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 l 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.

Peptide-derivatized dendrimers inhibit human cytomegalovirus infection by blocking virus binding to cell surface heparan sulfate

“…Among these, dendrimers and dendrimer-like molecules have recently been generated with surfaces formed of negative charges and screened for potential anti-herpes activities. Indeed, in vitro analysis has revealed that sulfonated and carboxylated polylysine dendrimers effectively block the HSV-1 and -2 infection of cells and non-primate animal studies have shown that they were able to protect animals against an intravaginal HSV-2 challenge (Bourne et al, 2000;Bernstein et al, 2003;Gong et al, 2005). However, in addition to inhibiting the HSV attachment, the sulfonate ddendrimers were also shown to act at a post-entry level by apparently inhibiting HSV DNA synthesis, which suggests that they could be used not only for prevention of HSV infection but also as inhibitors of viral replication (Gong et al, 2005).…”

Dendrimers as therapeutic agents: a systematic review

“…[31] Similar results were obtained by Bourne and colleagues upon administration of sulfonated (BRI-2999) and carboxylated (BRI-6741) dendrimers (Figure 3d) to mice prior to exposure to HSV. [68] Recently, Dixon and colleagues [69] have reported inhibitory action of sulfonated naphthyl polyphyrins against HIV infection of cells in vitro. Besides polyanionic dendrimers, unmodified polycationic PAMAM dendrimers have also been shown to inhibit viral replication by disrupting the interaction between HIV Tat protein and transacting response element (TAR) RNA, which is crucial in the life cycle of HIV-1.…”

Dendrimers as Antibacterial Agents

“…In most cases, Dendrimers have the ability of carrying biologically active agents by encapsulating them in the interior or generally, attaching them on the periphery of dendrimers. For example, most dendrimers displaying antimicrobial activities are terminated with antimicrobial agents, including ferrocene (Abd-Elzaher & Ali, 2006), quaternary ammonium , boron complexes (De Queiroz, 2006), carbohydrates (Rojo, 2004), and peptides (Bernstein et al, 2003, Bourne et al, 2000Janiszewska et al, 2006;Klajnert et al, 2006;Pini et al, 2005;Sechi et al, 2006).…”