Oxadaizols: Rationally designed compounds targeting HIV nuclear importation

Oxadaizols：合理设计的针对 HIV 核输入的化合物

• 批准号: 7497500
• 负责人: MICHAEL Ilya BUKRINSKY
• 金额: $ 22.76万
• 依托单位: GEORGE WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-30 至 2010-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7497500
• 关键词: Acquired Immunodeficiency Syndrome; Address; Anti-HIV Agents; Anti-HIV Therapy; Binding; Bioinformatics; Biology; CD4 Positive T Lymphocytes; Cell Nucleus; Cells; Class; Classification; Clinical; Clinical Research; Complex; Computer Assisted; Computer Simulation; Drug Design; Drug resistance; Drug toxicity; Drug usage; Employee Strikes; Exploratory/Developmental Grant; Genes; Goals; HIV; HIV-1; Investigation; Laboratories; Lead; Life Cycle Stages; Lymphoid Tissue; Mass Spectrum Analysis; Mediating; Molecular; Molecular Mechanisms of Action; Mutagenesis; Mutation; Nuclear; Nuclear Import; Nuclear Localization Signal; Nuclear Translocation; Patients; Phenotype; Polymerase Chain Reaction; Process; Proliferating; Property; Proteins; Proteomics; Public Health; Research; Resistance; Series; T-Lymphocyte; Testing; Time; Tyrosine; Variant; Viral; Virus; Work; base; concept; design; experience; fighting; inhibitor/antagonist; innovation; macrophage; matrix protein, Human immunodeficiency virus type 1; molecular modeling; novel; research study; viral DNA; vpr Gene Products

DESCRIPTION (provided by applicant): Despite recent progress in anti-HIV therapy, drug toxicity and emergence of drug-resistant isolates during long- term treatment of HIV-infected patients necessitate the search for new targets that can be used to develop novel anti-viral agents. One such target is the process of nuclear translocation of the HIV-1 pre-integration complex. In our preliminary studies, we identified a class of oxadiazol compounds that inhibit HIV-1 nuclear import by targeting the matrix protein (MA). These compounds were selected using computer-assisted drug design and are predicted to bind to MA near its nuclear localization signal (NLS) thus blocking MA-mediated nuclear import. The lead compound from this group, ITI-367, showed potent anti-HIV activity in cultures of T lymphocytes and macrophages, and also inhibited HIV-1 replication in ex vivo cultured lymphoid tissue. Real- time PCR analysis demonstrated that ITI-367 specifically inhibited nuclear import of viral DNA. In this application, we propose to further characterize the molecular mechanism of action of ITI-367 and to expand this analysis to other compounds related to ITI-367 in an attempt to identify the most potent inhibitor of HIV-1 replication. Towards these goals, the following Specific Aims will be pursued: 1. To produce and characterize the HIV-1 variants resistant to oxadiazol compounds. 2. To characterize interaction between oxadiazol derivatives and MA and analyze their anti-HIV activity. This exploratory proposal is fully consistent with the goals of this PA as it addresses an innovative concept in HIV research which has implications both for basic and clinical studies. Proposed experiments are expected to provide a direct test for the hypothesis regarding the mechanism of action of this new class of anti-HIV compounds. Upon completion, these studies are expected to define potent anti-HIV compounds working through a novel mechanism different from that of any other currently used drug. Studies proposed in this application will characterize a class of compounds aimed at a novel target in HIV life cycle: transport of the viral DNA to the nucleus. These studies are highly relevant to public health as they are expected to expand the repertoire of available anti-HIV drugs, thus providing an opportunity to fight drug resistance often seen in HIV-infected patients.

描述（由申请人提供）：尽管抗HIV治疗最近取得了进展，但在HIV感染患者的长期治疗期间，药物毒性和耐药分离株的出现使得有必要寻找可用于开发新型抗病毒药物的新靶点。其中一个目标是HIV-1整合前复合物的核转位过程。在我们的初步研究中，我们确定了一类恶二唑化合物，通过靶向基质蛋白（MA）抑制HIV-1核输入。使用计算机辅助药物设计选择这些化合物，并预测在其核定位信号（NLS）附近与MA结合，从而阻断MA介导的核输入。来自该组的先导化合物ITI-367在T淋巴细胞和巨噬细胞培养物中显示出有效的抗HIV活性，并且还在离体培养的淋巴组织中抑制HIV-1复制。真实的-时间PCR分析证明ITI-367特异性地抑制病毒DNA的核输入。在本申请中，我们建议进一步表征ITI-367的分子作用机制，并将该分析扩展到与ITI-367相关的其他化合物，以试图确定最有效的HIV-1复制抑制剂。为了实现这些目标，将追求以下具体目标：1。制备和表征对恶二唑化合物耐药的HIV-1变异体。2.研究恶二唑衍生物与MA的相互作用，并分析其抗HIV活性。这一探索性建议与本PA的目标完全一致，因为它涉及艾滋病毒研究中的创新概念，对基础和临床研究都有影响。拟议的实验预计将提供一个直接测试的假设，关于这类新的抗艾滋病毒化合物的作用机制。完成后，这些研究预计将确定有效的抗艾滋病毒化合物，通过一种不同于任何其他目前使用的药物的新机制发挥作用。本申请中提出的研究将表征一类针对HIV生命周期中新靶点的化合物：将病毒DNA转运到细胞核。这些研究与公共卫生高度相关，因为它们有望扩大现有抗艾滋病毒药物的范围，从而为抗击艾滋病毒感染患者中常见的耐药性提供机会。