Development of Small-Molecule HIV Entry Inhibitors

描述(由申请人提供)：迫切需要新的艾滋病毒治疗模式。目前针对HIV感染的治疗方法主要针对病毒酶、蛋白酶和逆转录酶。然而，由于多药耐药变种的传播和出现，这些疗法通常无法长期控制艾滋病毒，此外，这些疗法往往伴随着无法忍受的副作用，因此大多数艾滋病毒感染者最终用尽了他们的治疗选择。 进入艾滋病毒为新一代抗病毒药物提供了一个有希望的靶点，最近的临床试验已经证实进入是一个可行的治疗目标。然而，没有口服可用的艾滋病毒进入抑制剂进入高级临床测试。 在第一阶段项目中，我们使用一种新的脱毒方法对400万种类似药物的组合化合物进行了超高通量筛选，该方法准确地模拟了HIV进入的所有阶段，发现了几种活性化合物，最有希望的化合物是一种无毒和特异的HIV抑制剂，作用于膜融合水平，这种新化合物来自一个有希望的先导系列，具有类似药物的性质，简单的化学和有希望的构效关系。 这一第二阶段项目的总体目标是将铅系列开发成一种高度优化的化合物，作为一种新的艾滋病毒疗法，满足人类临床测试的所有标准。协作药物优化计划将Pharmacopeia，Inc.的药物和计算化学专业知识与Progenics制药公司和我们在阿尔伯特·爱因斯坦医学院的科学合作者的抗病毒和药物开发专业知识结合在一起。该项目将对1000多种化合物进行综合和迭代的合成和生物测试，这些化合物在抗病毒效力、选择性和类似药物方面得到逐步优化。更多的研究确定了HIV对该化合物的易感性的分子决定因素。最后，最优化的化合物将在动物身上进行口服药理学和耐受性测试，以确定最有理由进入人类临床测试的药物。 第二阶段项目的成功被定义为开发出一种新的、口服可用和耐受性良好的化合物，该化合物以纳摩尔效力广泛地抑制艾滋病毒的进入。项目的成功将导致编制临床级材料和法规文件，以支持这种新的艾滋病毒疗法的人体临床测试。

DESCRIPTION (provided by applicant): There is an urgent need for new modes of HIV therapy. Current therapies for HIV infection target the viral enzymes protease and reverse transcriptase. However, these therapies typically fail to control HIV long-term due to the transmission and emergence of multidrug-resistant variants, In addition, these treatments are associated with often intolerable side effects, and thus most HIV-infected individuals eventually exhaust their therapeutic options. HIV entry provides a promising target for a new generation of antiviral agents, and recent clinical trials have validated entry as a viable target for therapy. However, no orally available HIV entry inhibitor has entered advanced clinical testing. In the Phase I project, we performed ultra-high throughput screening of 4 million drug-like combinatorial compounds using a novel virus-free assay that accurately models all stages of HIV entry, Several active compounds were discovered, and the most promising compound was demonstrated to be a nontoxic and specific HIV inhibitor that acts at the level of membrane fusion, This novel compound derives from a promising lead series that possesses drug-like properties, facile chemistry and promising structure-activity relationships. The overall goal of this Phase II project is develop the lead series into a highly optimized compound that meets all criteria for human clinical testing as a new HIV therapy. The collaborative drug optimization program combines the medicinal and computational chemistry expertise of Pharmacopeia, Inc. with the antiviral and drug development expertise of Progenics Pharmaceuticals and our scientific collaborators at Albert Einstein College of Medicine. The project will employ an integrated and iterative process of synthesis and biological testing of more than 1000 compounds that are progressively optimized for antiviral potency, selectivity and drug-likeness. Additional studies wit1 establish the molecular determinants of HIV susceptibility to the compound. Lastly, the most highly optimized compounds will be tested for oral pharmacology and tolerability in animals in order to identify the agent that most warrants advancement into human clinical testing. Success in the Phase II project is defined as the development of a novel, orally available and well-tolerated compound that broadly inhibits HIV entry with nanomolar potency. Project success would lead to the preparation of clinical-grade material and regulatory documentation that would support human clinical testing of this new HIV therapy.