New Inhibitors of HIV replication

描述(申请人提供)：艾滋病毒进入潜伏状态的能力对通过抗逆转录病毒疗法根除艾滋病毒-1感染造成了根本障碍，并促使人们继续对开发阻止潜伏前病毒重新出现的抑制剂感兴趣。本研究项目的目标是继续开发针对HIV-1 TAR RNA的新的抗病毒线索，同时抑制HIV-1启动子的反转录和转录延伸。这种抑制剂将能够阻止病毒在急性和慢性感染细胞中的复制，并针对在高效抗逆转录病毒疗法(HAART)存在的情况下持续缓慢复制的病毒的储存库。在之前的资助期间，我们已经确定了一种新的环肽先导，通过将肽化学扩展到包括非天然多肽侧链，以前所未有的活性结合到HIV TAR RNA上。这些先导肽类化合物穿透细胞膜，抑制初级淋巴细胞中的病毒复制，其活性与奈韦拉平相当。我们已经证明了其抗病毒活性与抑制逆转录和转录延伸相一致。我们现在建议：1.通过利用额外的非天然多肽侧链和对多肽骨架的修饰来优化TAT蛋白环肽模拟物的抗病毒活性以抑制Tar2的功能2.建立多肽前导的分子作用机制3.产生抗性突变体以充分验证这些抗病毒前导的分子靶点

DESCRIPTION (provided by applicant): The ability of HIV to enter a latent state creates a fundamental obstacle to the eradication of HIV-1 infection by anti-retroviral therapy and has prompted continued interest in developing inhibitors that block the re-emergence of latent proviruses. The goal of this research project is to continue the development of new antiviral leads that target the HIV TAR RNA, and inhibit at the same time reverse transcription and transcriptional elongation from the HIV-1 promoter. Such an inhibitor would be able to block viral replication in both acutely and chronically infected cells and target the reservoir of slowly replicating viruses that persists in the presence of Highly Active Anti Retroviral Therapy (HAART). In the previous funding period, we have identified a new cyclic peptide lead that binds to the HIV TAR RNA with unprecedented activity by expanding peptide chemistry to include un-natural peptidic side chains. The lead peptidomimetic compounds penetrate cellular membranes and inhibit viral replication in primary lymphocytes with activity comparable to nevirapine. We have demonstrated that the antiviral activity coincides with inhibition of both reverse transcription and transcriptional elongation. We now propose to: 1. Optimize the antiviral activity of the cyclic peptide mimetics of the Tat protein to inhibit the function of TARby exploiting additional un-natural peptide side chains and modifications of the peptide backbone 2. Establish the molecular mechanism of action of the peptide leads 3. Generate resistance mutants to fully validate the molecular targets of these anti-viral leads