Structural and Chemical Analysis of Highly Potent ALLINI Platform

项目摘要-Kim 虽然目前的抗艾滋病毒治疗药物有助于有效抑制患者的艾滋病毒-1，但实际 由于病毒逃逸、交叉耐药和毒性，长期治疗的选择相当有限，要求 发现更新、更安全的抗艾滋病毒药物。 HIV-1病毒需要多种宿主细胞内因子才能完成其生命周期和致病过程。瞄准 病毒蛋白和这些宿主细胞内因子之间的相互作用作为一种 抗HIV药物靶向病毒与细胞内因子相互作用的潜在抗病毒发现途径 目前是有限的。埃默里药物发现中心(CDD)和ST 辉瑞制药有限公司发现了一种高效的抗艾滋病毒化合物，具有突出的体外和动物毒性，并 药代动力学，STP03-0404：STP03-0404最初被鉴定为抗HIV的随机抗- 独创系列化学脚手架文库的ST Pharm HIV化合物筛选操作 由圣帕姆制药公司开发。STP03-0404的EC50值由南方研究所(SRI， Frederick，MD)与人外周血单核细胞和各种临床HIV-1分离株结合，并由 Emory CDD在皮摩尔范围内。此外，基于组织培养的STP03-0404治疗指数 40,000-1,000,000只，对大鼠和狗的临床前动物调查表明 卓越的安全性和极佳的药代动力学。 令人兴奋的是，我们广泛的基于结构的计算搜索努力和初步的X射线结晶学 分析认为，STP03-0404针对的是LEDGF/p75结合口袋在两者之间的界面 HIV-1整合酶(IN)的单体，因此该化合物作为变构整合酶抑制剂发挥作用 (Allini)。重要的是，我们发现STP03-0404显示出高达~1000倍的抗HIV-1活性 比之前报道的ALLINI更高。此外，STP03-0404有效地抑制了临床HIV-1毒株 对催化部位整合酶抑制剂，如雷替格列韦的耐药性。因此，在此应用程序中，我们将 从结构和化学上研究了STP03-0404作为一个高效和安全的Allini平台。为 在这些研究中，我们建议采用一系列深入的生化、结构生物学、 病毒学/遗传学方法以及为新设计的药物化学/化学优化 STP03-0404的衍生物具有增强的抗性遗传屏障。此应用程序的最终目标是 通过临床前研究STP03-0404 AS来满足当前对更新和更安全的抗HIV药物的需求 一个新颖、有效、安全的抗艾滋病毒药物发现平台。

Project Summary – Kim While current anti-HIV therapeutic agents contribute to the effective suppression of HIV-1 in patients, actual choices for long-term treatment is rather limited due to viral escape, cross-resistance, and toxicity, demanding discovery of newer and safer classes of anti-HIV agents. HIV-1 requires various host intracellular factors for completing its life cycle and pathogenesis. Targeting the interactions between viral proteins and these host intracellular factors has been extensively explored as a potential anti-viral discovery path while anti-HIV agents targeting the viral interactions with intracellular factors are currently limited. A recent collaborative work between Emory Center for Drug Discovery (CDD) and ST Pharm, CO, LTD identified a highly potent anti-HIV compound with outstanding in vitro and animal toxicity and pharmacokinetics, STP03-0404: STP03-0404 was originally identified as an anti-HIV hit by the random anti- HIV compound screening operation of ST Pharm that employed a series of chemical scaffold libraries uniquely developed by ST Pharm. The EC50 values of STP03-0404 determined by Southern Research Institute (SRI, Frederick, MD) with human PBMCs and various clinical HIV-1 isolates, and also independently determined by Emory CDD are in pico-molar ranges. Furthermore, the tissue culture based therapeutic index of STP03-0404 was 40,000-1,000,000, and the preclinical animal investigations with rats and dogs demonstrated its outstanding safety and excellent pharmacokinetics. Excitingly, our extensive computational structure-based search efforts and initial X-ray crystallographic analysis proposed that STP03-0404 targets the LEDGF/p75 binding pocket at the interface between two monomers of HIV-1 integrase (IN) and therefore this compound works as an allosteric integrase inhibitor (ALLINI). Importantly, we found that STP03-0404 displays up to ~ 1,000 times more effective anti-HIV-1 activity than previously reported ALLINIs. Furthermore, STP03-0404 effectively inhibits clinical HIV-1 strains with resistance to catalytic site integrase inhibitors such as Raltegravir. Therefore, in this application, we will structurally and chemically investigate STP03-0404 as a highly potent and safe ALLINI platform. For these investigations, we propose to employ a series of in-depth biochemical, structural biology, virological/genetic approaches as well as medicinal chemistry/chemical optimization designed for new derivatives of STP03-0404 with enhanced genetic barrier to resistance. Ultimate goal of this application is to meet the current demand for newer and safer anti-HIV agents by pre-clinically investigating STP03-0404 as a novel, potent and safe anti-HIV drug discovery platform.