Tom McCarthy

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

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

Inhibition of destructive autoimmune arthritis in FcγRIIa transgenic mice by small chemical entities

The interaction of immune complexes with the human Fc receptor, FcγRIIa, initiates the release of inflammatory mediators and is implicated in the pathogenesis of human autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, so this FcR is a potential target for therapy. We have used the three‐dimensional structure of an FcγRIIa dimer to design small molecule inhibitors, modeled on a distinct groove and pocket created by receptor dimerization, adjacent to the ligand‐binding sites. These small chemical entities (SCEs) blocked immune complex‐induced platelet activation and aggregation and tumor necrosis factor secretion from macrophages in a human cell line and transgenic mouse macrophages. The SCE appeared specific for FcγRIIa, as they inhibited only immune complex‐induced responses and had no effect on responses to stimuli unrelated to FcR, for example platelet stimulation with arachidonic acid. In vivo testing of the SCE in FcγRIIa transgenic mice showed that they inhibited the development and stopped the progression of collagen‐induced arthritis (CIA). The SCEs were more potent than methotrexate and anti‐CD3 in sustained suppression of CIA. Thus, in vitro and in vivo activity of these SCE FcγRIIa receptor antagonists demonstrated their potential as anti‐inflammatory agents for autoimmune diseases involving immune complexes.

Dendrimers As Drugs: Discovery, Preclinical and Clinical Development of SPL7013 Gel (VivaGel™), a Dendrimer Based Microbicide for HIVand STI Prevention

Starpharma focuses on the use of dendrimers as drugs in their own right – in contrast to dendrimers as drug delivery vehicles or diagnostics. Dendrimers offer a unique platform for exploring chemical diversity on the nanoscale and the production of dendrimer libraries covering a diverse array of macromolecular structures can be used in drug discovery and development. One pharmaceutical application of dendrimers that Starpharma is pursuing is the development of microbicides for the prevention of HIV and sexually transmitted infections (STIs). This presentation will describe the dendrimer drug discovery and lead candidate selection process from which SPL7013 emerged as a microbicide development candidate. Pivotal preclinical data will be presented that lead to Starpharma submitting an Investigational New Drug application (IND) for SPL7013 gel (VivaGelTM) to the United States Food and Drug Administration (FDA) in June 2003, the first such submission for a dendrimer based drug. Finally, results of the first clinical trial under this IND will presented. from 2005 International Meeting of The Institute of Human Virology Baltimore, USA, 29 August – 2 September 2005