Defining an HIV Integrase Inhibitor Binding Pocket

描述（由申请人提供）：人类免疫缺陷病毒1型（HIV-1）是获得性免疫缺陷综合征（AIDS）的病原体。尽管在治疗方面取得了突破，但迫切需要针对病毒复制周期新位点的新型抗HIV药物。其中一个目标是整合酶（IN），一种HIV复制所必需的酶。已经确定了几种IN抑制剂，并描述了针对三种此类抑制剂的拟议抑制剂结合口袋。抑制剂结合口袋的性质以及口袋中的每个氨基酸在抑制剂结合，蛋白质的酶活性和HIV复制中所起的作用将被研究。此外，还将探索艾滋病毒对这些抑制剂产生耐药性的机制。为完成这一任务，提出了以下具体目标：

DESCRIPTION (provided by applicant): 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.