Publication details

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 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

Year of publication 2022
Type Article in Periodical
Magazine / Source Nucleic Acids Research
MU Faculty or unit

Faculty of Science

Citation
Web https://academic.oup.com/nar/advance-article/doi/10.1093/nar/gkac225/6568495?searchresult=1
Doi http://dx.doi.org/10.1093/nar/gkac225
Keywords guanine quadruplex; quadruplex; secondary structure; RNA; tick-borne encephalitis virus; antivirotics; TBEV
Description 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.

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