Anti-Human Immunodeficiency Virus Activity of Thiol-Ene Carbosilane Dendrimers and Their Potential Development as a Topical Microbicide.

The concept of a "microbicide" was born out of the lack of a vaccine against HIV and the difficulty of women in ensuring the use of preventive prophylaxis by their partners, especially in developing countries. Approaches using polyanionic carbosilane dendrimers have shown promise in the development of new microbicides. We have developed and evaluated two anionic carbosilane dendrimers with sulfonate and carboxylate terminal groups, G2-STE16 and G2-CTE16. Both dendrimers showed high biosafety in human epithelial cell lines derived from the vagina and in primary blood human cells (PBMCs). The dendrimers not only have a greater capacity to block the entry of different X4- and R5-HIV-1 isolates into epithelial cells but also prevent the HIV-1 infection of activated PBMCs. The treatment of epithelial cells with different carbosilane dendrimers did not produce changes in the activation or proliferation of PBMCs or in the expression of CD4, CCR5 or CXCR4. Computational modeling showed significantly higher affinities for the complexes G2-STE16/gp120 and G2-CTE16/gp120. Moreover, no irritation or vaginal lesions were detected in female BALB/c mice after vaginal administration of the dendrimers. Summing up, G2-STE16 and G2-CTE16 are easy to synthesize and compatible with functional groups, and the purification steps are easy and short. Our results have clearly demonstrated that these dendrimers have high potency as a topical microbicide against HIV-1 infection.