Defining an HIV Integrase Inhibitor Binding Pocket

Robinson, William

Abstract

The human immunodeficiency virus type 1 (HIV-1) is the causative agent in the acquired immune deficiency syndrome (AIDS). Despite breakthroughs in therapy, there is an urgent need for novel anti- HIV agents that are targeted at new sites of the viral replication cycle. One such target is integrase (IN), an enzyme essential for HIV replication. Several classes of IN inhibitor have been identified and a proposed inhibitor-binding pocket for three such classes of inhibitor has been described. The nature of the inhibitor-binding pocket and the role each amino acid within the pocket plays in inhibitor binding, on the enzymatic activities of the protein, and on HIV replication will be investigated. Furthermore, the mechanisms by which HIV becomes resistant to such inhibitors will be explored. To accomplish this task, the following specific aims are proposed: 1. Map an HIV IN inhibitor-binding pocket or pockets. 2. Determine the biological effects of mutations within a proposed IN inhibitor-binding pocket. 3. Determine the nature of resistance to IN inhibitors. 4. Co-crystallize IN with inhibitors. Through the successful completion of these aims, the nature of the inhibitor-binding pocket on HIV IN will be determined. Ultimately, these findings will be used to synthesize more potent inhibitors of HIV IN that may prove useful in the treatment of HIV infection. Specifically, molecules will be synthesized that interact maximally with each residue within the inhibitor-binding pocket based on chemical interactions, size, and charge within the pocket. Moreover, by understanding the nature of inhibitor resistance, new molecules with activity against inhibitor-resistant HIV can be designed and synthesized.