HIV-1 RT dimerization as an antiviral target

HIV-1 RT 二聚化作为抗病毒靶点

• 批准号: 6799016
• 负责人: NICOLAS PAUL SLUIS-CREMER
• 金额: $ 21.62万
• 依托单位: UNIVERSITY OF PITTSBURGH AT PITTSBURGH
• 依托单位国家: 美国
• 财政年份: 2004
• 资助国家: 美国
• 起止时间: 2004-03-01 至 2006-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6799016
• 关键词: DNA directed DNA polymerase; RNA directed DNA polymerase; SDS polyacrylamide gel electrophoresis; antiAIDS agent; antiviral agents; combinatorial chemistry; dimer; drug design /synthesis /production; enzyme activity; enzyme structure; gel filtration chromatography; high performance liquid chromatography; high throughput technology; human immunodeficiency virus 1; nucleosides; reverse transcriptase inhibitors; ribonuclease H; western blottings

DESCRIPTION (provided by applicant): Combinatorial anti-retroviral therapies have been remarkably effective in controlling the progression of AIDS and in prolonging the life of patients infected by HIV. However, while the current drug therapy can delay the progression of the disease it can not eradicate the virus, and its use readily leads to the emergence of drug resistant HIV strains. Furthermore, the emergence of viral resistance to one drug frequently results in a cross resistance to other drugs that exhibit similar chemical structures and mechanisms of action. Thus, the identification of novel viral targets and/or the development of new classes of antiviral compounds are essential in the fight against HIV/AIDS. HIV-1 reverse transcriptase (RT) is a heterodimeric enzyme consisting of a 66-kDa subunit (p66) and a p66- derived 51-kDa subunit (p51). The DNA polymerase and ribonuclease H (RNase H) activities of the enzyme are entirely dependent on the dimeric structure of the enzyme. Accordingly, dimerization of HIV-1 RT provides a novel therapeutic target for the identification of a new class of antiviral compounds. We have recently developed an in vitro high throughput screening (HTS) assay that reproducibly detects the intersubunit interactions between the p66 and p51 subunits of HIV-1 RT. Furthermore this assay is sensitive to compounds that have previously been shown to either inhibit or enhance the inter-subunit interactions of the enzyme. In light of this, the project described in this proposal comprises two Specific Aims: (1) to optimize and validate the in vitro HTS assay for HIV-1 RT dimerization; and (2) to screen a chemical and a natural product library for inhibitors of HIV-1 RT dimerization. Due to its essential role in HIV-1 replication, RT is already a primary target for the development of antiviral compounds. However, the elucidation and/or identification of inhibitors of HIV-1 RT dimerization would create a new therapeutic class of drugs that would exhibit mechanisms of action entirely different from the nucleoside and nonnucleoside RT inhibitors that are currently used in the treatment of HIV-1 infected individuals.

描述（由申请人提供）：联合抗逆转录病毒疗法在控制艾滋病进展和延长感染艾滋病毒的患者生命方面非常有效。然而，目前的药物治疗虽然可以延缓疾病的进展，但无法根除病毒，而且很容易导致耐药艾滋病毒株的出现。此外，病毒对一种药物产生耐药性常常会导致对具有相似化学结构和作用机制的其他药物产生交叉耐药性。因此，识别新的病毒靶标和/或开发新型抗病毒化合物对于对抗艾滋病毒/艾滋病至关重要。 HIV-1 逆转录酶 (RT) 是一种异二聚体酶，由 66 kDa 亚基 (p66) 和 p66 衍生的 51 kDa 亚基 (p51) 组成。该酶的 DNA 聚合酶和核糖核酸酶 H (RNase H) 活性完全取决于酶的二聚体结构。因此，HIV-1 RT的二聚化为鉴定一类新的抗病毒化合物提供了新的治疗靶点。我们最近开发了一种体外高通量筛选 (HTS) 测定法，可重复检测 HIV-1 RT 的 p66 和 p51 亚基之间的亚基间相互作用。此外，该测定对先前已被证明可以抑制或增强酶的亚基间相互作用的化合物敏感。有鉴于此，本提案中描述的项目包括两个具体目标：（1）优化和验证 HIV-1 RT 二聚化的体外 HTS 测定； (2) 筛选 HIV-1 RT 二聚化抑制剂的化学品和天然产物库。 由于其在 HIV-1 复制中的重要作用，RT 已经成为抗病毒化合物开发的主要目标。然而，HIV-1 RT二聚化抑制剂的阐明和/或鉴定将创造出一类新的治疗药物，其作用机制与目前用于治疗 HIV-1 的核苷和非核苷 RT 抑制剂完全不同。感染者。