Defining an HIV Integrase Inhibitor Binding Pocket

描述(申请人提供)：人类免疫缺陷病毒1型(HIV-1)是导致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置的新型抗艾滋病毒药物。其中一个靶点是整合酶(IN)，这是一种对艾滋病毒复制至关重要的酶。已经确定了几类IN抑制剂，并描述了建议的三类抑制剂的抑制剂结合口袋。将研究抑制物结合口袋的性质以及口袋内的每个氨基酸在抑制物结合、对蛋白质的酶活性和艾滋病毒复制方面所起的作用。此外，还将探索艾滋病毒对这种抑制剂产生抗药性的机制。为完成这项任务，提出了以下具体目标： 1.绘制HIV IN抑制剂结合口袋。 2.确定建议的IN抑制剂结合口袋内突变的生物学效应。 3.确定对IN抑制剂的抗性性质。 4.与抑制剂共结晶。 通过成功地完成这些目标，将确定HIV IN上的抑制剂结合口袋的性质。最终，这些发现将被用于合成更有效的HIV IN抑制剂，这些抑制剂可能被证明对治疗HIV感染有用。具体地说，将根据化学作用、大小和口袋内的电荷合成与抑制剂结合口袋内的每个残基最大限度地相互作用的分子。此外，通过了解抗药性的本质，可以设计和合成具有抗抗药性HIV活性的新分子。

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.