title: The Herpes Simplex Virus-1 genome contains multiple clusters of repeated G-quadruplex: Implications for the antiviral activity of a G-quadruplex ligand.
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.
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Sara
authors.initials: S
authors.lastname: Artusi
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Matteo
authors.initials: M
authors.lastname: Nadai
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Rosalba
authors.initials: R
authors.lastname: Perrone
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Maria Angela
authors.initials: MA
authors.lastname: Biasolo
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Giorgio
authors.initials: G
authors.lastname: Palù
authors.affiliation: Department of Microbiology, Infectious Diseases and Immunology, Laval University, Quebec City, Quebec, Canada.
authors.forename: Louis
authors.initials: L
authors.lastname: Flamand
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy.
authors.forename: Arianna
authors.initials: A
authors.lastname: Calistri
authors.affiliation: Department of Molecular Medicine, University of Padua, via Gabelli, 63, 35121 Padua, Italy. Electronic address: sara.richter@unipd.it.
authors.forename: Sara N
authors.initials: SN
authors.lastname: Richter
mesh_terms: D000166:Acridines / Q000378:metabolism*; D000998:Antiviral Agents / Q000378:metabolism*; D004279:DNA, Viral / Q000187:drug effects* / Q000235:genetics; D054856:G-Quadruplexes / Q000187:drug effects*; D016679:Genome, Viral; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000235:genetics* / Q000502:physiology; D006801:Humans; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000166:Acridines; D000998:Antiviral Agents; D004279:DNA, Viral; C454064:BRACO-19
keywords: Antiviral compound; DNA conformation; DNA secondary structure; G-quadruplex; G-rich sequence; Herpes Simplex Virus 1
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