Oxadaizols: Rationally designed compounds targeting HIV nuclear importation

描述（由申请人提供）：尽管最近在抗hiv治疗方面取得了进展，但在hiv感染患者的长期治疗过程中，药物毒性和耐药分离株的出现要求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预整合复合体的核易位过程。在我们的初步研究中，我们发现了一类通过靶向基质蛋白（MA）抑制HIV-1核输入的恶二唑化合物。这些化合物是通过计算机辅助药物设计选择的，预计会在MA的核定位信号（NLS）附近结合，从而阻断MA介导的核输入。该小组的先导化合物ti- 367在T淋巴细胞和巨噬细胞培养中显示出有效的抗hiv活性，并抑制体外培养淋巴组织中HIV-1的复制。实时PCR分析表明，ti -367特异性抑制病毒DNA的核输入。在本申请中，我们建议进一步表征ti -367的分子作用机制，并将此分析扩展到与ti -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。为实现这些目标，将追求下列具体目标：产生并表征对恶二唑化合物耐药的HIV-1变异。2. 表征恶二唑衍生物与MA的相互作用并分析其抗hiv活性。这一探索性提议完全符合该计划的目标，因为它解决了艾滋病毒研究中的一个创新概念，对基础研究和临床研究都有影响。提出的实验有望为这类新型抗hiv化合物的作用机制假说提供直接检验。一旦完成，这些研究有望通过一种不同于任何其他目前使用的药物的新机制确定有效的抗艾滋病毒化合物。在本应用中提出的研究将描述一类化合物的特征，这些化合物针对HIV生命周期中的新目标：病毒DNA到细胞核的运输。这些研究与公共卫生高度相关，因为预计它们将扩大现有抗艾滋病毒药物的种类，从而为防治艾滋病毒感染患者中常见的耐药性提供机会。

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.