Structure activity relationship of dendrimer microbicides with dual action antiviral activity

David Tyssen, Scott A. Henderson, Adam Johnson, Jasminka Sterjovski, Katie Moore, Jennifer La, Mark Zanin, Secondo Sonza, Peter Karellas, Michael P. Giannis, Guy Krippner, Steve Wesselingh, Tom McCarthy, Paul R. Gorry, Paul A. Ramsland, Richard Cone, Jeremy R.A. Paull, Gareth R. Lewis, Gilda Tachedjian

Research output: Contribution to journalArticle

104 Citations (Scopus)

Abstract

Background: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. Methods and Findings: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Timeof- addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. Conclusions: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGelH and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

LanguageEnglish
Article numbere12309
JournalPLoS ONE
Volume5
Issue number8
DOIs
Publication statusPublished - 19 Oct 2010

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)

Cite this

Tyssen, D., Henderson, S. A., Johnson, A., Sterjovski, J., Moore, K., La, J., ... Tachedjian, G. (2010). Structure activity relationship of dendrimer microbicides with dual action antiviral activity. PLoS ONE, 5(8), [e12309]. https://doi.org/10.1371/journal.pone.0012309
Tyssen, David ; Henderson, Scott A. ; Johnson, Adam ; Sterjovski, Jasminka ; Moore, Katie ; La, Jennifer ; Zanin, Mark ; Sonza, Secondo ; Karellas, Peter ; Giannis, Michael P. ; Krippner, Guy ; Wesselingh, Steve ; McCarthy, Tom ; Gorry, Paul R. ; Ramsland, Paul A. ; Cone, Richard ; Paull, Jeremy R.A. ; Lewis, Gareth R. ; Tachedjian, Gilda. / Structure activity relationship of dendrimer microbicides with dual action antiviral activity. In: PLoS ONE. 2010 ; Vol. 5, No. 8.
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Tyssen, D, Henderson, SA, Johnson, A, Sterjovski, J, Moore, K, La, J, Zanin, M, Sonza, S, Karellas, P, Giannis, MP, Krippner, G, Wesselingh, S, McCarthy, T, Gorry, PR, Ramsland, PA, Cone, R, Paull, JRA, Lewis, GR & Tachedjian, G 2010, 'Structure activity relationship of dendrimer microbicides with dual action antiviral activity', PLoS ONE, vol. 5, no. 8, e12309. https://doi.org/10.1371/journal.pone.0012309

Structure activity relationship of dendrimer microbicides with dual action antiviral activity. / Tyssen, David; Henderson, Scott A.; Johnson, Adam; Sterjovski, Jasminka; Moore, Katie; La, Jennifer; Zanin, Mark; Sonza, Secondo; Karellas, Peter; Giannis, Michael P.; Krippner, Guy; Wesselingh, Steve; McCarthy, Tom; Gorry, Paul R.; Ramsland, Paul A.; Cone, Richard; Paull, Jeremy R.A.; Lewis, Gareth R.; Tachedjian, Gilda.

In: PLoS ONE, Vol. 5, No. 8, e12309, 19.10.2010.

Research output: Contribution to journalArticle

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T1 - Structure activity relationship of dendrimer microbicides with dual action antiviral activity

AU - Tyssen, David

AU - Henderson, Scott A.

AU - Johnson, Adam

AU - Sterjovski, Jasminka

AU - Moore, Katie

AU - La, Jennifer

AU - Zanin, Mark

AU - Sonza, Secondo

AU - Karellas, Peter

AU - Giannis, Michael P.

AU - Krippner, Guy

AU - Wesselingh, Steve

AU - McCarthy, Tom

AU - Gorry, Paul R.

AU - Ramsland, Paul A.

AU - Cone, Richard

AU - Paull, Jeremy R.A.

AU - Lewis, Gareth R.

AU - Tachedjian, Gilda

PY - 2010/10/19

Y1 - 2010/10/19

N2 - Background: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. Methods and Findings: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Timeof- addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. Conclusions: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGelH and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

AB - Background: Topical microbicides, used by women to prevent the transmission of HIV and other sexually transmitted infections are urgently required. Dendrimers are highly branched nanoparticles being developed as microbicides. However, the anti-HIV and HSV structure-activity relationship of dendrimers comprising benzyhydryl amide cores and lysine branches, and a comprehensive analysis of their broad-spectrum anti-HIV activity and mechanism of action have not been published. Methods and Findings: Dendrimers with optimized activity against HIV-1 and HSV-2 were identified with respect to the number of lysine branches (generations) and surface groups. Antiviral activity was determined in cell culture assays. Timeof- addition assays were performed to determine dendrimer mechanism of action. In vivo toxicity and HSV-2 inhibitory activity were evaluated in the mouse HSV-2 susceptibility model. Surface groups imparting the most potent inhibitory activity against HIV-1 and HSV-2 were naphthalene disulfonic acid (DNAA) and 3,5-disulfobenzoic acid exhibiting the greatest anionic charge and hydrophobicity of the seven surface groups tested. Their anti-HIV-1 activity did not appreciably increase beyond a second-generation dendrimer while dendrimers larger than two generations were required for potent anti-HSV-2 activity. Second (SPL7115) and fourth generation (SPL7013) DNAA dendrimers demonstrated broad-spectrum anti-HIV activity. However, SPL7013 was more active against HSV and blocking HIV-1 envelope mediated cell-to-cell fusion. SPL7013 and SPL7115 inhibited viral entry with similar potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains. SPL7013 was not toxic and provided at least 12 h protection against HSV-2 in the mouse vagina. Conclusions: Dendrimers can be engineered with optimized potency against HIV and HSV representing a unique platform for the controlled synthesis of chemically defined multivalent agents as viral entry inhibitors. SPL7013 is formulated as VivaGelH and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

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Tyssen D, Henderson SA, Johnson A, Sterjovski J, Moore K, La J et al. Structure activity relationship of dendrimer microbicides with dual action antiviral activity. PLoS ONE. 2010 Oct 19;5(8). e12309. https://doi.org/10.1371/journal.pone.0012309