title: Inhibition of herpes simplex virus type 1 and type 2 infections by peptide-derivatized dendrimers.
abstract: In response to the need for new antiviral agents, dendrimer-based molecules have been recognized as having a large number of potential therapeutic applications. They include peptide-derivatized dendrimers, which are hyperbranched synthetic well-defined molecules which consist of a peptidyl branching core and covalently attached surface functional peptides. However, few studies have addressed their applications as direct-acting antiviral agents. Here, we report on the ability of the peptide dendrimer SB105 and its derivative, SB105_A10, to directly inhibit herpes simplex virus 1 (HSV-1) and HSV-2 in vitro replication, with favorable selective indexes discerned for both compounds. An analysis of their mode of action revealed that SB105 and SB105_A10 prevent HSV-1 and HSV-2 attachment to target cells, whereas SB104, a dendrimer with a different amino acid sequence within the functional group and minimal antiviral activity, was ineffective in blocking HSV attachment. Moreover, both SB105 and SB105_A10 retained their ability to inhibit HSV adsorption at pH 3.0 and 4.0 and in the presence of 10% human serum proteins, conditions mimicking the physiological properties of the vagina, a potential therapeutic location for such compounds. The inhibition of HSV adsorption is likely to stem from the ability of SB105_A10 to bind to the glycosaminoglycan moiety of cell surface heparan sulfate proteoglycans, thereby blocking virion attachment to target cells. Finally, when combined with acyclovir in checkerboard experiments SB105_A10 exhibited highly synergistic activity. Taken together, these findings suggest that SB105 and SB105_A10 are promising candidates for the development of novel topical microbicides for the prevention of HSV infections.
authors.affiliation: Department of Public Health and Microbiology, University of Turin, Turin, Italy.
authors.forename: Anna
authors.initials: A
authors.lastname: Luganini
authors.forename: Silvia Fabiole
authors.initials: SF
authors.lastname: Nicoletto
authors.forename: Lorena
authors.initials: L
authors.lastname: Pizzuto
authors.forename: Giovanna
authors.initials: G
authors.lastname: Pirri
authors.forename: Andrea
authors.initials: A
authors.lastname: Giuliani
authors.forename: Santo
authors.initials: S
authors.lastname: Landolfo
authors.forename: Giorgio
authors.initials: G
authors.lastname: Gribaudo
mesh_terms: D000818:Animals; D000998:Antiviral Agents / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D002460:Cell Line; D002522:Chlorocebus aethiops; D050091:Dendrimers / Q000138:chemical synthesis / Q000737:chemistry* / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects* / Q000502:physiology*; D018258:Herpesvirus 2, Human / Q000187:drug effects* / Q000502:physiology*; D006801:Humans; D006863:Hydrogen-Ion Concentration; D015151:Immunoblotting; D010455:Peptides / Q000737:chemistry*; D014709:Vero Cells; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D050091:Dendrimers; D010455:Peptides