HIV-1 NCp7 as a target for the design of novel antiviral agents

The treatment of AIDS, which is caused by the human immunodeficiency virus type-1 (HIV-1), has been significantly improved by the association of reverse transcriptase inhibitors and protease inhibitors. However, the major problems observed with these compounds are: 1) the ability of HIV-1 to generate mutants resistant to the therapeutic agents and which are able to replicate nearly as well as the wild-type viruses; 2) the numerous side effects triggered by polytherapy, leading in several cases to voluntary interruption of treatment; and 3) the natural resistance of some patients to these therapies. The resistance encountered with compounds directed against reverse transcriptase or protease is mainly due to the ability of these compounds to generate mutations, reducing the binding affinities of specific inhibitors without significantly reducing the enzymes' catalytic properties. Therefore, there is great interest in searching for new antiviral agents that are able to overcome this critical problem of acquired resistance. One possible strategy could be to target viral proteins (or nucleic acid sequences) whose biological functions are ensured by domains that cannot be modified without a complete loss of activity. The HIV-1 nucleocapsid protein NCp7, which plays a critical role at different steps of the retrovirus life cycle, could be used for the development of such a new antiviral agent. Indeed, NCp7 possesses a three-dimensional structure centered around two highly conserved zinc fingers, and nuclear magnetic resonance studies associated with site-directed mutagenesis have shown that any modification of this structure leads to a complete loss of HIV-1 infectivity. On the basis of these results, different classes of NCp7 inhibitors have been developed including: 1) structural peptidomimetics of the essential biological determinants of NCp7 rationally developed by using the NCp7 structure; and 2) chemicals screened for their ability to destroy NCp7 folding by ejecting the zinc atom. These compounds display antiviral properties by disrupting different steps of the retroviral life cycle. Moreover, virions with inactivated NCp7 have been recently used for putative vaccines and immunological approaches.