Preclinical Development of 2nd Generation HIV Maturation Inhibitors

项目摘要：虽然目前可用的抗逆转录病毒疗法非常有效，但它们 不能治愈。患者被要求继续接受终身治疗，这与 各种不良反应。随着时间的推移，病毒介导的耐药性很可能会构成 个人对治疗的问题日益严重。新课目的发展 与现有药物不同的是，阻断病毒复制的抑制剂仍然很高 优先考虑。成熟抑制药(MIs)代表了这样一类艾滋病毒治疗方法。Mis拦截病毒 通过干扰衣壳前体蛋白CA-SP1(P25)到 成熟的衣壳，CA(P24)，导致非传染性病毒颗粒的释放。不像 与病毒蛋白水解酶结合并抑制其作用的蛋白水解酶抑制物，错失直接靶向 HIV-1 Gag蛋白。这一新的作用机制使管理信息系统能够保持对 对批准类别的艾滋病毒药物具有抗药性的病毒。心肌梗死的临床概念验证 建立了一流的MI，bevirimat(BVM)。在一系列试验中，BVM被证明是 安全有效地减少受感染个人的艾滋病毒病毒载量，但缺乏 患者的反应也一致。对患者病毒的分析显示，单一的 病毒Gag蛋白SP1区的氨基酸多态是一个主要决定因素 病人的反应。这种多态涉及SP1氨基酸7：V7A的Val到Ala的变化。 约50%的HIV-1分离株含有V7病毒，并对BVM高度敏感，而 其余50%含有A7，缺乏敏感度。DFH Pharma目前的工作重点是 具有广泛抗HIV活性的新一代心肌梗死的鉴定。具体地说，我们已经确定 第二代MISs对广泛的HIV分离株表现出强大的活性。近期 测试已经确定，这些广谱活性化合物中最有效的化合物具有IC50 单位NM范围内的值。这一活性水平在艾滋病毒药物的可接受范围内 开发候选者，并与MI临床候选者进行比较。世界银行的目标是 本申请中概述的工作是i)在我们的第一阶段工作(1R41GM132683-01A1)的基础上进行的 确定第二代MI开发候选人，以进入支持IND的研究和ii)启动 努力确定配制作为长效剂交付的管理信息系统的可能性。 重要的是，这第二个目标认识到艾滋病毒治疗空间正在从每天 对支持每周、每月或甚至不太频繁用药的配方的口服剂量 申请。这些努力的成功将产生一种新的药物开发候选者，具有长期的 代理配方潜力推动IND-Enabling研究。

Project Summary: While currently available antiretroviral therapies are highly effective they are not curative. Patients are required to remain on life-long therapy which is associated with a variety adverse effects. Over time, viral-mediated drug resistance is likely to pose an increasingly serious problem for individuals on therapy. The development of novel classes of inhibitors that block viral replication differently from currently available drugs remains a high priority. Maturation inhibitors (MIs) represent one such class of HIV therapies. MIs block virus replication by disrupting the conversion of the capsid precursor protein, CA-SP1 (p25), to the mature form of capsid, CA (p24) resulting in the release of non-infectious viral particles. Unlike protease inhibitors that bind to and inhibit the action of the viral protease, MIs directly target the HIV-1 Gag protein. This novel mechanism of action allows MIs to retain full activity against viruses resistant to approved classes of HIV drugs. Clinical proof-of-concept for MIs was established with the first-in-class MI, bevirimat (BVM). In a series of trials, BVM was shown to be safe and effective in reducing HIV viral load in infected individuals, however, a lack of uniform patient response was also observed. Analysis of patient virus revealed that a single amino acid polymorphism in the SP1 region of the viral Gag protein was a primary determinant of patient response. This polymorphism involves a Val to Ala change at SP1 amino acid 7: V7A. Approximately 50% of HIV-1 isolates contain V7 and are highly sensitive to BVM while the remaining 50% contain A7 and lack sensitivity. DFH Pharma’s current efforts focus on the identification of next generation MIs with broad anti-HIV activity. Specifically, we have identified 2nd generation MIs that exhibit potent activity against the broad range of HIV isolates. Recent testing has determined that the most potent of these broadly active compounds exhibit IC50 values in the single digit nM range. This activity level is within the accepted range for HIV drug development candidates and compares favorably with MI clinical candidates. The goals of the work outlined in this application are to i) build on our phase I effort (1R41GM132683-01A1) to identify a 2nd gen MI development candidate to advance into IND-enabling studies and ii) initiate efforts to determine the potential for formulating MIs for delivery as long-acting agents. Importantly, this 2nd goal recognizes that the HIV treatment space is moving away from daily oral dosing towards formulations that support weekly, monthly or even less frequent drug application. Success in these efforts will result in a novel drug development candidate with long- acting formulation potential moving forward to IND-enabling studies.