Topical microbicides to stop sexually transmitted diseases, such as herpes simplex virus type 2 (HSV-2), are urgently needed. The emerging field of nanotechnology offers novel suitable tools for addressing this challenge. Our objective was to study, in vitro and in vivo, antiherpetic effect and antiviral mechanisms of several polyanionic carbosilane dendrimers with anti-HIV-1 activity to establish new potential microbicide candidates against sexually transmitted diseases. Plaque reduction assay on Vero cells proved that G2-S16, G1-S4, and G3-S16 are the dendrimers with the highest inhibitory response against HSV-2 infection. We also demonstrated that our dendrimers inhibit viral infection at the first steps of HSV-2 lifecycle: binding/entry-mediated events. G1-S4 and G3-S16 bind directly on the HSV-2, inactivating it, whereas G2-S16 adheres to host cell-surface proteins. Molecular modeling showed that G1-S4 binds better at binding sites on gB surface than G2-S16. Significantly better binding properties of G1-S4 than G2-S16 were found in an important position for affecting transition of gB trimer from G1-S4 prefusion to final postfusion state and in several positions where G1-S4 could interfere with gB/gH-gL interaction. We demonstrated that these polyanionic carbosilan dendrimers have a synergistic activity with acyclovir and tenofovir against HSV-2, in vitro. Topical vaginal or rectal administration of G1-S4 or G2-S16 prevents HSV-2 transmission in BALB/c mice in values close to 100%. This research represents the first demonstration that transmission of HSV-2 can be blocked by vaginal/rectal application of G1-S4 or G2-S16, providing a step forward to prevent HSV-2 transmission in humans.

• MeSH
• acyklovir farmakologie   MeSH
• antiinfekční látky farmakologie   MeSH
• antivirové látky farmakologie   MeSH
• aplikace rektální MeSH
• Cercopithecus aethiops MeSH
• dendrimery chemie   MeSH
• epitelové buňky účinky léků   virologie   MeSH
• herpes simplex MeSH
• koncentrace vodíkových iontů MeSH
• lidé MeSH
• lidský herpesvirus 2 účinky léků   MeSH
• molekulární modely MeSH
• myši inbrední BALB C MeSH
• polymery chemie   MeSH
• rektum účinky léků   virologie   MeSH
• silany chemie   MeSH
• tenofovir farmakologie   MeSH
• vagina účinky léků   virologie   MeSH
• Vero buňky MeSH
• virové proteiny metabolismus   MeSH
• zvířata MeSH
• Check Tag
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• zvířata MeSH
• Publikační typ
• časopisecké články MeSH

Nanotechnology-derived platforms, such as dendrimers, are very attractive in several biological applications. In the case of human immunodeficiency virus (HIV) infection, polyanionic carbosilane dendrimers have shown great potential as antiviral agents in the development of novel microbicides to prevent the sexual transmission of HIV-1. In this work, we studied the mechanism of two sulfated and naphthylsulfonated functionalized carbosilane dendrimers, G3-S16 and G2-NF16. They are able to inhibit viral infection at fusion and thus at the entry step. Both compounds impede the binding of viral particles to target cell surface and membrane fusion through the blockage of gp120-CD4 interaction. In addition, and for the first time, we demonstrate that dendrimers can inhibit cell-to-cell HIV transmission and difficult infectious synapse formation. Thus, carbosilane dendrimers' mode of action is a multifactorial process targeting several proteins from viral envelope and from host cells that could block HIV infection at different stages during the first step of infection.

• MeSH
• antivirové látky chemie   farmakologie   MeSH
• dendrimery chemie   MeSH
• fúze membrán účinky léků   MeSH
• HIV infekce prevence a kontrola   virologie   MeSH
• HIV obalový protein gp120 antagonisté a inhibitory   chemie   metabolismus   MeSH
• HIV-1 účinky léků   MeSH
• lidé MeSH
• molekulární modely MeSH
• polymery chemie   MeSH
• replikace viru účinky léků   MeSH
• silany chemie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH