The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand

Antiviral Res. 2015 Jun;118:123-31. doi: 10.1016/j.antiviral.2015.03.016. Epub 2015 Apr 3.

Abstract

Guanine-rich nucleic acids can fold into G-quadruplexes, secondary structures implicated in important regulatory functions at the genomic level in humans, prokaryotes and viruses. The remarkably high guanine content of the Herpes Simplex Virus-1 (HSV-1) genome prompted us to investigate both the presence of G-quadruplex forming sequences in the viral genome and the possibility to target them with G-quadruplex ligands to obtain anti-HSV-1 effects with a novel mechanism of action. Using biophysical, molecular biology and antiviral assays, we showed that the HSV-1 genome displays multiple clusters of repeated sequences that form very stable G-quadruplexes. These sequences are mainly located in the inverted repeats of the HSV-1 genome. Treatment of HSV-1 infected cells with the G-quadruplex ligand BRACO-19 induced inhibition of virus production. BRACO-19 was able to inhibit Taq polymerase processing at G-quadruplex forming sequences in the HSV-1 genome, and decreased intracellular viral DNA in infected cells. The last step targeted by BRACO-19 was viral DNA replication, while no effect on virus entry in the cells was observed. This work, presents the first evidence of extended G-quadruplex sites in key regions of the HSV-1 genome, indicates the possibility to block viral DNA replication by G-quadruplex-ligand and therefore provides a proof of concept for the use of G-quadruplex ligands as new anti-herpetic therapeutic options.

Keywords: Antiviral compound; DNA conformation; DNA secondary structure; G-quadruplex; G-rich sequence; Herpes Simplex Virus 1.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Acridines / metabolism*
  • Antiviral Agents / metabolism*
  • DNA, Viral / drug effects*
  • DNA, Viral / genetics
  • G-Quadruplexes / drug effects*
  • Genome, Viral*
  • Herpesvirus 1, Human / drug effects*
  • Herpesvirus 1, Human / genetics*
  • Herpesvirus 1, Human / physiology
  • Humans
  • Virus Replication / drug effects

Substances

  • Acridines
  • Antiviral Agents
  • DNA, Viral
  • BRACO-19