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）：对当前抗 HIV 药物耐药的 HIV 表型的不断出现表明需要开发具有替代抑制机制的新疗法。 HIV整合酶（IN）通常被视为重要的抗病毒靶点，原因如下：其催化活性是病毒复制所必需的，没有与IN密切相关的细胞等价物，并且特定的IN抑制剂可能对耐药病毒株有效目前可用的疗法。目前的提案重点是利用 HIV IN 多聚体作为新的治疗靶点。我的方法的主要新颖之处在于稳定而不是破坏非活性构象中的多聚体的稳定。我最近的研究结果提供了其基本原理，该研究结果表明，未配体的 IN 亚基必须具有高度动态性和灵活性，才能在病毒 DNA 存在的情况下形成功能性多聚体。限制 IN 的灵活性会对其催化活性产生不利影响。作为原理证明，我报告了一种小分子抑制剂（化合物 1），它可以有效地结合在 IN 二聚体界面上，并将相互作用的亚基稳定为非活性构象。这些发现使我得出以下假设：HIV IN 具有独特的结构袋，可以被小分子选择性地靶向，通过将 IN 锁定为非生产性多聚体状态来抑制病毒整合。为了解决这个假设，我的初步研究在 IN 二聚体界面上确定了两个独立的位点（此处称为“底部”和“侧”袋），适合与小变构抑制剂结合。目标 1 将重点提高化合物 1 对“底部”口袋的结合特异性和亲和力；目标2将合理设计新的变构分子选择性地结合“侧”袋。