Structure Activity Relationship of Dendrimer Microbicides with Dual Action Antiviral Activity

Abstract

BackgroundTopical 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 FindingsDendrimers 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.ConclusionsDendrimers 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® and is currently in clinical development to provide protection against HIV and HSV. SPL7013 could also be combined with other microbicides.

Dendrimers as tunable vectors of drug delivery systems and biomedical and ocular applications

“…43 Efficacious topical microbicides, such as SPL7013 and VivaGel, are essential for the prevention of the transmission of HIV and HSV-2 and other genital infections in women. The data presented in the study by Tyssen et al, 47 in addition to those of previous studies presented earlier in this review, support the need for further evaluation of VivaGel in clinical trials for the assessment of its therapeutic potential as an efficacious topical microbicide in women with genital infections, when administered intravaginally, either alone or in conjunction with other antiviral agents.…”

“…47 Most importantly, it was shown that SPL7013 was not absorbed into the systemic circulation, reducing possible toxicity.…”

Dendrimers as anti-inflammatory agents

“…These dendrimers have shown to dissociate the homodimers of CTD (K d ~ 10 μM) similar to designed peptide inhibitors weakening the dimerization process (Garzon et al, 2004;Stitch et al, 2005;Neira, 2009). In another study, the second (SPL7115) and fourth generation (SPL7013) dendrimers comprising benzyhydryl amide cores and lysine branches have shown anti-HIV activity by blocking HIV-envelope mediated cell-to-cell fusion (Rupp et al, 2007;Tyssen et al, 2010). SPL7115 and SPL7013 also inhibited the viral entry, through different mechanism of action, by showing high potency against CXCR4-(X4) and CCR5-using (R5) HIV-1 strains (Telwatte et al, 2011).…”

Antiviral mechanism of polyanionic carbosilane dendrimers against HIV-1

“…The type of core and branching units can be engineered to generate a broad variety of dendrimers with different sizes, shapes, and surface chemical functionalized groups that can provide distinct biological and pharmacological properties. 18 Unlike small molecule drugs, dendrimers can bind to their target in a multivalent manner due to their hyperbranched structure, offering unique opportunities in the synthesis of novel antiviral agents.…”

“…In this way, anionic dendrimers comprising benzyhydryl amide cores and lysine branches, which were functionalized with naphthalene disulfonic acid or 3,5-disulfobenzoic acid groups, exhibited great activity against HIV-1 and herpes simplex virus 2 (HSV-2) infections, preventing viral entry and HIV envelope-mediated cell-to-cell fusion. 18,19 Moreover, polycationic "viologen"-based dendrimers have also shown anti-HIV activity by interaction with the chemokine receptor CXCR4. 20 Other dendrimers have presented dual acting mechanism such as four-generation polyamidoamine (PAMAM) branchednaphthalene disulfonic surface groups ended SPL2923 18 or polysulfonated dendrimer BRI2923, 21 which inhibited not only HIV-1 entry but also later steps (reverse transcriptase/ integrase) of the viral replicative cycle.…”