Dendrimers, a New Class of Candidate Topical Microbicides with Activity against Herpes Simplex Virus Infection

Abstract

Dendrimers are large highly branched macromolecules synthesized from a polyfunctional core. They have shown a variety of biological properties, including, in some instances, antiviral activity. In this study, five dendrimers were evaluated for in vitro activity against herpes simplex virus (HSV) types 1 and 2 by cytopathic effect (CPE) inhibition and plaque reduction (PR) assay in human foreskin fibroblast cells. All of the compounds were active against both virus types in the CPE inhibition assay, in which drug was added to the cells prior to the addition of virus. Antiviral activity was reduced or lost in the PR assays, in which the cells were incubated with the virus before the drug was added. The prophylactic efficacy suggested that the dendrimers might have potential as topical microbicides, products intended to be applied to the vaginal or rectal mucosa to protect against sexually transmitted infections. Three dendrimers were evaluated for this application against genital HSV infection in mice. Two of the compounds, BRI-2999 and BRI-6741, significantly reduced infection rates when 15 μl of a 100-mg/ml solution was administered immediately prior to intravaginal challenge, and the most effective compound, BRI-2999, provided significant protection even when applied 30 min before challenge. This is the first report of microbicidal activity by dendrimers in vivo.