
KW  - secondary structure
KW  - RNA
KW  - tick-borne encephalitis virus
KW  - antivirotics
KW  - TBEV
UR  - https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac225/6568495?searchresult=1
N2  - We have identified seven putative guanine quadruplexes (G4) in the RNA genome of tick-borne encephalitis virus (TBEV), a flavivirus causing thousands of human infections and numerous deaths every year. The formation of G4s was confirmed by biophysical methods on synthetic oligonucleotides derived from the predicted TBEV sequences. TBEV-5, located at the NS4b/NS5 boundary and conserved among all known flaviviruses, was tested along with its mutated variants for interactions with a panel of known G4 ligands, for the ability to affect RNA synthesis by the flaviviral RNA-dependent RNA polymerase (RdRp) and for effects on TBEV replication fitness in cells. G4-stabilizing TBEV-5 mutations strongly inhibited RdRp RNA synthesis and exhibited substantially reduced replication fitness, different plaque morphology and increased sensitivity to G4-binding ligands in cell-based systems. In contrast, strongly destabilizing TBEV-5 G4 mutations caused rapid reversion to the wild-type genotype. Our results suggest that there is a threshold of stability for G4 sequences in the TBEV genome, with any deviation resulting in either dramatic changes in viral phenotype or a rapid return to this optimal level of G4 stability. The data indicate that G4s are critical elements for efficient TBEV replication and are suitable targets to tackle TBEV infection.
ER  -

HOLOUBEK, Jiří, Klára BEDNÁŘOVÁ, Jan HAVIERNIK, Ivana HUVAROVÁ, Zuzana DVOŘÁKOVÁ, Jiří ČERNÝ, Martina OUTLÁ, Jiří SALÁT, Eva KONKOLOVA, Evzen BOURA, Daniel RŮŽEK, Michaela VORLÍČKOVÁ, Luděk EYER and Daniel RENČIUK. Guanine quadruplexes in the RNA genome of the tick-borne encephalitis virus: their role as a new antiviral target and in virus biology. \textit{Nucleic Acids Research}. Oxford University Press, 2022, vol.~50, No~8, p.~4574-4600. ISSN~0305-1048. Available from: https://dx.doi.org/10.1093/nar/gkac225.

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