title: Evaluation of dendrimer SPL7013, a lead microbicide candidate against herpes simplex viruses.
abstract: Dendrimers are a novel class of polyanionic macromolecules with broad-spectrum antiviral activities and minimal toxicities. A new generation of amide dendrimer, SPL7013, was evaluated as a lead microbicide candidate against herpes simplex viruses (HSV). The plaque reduction assays showed that the 50% effective concentrations (EC(50)) determined by pre-treatment of cells were 2.0 microg/ml for HSV-1 and 0.5 microg/ml for HSV-2. Inhibitory effects were also observed on HSV-infected cells with EC(50)s of 6.1 microg/ml for HSV-1 and 3.8 microg/ml for HSV-2. These are the mean values from the test results of six batches of SPL7013. SPL7013 was also shown to be equally potent against HSV drug-resistant strains. SPL7013 completely inhibited viral adsorption to Vero cells at concentrations of higher than 3 microg/ml. Analyzed by a LightCycler assay after treatment of HSV-infected cells for 17 h, SPL7013 showed strong inhibition of HSV DNA synthesis with EC(50)s of approximately 6.2 and 2.0 microg/ml for HSV-1 and HSV-2, respectively. SPL7013 retained its anti-HSV activity even after treatment at acidic pHs 3.0 and 4.0 for 2 h. The presence of 10% human serum proteins did not affect the anti-HSV activity of SPL7013. SPL7013 was not toxic to Vero cells up to the highest concentration tested (10,000 microg/ml). Effects on cell proliferation were tested on two epithelial cell lines in both stationary and dividing phases. The 50% cytotoxic concentrations (CC(50)) in all cases were greater than 10,000 microg/ml. Our data indicate that SPL7013 is a promising candidate for development as a vaginal microbicide and a therapeutic agent.
authors.affiliation: Viridae Clinical Sciences Inc., Vancouver, BC, Canada. gongedwin@yahoo.com
authors.forename: Edwin
authors.initials: E
authors.lastname: Gong
authors.forename: Barry
authors.initials: B
authors.lastname: Matthews
authors.forename: Tom
authors.initials: T
authors.lastname: McCarthy
authors.forename: Jianhua
authors.initials: J
authors.lastname: Chu
authors.forename: George
authors.initials: G
authors.lastname: Holan
authors.forename: John
authors.initials: J
authors.lastname: Raff
authors.forename: Stephen
authors.initials: S
authors.lastname: Sacks
mesh_terms: D000890:Anti-Infective Agents / Q000494:pharmacology; D000998:Antiviral Agents / Q000494:pharmacology*; D002460:Cell Line; D050091:Dendrimers; D005069:Evaluation Studies as Topic; D006561:Herpes Simplex / Q000821:virology; D018259:Herpesvirus 1, Human / Q000187:drug effects*; D018258:Herpesvirus 2, Human / Q000187:drug effects*; D008826:Microbial Sensitivity Tests; D011107:Polylysine / Q000494:pharmacology*; D014779:Virus Replication / Q000187:drug effects*
chemical_list: D000890:Anti-Infective Agents; D000998:Antiviral Agents; D050091:Dendrimers; D011107:Polylysine; C480351:astodrimer