Development of Small-Molecule HIV Entry Inhibitors

HIV-1研究的一个主要目标是开发针对病毒复制周期的非酶阶段的药物。HIV-1的进入涉及一系列易受治疗干预的事件，包括gp120-CD4连接、gp120-共受体相互作用和gp41介导的融合。T-20等药物的临床试验证实了HIV-1进入治疗靶点，但迫切需要适合长期给药的口服药物。这一第一阶段项目的目标是确定艾滋病毒-1进入的小分子抑制剂。一种新的，无病毒的荧光共振能量转移分析，准确地再现了HIV-1进入的所有阶段，将被用于组合化学库的高通量筛选。活性化合物将被分析为特异性、有效性和广度的抗病毒活性，并进一步被表征为附着、共受体或融合抑制剂。在第二阶段项目中，活性化合物将利用传统化学、组合化学和计算化学对抗病毒性能、耐受性和口服利用度进行优化。将使用现有的最好的HIV-1感染模型来检查优化后的药物的效力、广度和抗病毒效果的持久性。该项目结合了先进的筛选方法、新兴的组合化学领域和最先进的病毒学模型，以开发新的口服HIV-1进入抑制剂。拟议的商业应用：该项目寻求开发一种新型的抗HIV-1药物。对于一种安全有效地阻断艾滋病毒-1复制周期早期步骤且没有类似疗法的口服药物，市场将是通过现有疗法进行次优治疗的艾滋病毒感染者。这些人包括那些尽管接受了高效抗逆转录病毒治疗但病毒载量可测量的人，以及那些经历了重大治疗毒性的人。目前，这些人组成了相当大的比例，如果不是大多数艾滋病毒感染者，目前在美国约有90万人。

A major goal of HIV-1 research is the development of agents that target non-enzymatic stages of the viral replicative cycle. HIV-1 entry involves a cascade of events that are vulnerable to therapeutic intervention, including gp120-CD4 attachment, gp120-co-receptor interactions, and gp41-mediated fusion. Clinical trials of agents such as T-20 have validated HIV-1 entry as a therapeutic target, but there is an urgent need for orally available agents suitable for chronic administration. The goal of this Phase I project is to identify small-molecule inhibitors of HIV-1 entry. A novel, virus-free fluorescence Resonance Energy Transfer assay that accurately reproduces all stages of HIV-1 entry will be used for high throughput screening of combinatorial chemical libraries. Active compounds will be analyzed for specificity, potency, and breadth of antiviral activity and further characterized as attachment, co-receptor or fusion inhibitors. During the Phase II project, active compounds will be optimized for antiviral properties, tolerability and oral availability using traditional, combinatorial, and computational chemistry. The optimized agents will be examined for potency, breadth, and durability of antiviral effects using the best available models of HIV-1 infection. This project combines advanced screening methods, the emerging field of combinatorial chemistry, and state-of-the-art virologic models for the development of new, orally available inhibitors of HIV-1 entry. PROPOSED COMMERCIAL APPLICATIONS: This project seeks to develop a novel class of anti-HIV-1 agents. For an orally available drug that safely and effectively blocks an early step of the HIV-1 replicative cycle and for which there are no comparable therapies, the market would be HIV-infected individuals who are suboptimally treated by existing therapies. These individuals include those with measurable viral loads despite highly active antiretroviral therapy and those who experience significant treatment toxicities. Currently, these individuals comprise a sizeable if not majority fraction of HIV-infected individuals, who currently number approximately 900,000 in the U.S.