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