Structural and Chemical Analysis of Highly Potent ALLINI Platform

项目概要- Kim 虽然目前的抗HIV治疗剂有助于有效抑制患者中的HIV-1，但实际上， 由于病毒逃逸、交叉耐药性和毒性，长期治疗的选择相当有限， 发现更新、更安全的抗艾滋病毒药物。 HIV-1需要各种宿主细胞内因子来完成其生命周期和发病机制。靶向 病毒蛋白质和这些宿主细胞内因子之间的相互作用已经被广泛探索， 潜在的抗病毒发现途径，而抗HIV药物靶向病毒与细胞内因子的相互作用 目前有限。埃默里药物发现中心（CDD）和ST Pharm，CO，LTD鉴定了一种具有显著体外和动物毒性的高效抗HIV化合物， 药代动力学，STP 03 -0404：STP 03 -0404最初被确定为随机抗- ST Pharm独特地采用一系列化学支架库的HIV化合物筛选操作 由南方研究所（SRI， Frederick，MD）与人PBMC和各种临床HIV-1分离株的比较，并且还通过 Emory CDD在皮摩尔范围内。此外，STP 03 -0404的基于组织培养的治疗指数 为40，000 - 1，000，000，并且对大鼠和犬的临床前动物研究证明了其 出色的安全性和出色的药代动力学。 令人兴奋的是，我们广泛的基于计算结构的搜索努力和最初的X射线晶体学 分析表明，STP 03 -0404靶向两个细胞之间的界面处的LEDGF/p75结合口袋， 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起作用 （阿利尼）。重要的是，我们发现STP 03 -0404显示出高达1,000倍的有效抗HIV-1活性 比以前报道的ALLINI更好。此外，STP 03 -0404有效抑制临床HIV-1菌株， 对催化位点整合酶抑制剂如雷特格韦的耐药性。因此，在本申请中，我们将 从结构和化学上研究了STP 03 -0404作为高效和安全ALLINI平台。为 这些调查，我们建议采用一系列深入的生物化学，结构生物学， 病毒学/遗传学方法以及药物化学/化学优化设计的新的 具有增强的抗性遗传屏障的STP 03 -0404的衍生物。此应用程序的最终目标是 通过临床前研究STP 03 -0404，满足当前对更新和更安全的抗HIV药物的需求， 一个新的，有效的和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.