Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression

Esmeralda M. Guzman, Natalia V. Cheshenko, Vikas Shende, Marla J. Keller, Nathalie Goyette, Jean Marc Juteau, Guy Boivin, Andrew Vaillant, Betsy Herold

Research output: Contribution to journalArticle

28 Citations (Scopus)

Abstract

Background: Amphipathic DNA polymers are promising therapies for the prevention of HIV and genital herpes infections. Recent studies on a panel of such compounds indicated potent activity against HIV binding and entry. This current study was conducted to explore the antiherpes simplex virus (HSV) activity of the same panel of compounds and to determine their mechanism of activity. Methods: The anti-HSV activity of a 40-nucleotide degenerate polymer (REP 9), a 40-nucleotide polycytidine amphipathic DNA polymer (REP 9C) and an analogue lacking amphipathic activity (Randomer 3) were compared in plaque reduction assays in the absence or presence of human genital tract secretions; the mechanisms of anti-HSV activity were explored. Results: REP 9 inhibited HSV infection 10,000-fold, whereas Randomer 3 displayed no anti-HSV activity. The antiviral activity was independent of sequence but was dependent on size: the most potent activity was observed for analogues of 40 nucleotides in length. Mechanistic studies indicated that REP 9 and REP 9C blocked HSV-2 binding and entry, were active when added post-entry, inhibited viral gene expression and blocked HSV-induced apoptosis. Confocal microscopy studies showed rapid delivery of fluorescently tagged REP 9 and REP 9C into human epithelial cells, and delivery was significantly greater in infected cells as compared with uninfected cells. REP 9 exhibited no cytotoxicity and retained anti-HSV activity in the presence of cervicovaginal secretions and when virus was introduced in seminal plasma. Conclusions: REP 9 and REP 9C represent a novel class of antiviral agents that act by multiple mechanisms. These compounds warrant further development for systemic or topical delivery for the prevention and treatment of HIV and HSV.

Original languageEnglish (US)
Pages (from-to)1147-1156
Number of pages10
JournalAntiviral Therapy
Volume12
Issue number8
StatePublished - 2007

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Virus Attachment
Virus Internalization
Viral Genes
Simplexvirus
Anti-Infective Agents
Polymers
Nucleotides
HIV
Gene Expression
Antiviral Agents
DNA
Viruses
Herpes Genitalis
Human Herpesvirus 2
Infection
Semen
Confocal Microscopy
Epithelial Cells
Apoptosis
Therapeutics

ASJC Scopus subject areas

  • Pharmacology

Cite this

Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression. / Guzman, Esmeralda M.; Cheshenko, Natalia V.; Shende, Vikas; Keller, Marla J.; Goyette, Nathalie; Juteau, Jean Marc; Boivin, Guy; Vaillant, Andrew; Herold, Betsy.

In: Antiviral Therapy, Vol. 12, No. 8, 2007, p. 1147-1156.

Research output: Contribution to journalArticle

Guzman, Esmeralda M. ; Cheshenko, Natalia V. ; Shende, Vikas ; Keller, Marla J. ; Goyette, Nathalie ; Juteau, Jean Marc ; Boivin, Guy ; Vaillant, Andrew ; Herold, Betsy. / Amphipathic DNA polymers are candidate vaginal microbicides and block herpes simplex virus binding, entry and viral gene expression. In: Antiviral Therapy. 2007 ; Vol. 12, No. 8. pp. 1147-1156.
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AU - Guzman, Esmeralda M.

AU - Cheshenko, Natalia V.

AU - Shende, Vikas

AU - Keller, Marla J.

AU - Goyette, Nathalie

AU - Juteau, Jean Marc

AU - Boivin, Guy

AU - Vaillant, Andrew

AU - Herold, Betsy

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N2 - Background: Amphipathic DNA polymers are promising therapies for the prevention of HIV and genital herpes infections. Recent studies on a panel of such compounds indicated potent activity against HIV binding and entry. This current study was conducted to explore the antiherpes simplex virus (HSV) activity of the same panel of compounds and to determine their mechanism of activity. Methods: The anti-HSV activity of a 40-nucleotide degenerate polymer (REP 9), a 40-nucleotide polycytidine amphipathic DNA polymer (REP 9C) and an analogue lacking amphipathic activity (Randomer 3) were compared in plaque reduction assays in the absence or presence of human genital tract secretions; the mechanisms of anti-HSV activity were explored. Results: REP 9 inhibited HSV infection 10,000-fold, whereas Randomer 3 displayed no anti-HSV activity. The antiviral activity was independent of sequence but was dependent on size: the most potent activity was observed for analogues of 40 nucleotides in length. Mechanistic studies indicated that REP 9 and REP 9C blocked HSV-2 binding and entry, were active when added post-entry, inhibited viral gene expression and blocked HSV-induced apoptosis. Confocal microscopy studies showed rapid delivery of fluorescently tagged REP 9 and REP 9C into human epithelial cells, and delivery was significantly greater in infected cells as compared with uninfected cells. REP 9 exhibited no cytotoxicity and retained anti-HSV activity in the presence of cervicovaginal secretions and when virus was introduced in seminal plasma. Conclusions: REP 9 and REP 9C represent a novel class of antiviral agents that act by multiple mechanisms. These compounds warrant further development for systemic or topical delivery for the prevention and treatment of HIV and HSV.

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