Resumen de Polyanionic carbosilane dendrimers against viral infections: Human immunodeficiency Virus Type 1, Herpes Simplex Type 2 and Respiratory Syncytial Virus
The most common way to become infected by HIV-1 is by sexual intercourse. In the absence of an effective vaccine, topical microbicides provide a new approach to avoid the infection. However, during the recent years countless compounds have been evaluated in clinical trials to prevent HIV-1 infection, but all have failed due to “semen-derived enhanced virus infection” (SEVI) or induction of vaginal irritation and inflammation. Dendrimers have shown the ability to abrogate semen-enhanced viral infection in vitro when combined with antiretrovirals such us Tenofovir Disopropil Fumarate (TDF) or Maraviroc (MVC). When the biocompatibility of the polyanionic carbosilane dendrimer G2-S16 was evaluated in vivo, it was observed that 3% (w/v) vaginal application of G2-S16, in BALB/c mice, limits its distribution to the female vaginal tract, specifically to the non-sterile part, and that its vaginal application during 7 consecutive days did not produce vaginal irritation.
Importantly, many sexual transmitted infections (STIs), such as HSV-2, may increase vulnerability to HIV-1 infection. A screening was performed to evaluate the ability of polyanionic carbosilane dendrimers with anti-HIV-1 activity against HSV-2. These polyanionic carbosilane dendrimers inhibit the viral infection during the first steps of the HSV-2 life-cycle: binding/entry-mediated events. Molecular modeling of G1-S4 and G2-S16 with HSV-2 glycoprotein B (gB) showed that, in general, G1-S4 binds better than G2-S16 to selected binding sites on HSV-2 gB surface. Moreover, G1-S4, G2-16 and G3-S16 showed synergistic or additive effect in combination with TDF or Acyclovir (ACV).
In addition to STIs, there are about 200 million pregnancies every year, being 40% unintended. To also address this problem, studies based on the combination of the spermicide Platycodin D (PD) with different polyanionic carbosilane dendrimers (G1-S4 or G2-S16) showed that not only HIV-1 and HSV-2 infections were decreased, but also the combination acted as a spermicide which can also reduce the rate of unintended pregnancies.
Respiratory syncytial virus (RSV) is the most common cause of respiratory infection and bronchiolitis requiring hospitalization for infants under one year of age. RSV entry into the host cell is highly associated to heparin sulfate (HS). By using a cell-based screening, we have identified G1-S4, G2-S16 and G3-S16 as RSV inhibitors in vitro. These dendrimers inhibit early aspects of RSV infection: G1-S4 and G3-S16 bind directly to the virus, inactivating it, whereas G2-S16 adheres to the host cell surface proteins preventing further virus binding. Furthermore, when evaluated in vivo, G2-S16 inhibited RSV replication by 80%. In conclusion, G2-S16 is effective against RSV, supporting additional clinical research on the development of an effective therapy against RSV infection.
