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.
  
  
  RESULTS
  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.
authors.affiliation: Centres for Virology and Immunology, Burnet Institute, Melbourne, Victoria, Australia.
authors.forename: David
authors.initials: D
authors.lastname: Tyssen
authors.forename: Scott A
authors.initials: SA
authors.lastname: Henderson
authors.forename: Adam
authors.initials: A
authors.lastname: Johnson
authors.forename: Jasminka
authors.initials: J
authors.lastname: Sterjovski
authors.forename: Katie
authors.initials: K
authors.lastname: Moore
authors.forename: Jennifer
authors.initials: J
authors.lastname: La
authors.forename: Mark
authors.initials: M
authors.lastname: Zanin
authors.forename: Secondo
authors.initials: S
authors.lastname: Sonza
authors.forename: Peter
authors.initials: P
authors.lastname: Karellas
authors.forename: Michael P
authors.initials: MP
authors.lastname: Giannis
authors.forename: Guy
authors.initials: G
authors.lastname: Krippner
authors.forename: Steve
authors.initials: S
authors.lastname: Wesselingh
authors.forename: Tom
authors.initials: T
authors.lastname: McCarthy
authors.forename: Paul R
authors.initials: PR
authors.lastname: Gorry
authors.forename: Paul A
authors.initials: PA
authors.lastname: Ramsland
authors.forename: Richard
authors.initials: R
authors.lastname: Cone
authors.forename: Jeremy R A
authors.initials: JR
authors.lastname: Paull
authors.forename: Gareth R
authors.initials: GR
authors.lastname: Lewis
authors.forename: Gilda
authors.initials: G
authors.lastname: Tachedjian
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D002460:Cell Line; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology*; D004355:Drug Stability; D005260:Female; D015699:HIV Envelope Protein gp120 / Q000737:chemistry / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects / Q000378:metabolism; D018258:Herpesvirus 2, Human / Q000187:drug effects; D006801:Humans; D008239:Lysine / Q000737:chemistry; D051379:Mice; D008958:Models, Molecular; D008968:Molecular Conformation; D019713:Receptors, CCR5 / Q000378:metabolism; D019718:Receptors, CXCR4 / Q000378:metabolism; D013329:Structure-Activity Relationship
chemical_list: D000998:Antiviral Agents; D050091:Dendrimers; D015699:HIV Envelope Protein gp120; C104700:PAMAM Starburst; D019713:Receptors, CCR5; D019718:Receptors, CXCR4; C514793:gp120 protein, Human immunodeficiency virus 1; D008239:Lysine
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