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

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 Res. 2022 May 6;50(8):4574-4600. doi: 10.1093/nar/gkac225.
Jiří Holoubek 1 2 3,  Klára Bednářová 4,  Jan Haviernik 1 3,  Ivana Huvarová 1,  Zuzana Dvořáková 4,  Jiří Černý 5,  Martina Outlá 6 7,  Jiří Salát 1 3,  Eva Konkol'ová 8,  Evzen Boura 8,  Daniel Růžek 1 2 3,  Michaela Vorlíčková 4,  Luděk Eyer 1 3,  Daniel Renčiuk 4
Affiliations

Affiliations

  • 1 Veterinary Research Institute, Emerging Viral Diseases, Brno CZ-62100, Czech Republic.
  • 2 Department of Experimental Biology, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic.
  • 3 Institute of Parasitology, Biology Centre of the Czech Academy of Sciences, CZ-37005 Ceske Budejovice, Czech Republic.
  • 4 Department of Biophysics of Nucleic Acids, Institute of Biophysics of the Czech Academy of Sciences, Brno CZ-61200, Czech Republic.
  • 5 Faculty of Tropical Agrisciences, Czech University of Life Sciences Prague, CZ-16500 Prague, Czech Republic.
  • 6 Department of Biophysical Chemistry and Molecular Oncology, Institute of Biophysics of the Czech Academy of Sciences, Brno CZ-61200, Czech Republic.
  • 7 National Centre for Biomolecular Research, Faculty of Science, Masaryk University, CZ-62500 Brno, Czech Republic.
  • 8 Institute of Organic Chemistry and Biochemistry of the Czech Academy ofSciences, CZ-16000 Prague, Czech Republic.
PMID: 35420134 DOI: 10.1093/nar/gkac225
Abstract

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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