New Inhibitors of HIV replication

描述（由申请人提供）：HIV进入潜伏状态的能力对通过抗逆转录病毒治疗根除HIV-1感染造成了根本性障碍，并促使人们继续关注开发阻断潜伏前病毒重新出现的抑制剂。该研究项目的目标是继续开发靶向HIV TAR RNA的新的抗病毒先导物，并同时抑制HIV-1启动子的逆转录和转录延伸。这种抑制剂将能够阻断急性和慢性感染细胞中的病毒复制，并靶向在高活性抗逆转录病毒疗法（HAART）存在下持续存在的缓慢复制病毒的储存库。 在上一个资助期内，我们已经确定了一种新的环肽先导化合物，它通过扩展肽化学以包括非天然肽侧链，以前所未有的活性与HIV TAR RNA结合。先导拟肽化合物可穿透细胞膜，抑制原代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，抗病毒活性与抑制逆转录和转录延伸相一致。我们现建议：1.优化达特蛋白的环状肽模拟物的抗病毒活性，通过利用额外的非天然肽侧链和肽骨架的修饰来抑制TAR的功能2。建立肽先导化合物作用的分子机制3.产生耐药突变体，以充分验证这些抗病毒先导化合物的分子靶点

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