Structure activity relationship of dendrimer microbicides with dual action antiviral activity

David Tyssen, Scott Andrew Henderson, Adam Johnson, Jasminka Sterjovski, Katie Moore, Jennifer La, Mark P Zanin, Secondo Sonza, Peter Karellas, Michael Giannis, Guy Y Krippner, Steven Lodewyk Wesselingh, Tom D McCarthy, Paul R Gorry, Paul Allen Ramsland, Richard Cone, Jeremy RA Paull, Gareth R Lewis, Gilda Tachedjian

Research output: Contribution to journalArticleResearchpeer-review

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. Time-of-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...
Original languageEnglish
Pages (from-to)1 - 15
Number of pages15
JournalPLoS ONE
Volume5
Issue number8 (e12309)
DOIs
Publication statusPublished - 2010

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)), 1 - 15. https://doi.org/10.1371/journal.pone.0012309
Tyssen, David ; Henderson, Scott Andrew ; Johnson, Adam ; Sterjovski, Jasminka ; Moore, Katie ; La, Jennifer ; Zanin, Mark P ; Sonza, Secondo ; Karellas, Peter ; Giannis, Michael ; Krippner, Guy Y ; Wesselingh, Steven Lodewyk ; McCarthy, Tom D ; Gorry, Paul R ; Ramsland, Paul Allen ; Cone, Richard ; Paull, Jeremy RA ; Lewis, Gareth R ; Tachedjian, Gilda. / Structure activity relationship of dendrimer microbicides with dual action antiviral activity. In: PLoS ONE. 2010 ; Vol. 5, No. 8 (e12309). pp. 1 - 15.
@article{c9dcbbd3e3b44a8b9279dc0e95043c3a,
title = "Structure activity relationship of dendrimer microbicides with dual action antiviral activity",
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. Time-of-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...",
author = "David Tyssen and Henderson, {Scott Andrew} and Adam Johnson and Jasminka Sterjovski and Katie Moore and Jennifer La and Zanin, {Mark P} and Secondo Sonza and Peter Karellas and Michael Giannis and Krippner, {Guy Y} and Wesselingh, {Steven Lodewyk} and McCarthy, {Tom D} and Gorry, {Paul R} and Ramsland, {Paul Allen} and Richard Cone and Paull, {Jeremy RA} and Lewis, {Gareth R} and Gilda Tachedjian",
year = "2010",
doi = "10.1371/journal.pone.0012309",
language = "English",
volume = "5",
pages = "1 -- 15",
journal = "PLoS ONE",
issn = "1932-6203",
publisher = "Public Library of Science",
number = "8 (e12309)",

}

Tyssen, D, Henderson, SA, Johnson, A, Sterjovski, J, Moore, K, La, J, Zanin, MP, Sonza, S, Karellas, P, Giannis, M, Krippner, GY, Wesselingh, SL, McCarthy, TD, 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), pp. 1 - 15. https://doi.org/10.1371/journal.pone.0012309

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

In: PLoS ONE, Vol. 5, No. 8 (e12309), 2010, p. 1 - 15.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

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

AU - Tyssen, David

AU - Henderson, Scott Andrew

AU - Johnson, Adam

AU - Sterjovski, Jasminka

AU - Moore, Katie

AU - La, Jennifer

AU - Zanin, Mark P

AU - Sonza, Secondo

AU - Karellas, Peter

AU - Giannis, Michael

AU - Krippner, Guy Y

AU - Wesselingh, Steven Lodewyk

AU - McCarthy, Tom D

AU - Gorry, Paul R

AU - Ramsland, Paul Allen

AU - Cone, Richard

AU - Paull, Jeremy RA

AU - Lewis, Gareth R

AU - Tachedjian, Gilda

PY - 2010

Y1 - 2010

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. Time-of-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...

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. Time-of-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...

UR - http://www.ncbi.nlm.nih.gov/pubmed/20808791

U2 - 10.1371/journal.pone.0012309

DO - 10.1371/journal.pone.0012309

M3 - Article

VL - 5

SP - 1

EP - 15

JO - PLoS ONE

JF - PLoS ONE

SN - 1932-6203

IS - 8 (e12309)

ER -

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;5(8 (e12309)):1 - 15. https://doi.org/10.1371/journal.pone.0012309