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PROTACS Against Nef as a Functional Cure for HIV Infection

PROTACS Against Nef as a Functional Cure for HIV Infection
PROTACS 针对 Nef 作为 HIV 感染的功能性治疗
批准号:
10079715
负责人:
Thomas E. Smithgall
金额:
$30.0万
依托单位国家:
美国
项目类别:
财政年份:
2020
资助国家:
美国
项目状态:
已结题
起止时间:
2020-07-01 至 2022-06-30
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中文摘要
翻译
抽象的。现有的抗逆转录病毒药物并没有清除HIV-1潜伏的宿主,这突显出迫切需要 新的治疗策略。HIV-1 Nef辅助因子是药物开发的一个有吸引力的目标,因为 它在艾滋病毒-1生命周期和免疫系统逃逸中的关键作用。我们小组发现了新奇的小 直接与Nef结合并阻断其许多功能的分子,包括增强病毒感染性和 供者外周血单核细胞的复制。重要的是,我们的Nef抑制剂在潜伏期内拯救了细胞表面MHC-I的表达。 感染的患者来源的CD4T细胞,能够通过自体CTL识别和杀伤。因此,Nef抑制剂 代表了一种抗逆转录病毒治疗的创新方法,可能提供了一条根除病毒感染的途径 太棒了。我们最有希望的一类抑制剂(羟基吡唑)在体外与其Nef蛋白靶标紧密结合 Kd值在Nm到Pm范围内。然而,Nef缺乏一个活跃的网站,这使得传统的 体内试验中现有化合物的药物化学优化由于缺乏相关性 NEF体外结合亲和力和细胞系统中的抗逆转录病毒活性。 为了绕过这个问题,我们建议使用我们现有的Nef结合化合物来开发蛋白水解剂 靶向嵌合体(PROTAC)分子,靶向破坏艾滋病毒感染细胞中的Nef蛋白。在……里面 这种方法,现有的羟基吡唑Nef结合化合物将偶联到泛素E3lig- ASE通过灵活的链接器。由此产生的Nef PROTAC有望催化蛋白质降解 NEF通过E3介导的多泛素化和蛋白酶体靶向。PROTAC方法的一个主要优势 它只需要目标蛋白的选择性结合物(在这种情况下是Nef),而不需要功能抑制物。我们 预计PROTAC介导的选择性降解将消除所有Nef功能,包括拯救细胞 表面MHC-I介导的HIV-1抗原递呈,导致通过CTL反应清除HIV+细胞 作为潜在油藏减少和功能治愈战略的一部分。更广泛地说,PROTAC方法具有 在制药行业引起了极大的兴奋,因为它提供了新的途径来抑制 以前被认为不能下药的蛋白质。而PROTAC具有更高的分子量,而典型的小分子 分子药物,最近的临床前和I期临床研究显示了体内和口服的活性。 生物利用度。对于这个第一阶段的STTR项目,HIV-1 Nef PROTAC的开发将结合药物 福克斯·蔡斯化学多样性中心的药物化学专业知识(www.fc-cdci.com;FCCDC) 与匹兹堡大学Smithgall实验室在HIV-1 Nef结构、功能和抑制剂方面的专业知识 分析。我们的广泛目标是合成和测试一系列具有不同Nef靶向部分的Nef PROTAC, 连接物和E3泛素连接酶配体,以确定适合体内概念验证研究的化合物。Suc- 第一阶段的圆满完成将为#年扩大药物开发计划奠定坚实的基础 第二阶段,以临床翻译为最终目标。
英文摘要
Abstract. Existing antiretroviral drugs do not clear HIV-1 latent reservoirs, underscoring the urgent need for new therapeutic strategies. The HIV-1 Nef accessory factor is an attractive target for drug development because of its critical roles in the HIV-1 life cycle and immune system escape. Our group has discovered novel small molecules that bind directly to Nef and block many of its functions, including enhancement of viral infectivity and replication in donor PBMCs. Importantly, our Nef inhibitors rescue cell-surface MHC-I expression in latently in- fected, patient-derived CD4 T-cells, enabling recognition and killing by autologous CTLs. Thus, Nef inhibitors represent an innovative approach to antiretroviral therapy that may provide a path to eradication of viral reser- voirs. Our most promising class of inhibitors (hydroxypyrazoles) bind tightly to their Nef protein target in vitro with KD values in the nM to pM range. However, Nef lacks an active site, which has complicated traditional medicinal chemistry optimization of existing compounds for in vivo testing due to the lack of correlation between Nef binding affinity in vitro and antiretroviral activity in cell-based systems. To circumvent this issue, we propose to use our existing Nef-binding compounds to develop Proteolytic Targeting Chimera (PROTAC) molecules for the targeted destruction of the Nef protein in HIV-infected cells. In this approach, existing hydroxypyrazole Nef-binding compounds will be coupled to ligands for ubiquitin E3 lig- ases via a flexible linker. The resulting Nef PROTACs are anticipated to catalyze the proteolytic degradation of Nef via E3-mediated polyubiquitination and proteasomal targeting. A major advantage of the PROTAC approach is that it requires only a selective binder of the target protein (Nef in this case) and not a functional inhibitor. We anticipate that selective PROTAC-mediated degradation will eliminate all Nef functions, including rescue of cell surface MHC-I mediated HIV-1 antigen presentation, leading to clearance of HIV+ cells via the CTL response as part of a strategy for latent reservoir reduction and functional cure. More generally, the PROTAC approach has generated a great deal of excitement in the pharmaceutical industry, because it provides new avenues to inhibit proteins previously considered undruggable. While PROTACs have higher molecular weights that typical small molecule drugs, recent preclinical and Phase I clinical studies have demonstrated activity in vivo as well as oral bioavailability. For this Phase I STTR project, HIV-1 Nef PROTAC development will combine the pharmaceutical and medicinal chemistry expertise of the Fox Chase Chemical Diversity Center, Inc. (www.fc-cdci.com; FCCDC) with the expertise of the Smithgall Lab at the University of Pittsburgh in HIV-1 Nef structure, function and inhibitor analysis. Our broad goal is to synthesize and test a series of Nef PROTACs with different Nef-targeting moieties, linkers, and E3 ubiquitin ligase ligands to identify compounds suitable for in vivo proof-of-concept studies. Suc- cessful completion of Phase I will provide a strong foundation for an expanded drug development program in Phase II, with the ultimate goal of clinical translation.
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Chemical Biology of HIV-1 Nef
PROTACS Against Nef as a Functional Cure for HIV Infection
Chemical Biology of HIV-1 Nef
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