Inhibitors Targeting HIV Integrase Multimers

针对 HIV 整合酶多聚体的抑制剂

• 批准号: 8294551
• 负责人: Jacques J. Kessl
• 金额: $ 22.88万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-01 至 2014-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8294551
• 关键词: 2-cyclopentyl-5-(5-isoquinolylsulfonyl)-6-nitro-1H-benzo(D)imidazole; Address; Affect; Affinity; Anti-HIV Agents; Antiviral Agents; Binding; Biological Assay; Clinical; Computers; Development; Enzymes; HIV; HIV Integrase; HIV Integrase Inhibitors; HIV-1; In Vitro; Individual; Inhibitory Concentration 50; Integrase; Integrase Inhibitors; Lead; Molecular Conformation; Pharmaceutical Preparations; Phenotype; Reporting; Resistance; Side; Site; Specificity; Structure; Testing; Viral; analog; antiretroviral therapy; base; design; dimer; drug discovery; flexibility; functional group; improved; inhibitor/antagonist; new therapeutic target; novel; resistant strain; small molecule; tool; viral DNA

DESCRIPTION (provided by applicant): The continuous emergence of HIV phenotypes resistant to the current anti-HIV drugs dictates a need to develop new therapies with alternative mechanisms of inhibition. HIV integrase (IN) is commonly viewed as an important antiviral target for the following reasons: its catalytic activities are required for viral replication, there is no closely related cellular equivalent of IN, and specific IN inhibitors are likely to be effective against viral strains resistant to currently available therapies. The present proposal focuses on exploiting HIV IN multimers as a new therapeutic target. The main novelty of my approach is to stabilize rather than destabilize IN multimers in the inactive conformation. The rationale for this has been provided by my recent findings which demonstrated that unliganded IN subunits have to be highly dynamic and flexible in order to form functional multimers in the presence of viral DNA. Restricting IN flexibility adversely affects its catalytic activities. As a proof of principle I have reported a small molecule inhibitor (compound 1) that effectively binds at the IN dimer interface and stabilizes interacting subunits into an inactive conformation. These findings led me to the following hypothesis: HIV IN possesses unique structural pockets that can be selectively targeted by small molecules to inhibit viral integration by locking IN into an unproductive multimeric state. To address this hypothesis, my preliminary studies have identified two separate sites (which are termed here as "bottom" and "side" pockets) at the IN dimer interface suitable for binding of small allosteric inhibitors. Aim 1 will focus to increase the binding specificity and affinity of compound 1 for the "bottom" pocket; aim 2 will rationally design new allosteric molecules selectively binding the "side" pocket.

描述（由申请人提供）：抗当前抗HIV药物的HIV表型的连续出现决定了需要采用具有替代性抑制机制的新疗法。由于以下原因，HIV整合酶（IN）通常被视为重要的抗病毒靶标：其催化活性是病毒复制所必需的，没有密切相关的细胞等效性，并且抑制剂中的特异性可能有效地抵抗了抗当前可用疗法的病毒株。本提案的重点是利用多聚体中的艾滋病毒作为新的治疗靶点。我方法的主要新颖性是在不活动构象中稳定而不是在多聚体中稳定。我最近的发现表明，亚基中非配置必须具有高度动态和灵活性，才能在病毒DNA的存在下形成功能多聚体。限制灵活性会对其催化活性产生不利影响。作为原理的证明，我报道了一个小分子抑制剂（化合物1），该抑制剂可有效地在二聚体界面结合并将相互作用的亚基稳定为无活性构象。这些发现导致我提出了以下假设：HIV具有独特的结构口袋，可以通过锁定成非生产力的多聚体状态来选择性地靶向小分子来抑制病毒整合。为了解决这一假设，我的初步研究已经确定了两个单独的位点（在这里称为“底部”和“侧面”口袋），适用于适合于小型变构抑制剂结合的二聚体界面。 AIM 1将集中精力增加化合物1对“底部”袋的结合特异性和亲和力； AIM 2将合理设计新的变构分子选择性地结合“侧面”袋。