Journal
ANTIVIRAL RESEARCH
Volume 118, Issue -, Pages 123-131Publisher
ELSEVIER
DOI: 10.1016/j.antiviral.2015.03.016
Keywords
Antiviral compound; G-rich sequence; G-quadruplex; DNA conformation; DNA secondary structure; Herpes Simplex Virus 1
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Funding
- Italian Ministry of University and Research [FIRB-Ideas RBID082ATK_001]
- Bill and Melinda Gates Foundation (GCE) [OPP1035881, OPP1097238]
- European Research Council (ERC Consolidator) [615879]
- Canadian Institute of Health Research
- European Research Council (ERC) [615879] Funding Source: European Research Council (ERC)
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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 Tag 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. (C) 2015 Elsevier B.V. All rights reserved.
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