Preclinical Development of 2nd Generation HIV Maturation Inhibitors

第二代HIV成熟抑制剂的临床前开发

• 批准号: 10080449
• 负责人: Carl Wild
• 金额: $ 51.87万
• 依托单位: DFH PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-07-08 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10080449
• 关键词: Adverse effects; Amino Acids; Animal Model; Animals; Binding; Binding Proteins; Canis familiaris; Capsid; Characteristics; Clinical; Data; Development; Digit structure; Dose; Drug resistance; Exhibits; Formulation; Funding; Generations; Genetic Polymorphism; Goals; HIV; HIV therapy; HIV-1; Hepatocyte; Implant; In Vitro; Individual; Injectable; Injections; Life; Link; Mediating; Metabolic; Mus; Oral; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Phase; Polymorph; Protease Inhibitor; Protein Precursors; Rattus; Research; Resistance; Resistance development; Rodent; SP1 gene; Series; Testing; Therapeutic; Time; Toxic effect; Viral; Viral Load result; Virus; Virus Replication; Work; antiretroviral therapy; clinical candidate; drug development; gag Gene Products; in vivo; inhibitor/antagonist; lead candidate; next generation; nonhuman primate; novel; novel therapeutics; particle; patient response; pre-clinical; preclinical development; receptor; research clinical testing; response; success

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.

项目摘要：虽然目前可用的抗逆转录病毒疗法非常有效， 不是治愈的。患者需要继续接受终身治疗，这与 各种不利影响。随着时间的推移，病毒介导的耐药性很可能会导致 越来越严重的问题。小说类的发展 与目前可用的药物不同的阻断病毒复制的抑制剂仍然很高， 要务成熟抑制剂（MI）代表了一类这样的HIV疗法。MIs阻断病毒 通过破坏衣壳前体蛋白CA-SP1（p25）向 衣壳CA（p24）的成熟形式，导致非感染性病毒颗粒的释放。不像 与病毒蛋白酶结合并抑制其作用的蛋白酶抑制剂，MI直接靶向病毒蛋白酶。 HIV-1 Gag蛋白。这种新的作用机制使MI能够保持对 对已批准的HIV药物具有耐药性的病毒。MI的临床概念验证是 第一次，他在一个叫Bevirimat的地方。在一系列试验中，BVM被证明 安全有效地减少感染者的艾滋病毒载量，然而，缺乏 还观察到一致的患者反应。对患者病毒的分析显示， 病毒Gag蛋白SP1区的氨基酸多态性是主要决定因素 患者的反应。该多态性涉及SP1氨基酸7：V7 A处的瓦尔至Ala的变化。 大约50%的HIV-1分离株含有V7，对BVM高度敏感， 剩下的50%含有A7并且缺乏灵敏度。DFH Pharma目前的工作重点是 鉴定具有广泛抗HIV活性的下一代MI。具体来说，我们已经确定了 第二代MI对广泛的HIV分离株表现出强效活性。最近 测试已经确定，这些广泛活性的化合物中最有效的表现出IC 50 数值在一位数nM范围内。该活性水平在HIV药物的可接受范围内 开发候选人，并与MI临床候选人相媲美。的目标 本申请中概述的工作是i）在我们第一阶段工作（1 R41 GM 132683 - 01 A1）的基础上， 确定第二代MI开发候选者，以推进IND赋能研究，以及ii）启动 努力确定配制MI作为长效剂递送的潜力。 重要的是，这第二个目标认识到艾滋病毒治疗空间正在远离日常生活， 口服给药，以支持每周、每月或更低频率的药物给药 应用程序.这些努力的成功将导致一种新的药物开发候选人， 代理配方潜力正在向IND赋能研究迈进。