Rational Design of antivrials targeted to HIV-1 capsid

摘要 高效抗逆转录病毒疗法(HAART)的引入显著 降低了HIV-1感染者的发病率和死亡率。然而， 耐药性的发展对现有的治疗方案构成了严重威胁 对病人来说。此外，最近关于默克HIV-1临床试验失败的报道 疫苗和几种杀微生物剂加强了识别和开发新的 抗HIV-1药物的靶标。新药将拓宽联合治疗的范围 并将有助于减少抗药性HIV-1变种的发展。衣壳 HIV-1 Gag多聚蛋白的结构域在病毒组装和 成熟，因此是开发药物的一个重要的潜在靶点 用于艾滋病治疗。我们建议开发新的抗HIV-1药物，目标是高度 保守的疏水口袋和C-末端结构域的二聚界面 HIV-1衣壳蛋白(CTD)。我们的发现工作将基于我们广泛的 用几个合理设计的螺旋稳定电池获得的初步数据 穿透性多肽和小分子先导化合物。我们的方法将采取 我们最近的一种细胞穿透肽(Nyad-1)溶液结构的优势 1)与CTD的复合体。我们将优化先导肽和小分子 使用药物化学和计算机辅助设计相结合的化合物 接近了。此外，我们还将通过对接继续搜索锌数据库- 基于虚拟筛选技术来识别具有 可能结合到疏水口袋和二聚体界面并抑制病毒 组装和成熟。我们将详细阐明其分子机制。 这些抑制物会破坏HIV-1的组装和成熟。建议的目标是 研究包括两个方面：1)使用基于结构的合理设计来开发强大的细胞- 抑制HIV-1组装和成熟的穿透性多肽和小分子 以及2)建立这些抑制物破坏HIV-1组装的机制 和成熟。这些研究中确定的衣壳类CTD抑制剂将发挥作用 作为阐明在形成未成熟和 成熟的病毒颗粒。本提案中描述的研究可能会导致 针对HIV-1衣壳的新型抗逆转录病毒治疗药物的开发。

Abstract The introduction of highly active antiretroviral therapy (HAART) has significantly decreased the morbidity and mortality among HIV-1 infected people. However, the development of drug resistance poses a serious threat to the treatment options available to patients. Furthermore, recent reports of failure in clinical trials of Merck HIV-1 vaccines and several microbicides reinforce the critical need to identify and develop new targets for anti-HIV-1 drugs. Novel drugs will broaden the scope of combination therapy and will help in reducing development of drug-resistant HIV-1 variants. The capsid domain of the HIV-1 Gag polyprotein plays a critical role in virus assembly and maturation and therefore represents an important potential target for developing drugs for AIDS therapy. We propose to develop novel anti-HIV-1 agents targeted to a highly conserved hydrophobic pocket and to the dimerization interface in the C-terminal domain (CTD) of the HIV-1 capsid. Our discovery effort will be based on our extensive preliminary data obtained with several rationally designed ¿-helically stable cell- penetrating peptides and small-molecule lead compounds. Our approach will take advantage of our recent solution structure of one of the cell-penetrating peptides (NYAD- 1) in complex with the CTD. We will optimize the lead peptides and small-molecule compounds using a combination of medicinal chemistry and computer-aided design approaches. In addition, we will continue searching the ZINC database by docking- based virtual screening techniques to identify small drug-like compounds which have the potential to bind to the hydrophobic pocket and the dimer interface and inhibit viral assembly and maturation. We will elucidate in detail the molecular mechanism by which these inhibitors disrupt HIV-1 assembly and maturation. The goals of the proposed studies are two-fold: 1) To use structure-based rational design to develop potent cell- penetrating peptides and small molecules that inhibit HIV-1 assembly and maturation and 2) To establish the mechanism by which these inhibitors disrupt HIV-1 assembly and maturation. The capsid CTD-based inhibitors identified in these studies will serve as probes for elucidating the underlying structural requirements in forming immature and mature virus particles. The studies described in this proposal may lead to the development of a new class of antiretroviral therapeutics targeting the HIV-1 capsid.