Topical microbicides: a promising approach for controlling the AIDS pandemic via retroviral zinc finger inhibitors.

Publisher Summary Topical microbicides have the potential to significantly impact the human immunodeficiency virus/acquired immune deficiency syndrome (HIV/AIDS) pandemic by providing vulnerable populations with a self administered method to prevent HIV infection. The identification of a safe and effective HIV‐specific, virucidal microbicide has not been a priority for development, as evidenced by their limited representation in the microbicide pipeline since safety concerns were raised for the nonspecific, detergent, virucide Nonoxynol‐9. The optimal virucidal microbicide would be one that targets not only cell‐free but also cell‐associated virus, acting as a pluripotent, HIV‐specific virucide, capable of targeting multiple steps in the HIV replication cycle. This potentially has been achieved through the discovery and development of the thioester‐based, S‐acyl‐2‐mercaptobenzamide compounds targeting the HIV‐1 NCp7 nucleocapsid zinc finger. Experimental evidence shows that these inhibitors interact with a highly conserved protein sequence in a covalent manner to prevent the replication of both cell‐free (virucidal) and cell‐associated virus by irreversibly ejecting the coordinated zinc ion from the protein, thus altering its structure.