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Structure activity relationship of dendrimer microbicides with dual action antiviral activity.

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 JR, Lewis GR, Tachedjian G - PLoS ONE (2010)

Bottom Line: 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.SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV.SPL7013 could also be combined with other microbicides.

View Article: PubMed Central - PubMed

Affiliation: Centres for Virology and Immunology, Burnet Institute, Melbourne, Victoria, Australia.

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 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 VivaGel(R) 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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Dendrimer structure and SAR of L-lysine dendrimers against HIV-1 and HSV-2.(A). Model representation of dendrimer structure showing central core, branches in black, red and green for first (G1), second (G2) and third (G3) generations and surface groups denoted as blue round spheres. (B). Different types of cores and branches used in the synthesis of dendrimers. (C). Seven surface groups, L-glutamic acid, 2-thio-3-SO3Na, MNAA, 4-Ph-SO3Na, 3,5-Ph-(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 evaluated in SAR studies. (D). SAR of L-lysine dendrimers against HIV-1 strain NL4.3 performed in MT-2 cells. G1–G5 dendrimers were evaluated for five of the seven surface groups except for MNAA where G1-G2 and G5 were not tested and 2-thio-3-SO3Na where G1 and G5 dendrimers were not tested. The EC50 values were obtained from at least two independent assays except for G1–G5 dendrimers with the glutamic surface group, G1 dendrimers with the 2-thio-3-SO3Na, 3,5-Ph(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 surface groups and the G3 MNAA dendrimer, where one assay was performed. (E). SAR of L-lysine dendrimers against HSV-2 performed in HEL cells. G4-G5 and G2, G4-G5 were not tested for dendrimers with the 3,5-Ph-(SO3Na)2 and 4-Ph-SO3Na surface groups, respectively. EC50 values were obtained from at least three independent assays. Error bars denote standard error of the mean.
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pone-0012309-g001: Dendrimer structure and SAR of L-lysine dendrimers against HIV-1 and HSV-2.(A). Model representation of dendrimer structure showing central core, branches in black, red and green for first (G1), second (G2) and third (G3) generations and surface groups denoted as blue round spheres. (B). Different types of cores and branches used in the synthesis of dendrimers. (C). Seven surface groups, L-glutamic acid, 2-thio-3-SO3Na, MNAA, 4-Ph-SO3Na, 3,5-Ph-(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 evaluated in SAR studies. (D). SAR of L-lysine dendrimers against HIV-1 strain NL4.3 performed in MT-2 cells. G1–G5 dendrimers were evaluated for five of the seven surface groups except for MNAA where G1-G2 and G5 were not tested and 2-thio-3-SO3Na where G1 and G5 dendrimers were not tested. The EC50 values were obtained from at least two independent assays except for G1–G5 dendrimers with the glutamic surface group, G1 dendrimers with the 2-thio-3-SO3Na, 3,5-Ph(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 surface groups and the G3 MNAA dendrimer, where one assay was performed. (E). SAR of L-lysine dendrimers against HSV-2 performed in HEL cells. G4-G5 and G2, G4-G5 were not tested for dendrimers with the 3,5-Ph-(SO3Na)2 and 4-Ph-SO3Na surface groups, respectively. EC50 values were obtained from at least three independent assays. Error bars denote standard error of the mean.

Mentions: Recognised as a key building block of nanotechnology, dendrimers (dendri- = tree, -mer = branching) are a relatively new class of macromolecule characterised by highly branched, well-defined, three-dimensional structures that are being developed as drug delivery vehicles and as therapeutic agents [7], [8]. The controlled synthesis of dendrimers allows the assembly of highly defined, single molecule structures that radiate out in branches from a central initiator core (Figure 1A). The type of core and branching units (Figure 1B) can be altered to generate dendrimers of varying size and shape. In addition, dendrimer branches can be capped with different surface groups (Figure 1C) that can impart distinct biological and pharmacological properties. Thus dendrimers offer unique opportunities in the synthesis of agents with broad-spectrum antiviral activity [9]. Viruses rely on interactions with host receptors for binding and entry into target cells. Unlike small molecule drugs that tend to make monovalent contacts, dendrimers can bind to their target in a multivalent manner and overcome intrinsically weak monovalent interactions thus representing an attractive strategy for the development of viral entry inhibitors.


Structure activity relationship of dendrimer microbicides with dual action antiviral activity.

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 JR, Lewis GR, Tachedjian G - PLoS ONE (2010)

Dendrimer structure and SAR of L-lysine dendrimers against HIV-1 and HSV-2.(A). Model representation of dendrimer structure showing central core, branches in black, red and green for first (G1), second (G2) and third (G3) generations and surface groups denoted as blue round spheres. (B). Different types of cores and branches used in the synthesis of dendrimers. (C). Seven surface groups, L-glutamic acid, 2-thio-3-SO3Na, MNAA, 4-Ph-SO3Na, 3,5-Ph-(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 evaluated in SAR studies. (D). SAR of L-lysine dendrimers against HIV-1 strain NL4.3 performed in MT-2 cells. G1–G5 dendrimers were evaluated for five of the seven surface groups except for MNAA where G1-G2 and G5 were not tested and 2-thio-3-SO3Na where G1 and G5 dendrimers were not tested. The EC50 values were obtained from at least two independent assays except for G1–G5 dendrimers with the glutamic surface group, G1 dendrimers with the 2-thio-3-SO3Na, 3,5-Ph(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 surface groups and the G3 MNAA dendrimer, where one assay was performed. (E). SAR of L-lysine dendrimers against HSV-2 performed in HEL cells. G4-G5 and G2, G4-G5 were not tested for dendrimers with the 3,5-Ph-(SO3Na)2 and 4-Ph-SO3Na surface groups, respectively. EC50 values were obtained from at least three independent assays. Error bars denote standard error of the mean.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2925893&req=5

pone-0012309-g001: Dendrimer structure and SAR of L-lysine dendrimers against HIV-1 and HSV-2.(A). Model representation of dendrimer structure showing central core, branches in black, red and green for first (G1), second (G2) and third (G3) generations and surface groups denoted as blue round spheres. (B). Different types of cores and branches used in the synthesis of dendrimers. (C). Seven surface groups, L-glutamic acid, 2-thio-3-SO3Na, MNAA, 4-Ph-SO3Na, 3,5-Ph-(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 evaluated in SAR studies. (D). SAR of L-lysine dendrimers against HIV-1 strain NL4.3 performed in MT-2 cells. G1–G5 dendrimers were evaluated for five of the seven surface groups except for MNAA where G1-G2 and G5 were not tested and 2-thio-3-SO3Na where G1 and G5 dendrimers were not tested. The EC50 values were obtained from at least two independent assays except for G1–G5 dendrimers with the glutamic surface group, G1 dendrimers with the 2-thio-3-SO3Na, 3,5-Ph(SO3Na)2, DNAA and 3,5-Ph-(CO2Na)2 surface groups and the G3 MNAA dendrimer, where one assay was performed. (E). SAR of L-lysine dendrimers against HSV-2 performed in HEL cells. G4-G5 and G2, G4-G5 were not tested for dendrimers with the 3,5-Ph-(SO3Na)2 and 4-Ph-SO3Na surface groups, respectively. EC50 values were obtained from at least three independent assays. Error bars denote standard error of the mean.
Mentions: Recognised as a key building block of nanotechnology, dendrimers (dendri- = tree, -mer = branching) are a relatively new class of macromolecule characterised by highly branched, well-defined, three-dimensional structures that are being developed as drug delivery vehicles and as therapeutic agents [7], [8]. The controlled synthesis of dendrimers allows the assembly of highly defined, single molecule structures that radiate out in branches from a central initiator core (Figure 1A). The type of core and branching units (Figure 1B) can be altered to generate dendrimers of varying size and shape. In addition, dendrimer branches can be capped with different surface groups (Figure 1C) that can impart distinct biological and pharmacological properties. Thus dendrimers offer unique opportunities in the synthesis of agents with broad-spectrum antiviral activity [9]. Viruses rely on interactions with host receptors for binding and entry into target cells. Unlike small molecule drugs that tend to make monovalent contacts, dendrimers can bind to their target in a multivalent manner and overcome intrinsically weak monovalent interactions thus representing an attractive strategy for the development of viral entry inhibitors.

Bottom Line: 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.SPL7013 is formulated as VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV.SPL7013 could also be combined with other microbicides.

View Article: PubMed Central - PubMed

Affiliation: Centres for Virology and Immunology, Burnet Institute, Melbourne, Victoria, Australia.

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 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 VivaGel(R) and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

Show MeSH
Related in: MedlinePlus