Preparation and Characterization of 2nd Generation HIV-1 Maturation Inhibitor Dru

描述(由申请人提供)：尽管艾滋病毒药物的开发取得了进展，但仍然需要新的治疗方法。与长期使用许多已获批准的艾滋病毒药物有关的毒性，加上耐药性的产生，促使对新的和新的抗病毒药物的需求。成熟抑制药(MIs)代表了这样一类艾滋病毒治疗方法。HIV成熟抑制剂通过破坏衣壳前体蛋白CA-SP1(P25)到成熟衣壳形式CA(P24)的转换来阻止病毒复制，从而形成非传染性病毒颗粒。与结合并抑制VERL蛋白酶作用的蛋白酶抑制剂不同，Mis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已对批准类别的艾滋病毒药物产生抗药性的病毒的全部活性。成熟抑制剂的临床概念验证是通过一流的MI，bevirimat(BVM)建立的。在一系列试验中，BVM被证明在减少感染者的艾滋病毒病毒载量方面是安全和有效的，然而，也观察到缺乏统一的患者反应。对患者病毒的分析显示，病毒Gag蛋白SP1区域的单一氨基酸多态性是患者反应的主要决定因素。这种多态涉及SP1氨基酸7：V7A的Val到Ala的变化。大约50%的HIV-1分离株含有V7病毒，对BVM高度敏感，其余50%含有A7病毒，缺乏敏感性。作为这一观察的结果，脑血管畸形的临床发展被终止。DFH Pharma正专注于鉴定具有广泛抗艾滋病毒活性的下一代MI，包括耐BVM菌株。这项工作导致了Bevirimat类似物的发现，这些类似物对BVM敏感病毒和那些表现出多态介导的耐药性的病毒都具有高度的活性。虽然在结构上类似于Bevirimat，但这些第二代导弹在C-28位置进行了改进。在新发现的最有效的抑制剂中，对BVM敏感病毒和耐药A7多型体都显示出NM IC50值。这些化合物表现出的抗A7病毒的增强活性比使用BVM观察到的活性增加了100倍。重要的是，到目前为止的努力表明，这些第二代MI将保留与Bevirimat观察到的有前景的药物开发概况。这项拟议研究的目标是继续鉴定适合作为药物开发候选者的第二代mis。具体地说，DFH Pharma将：i)继续识别对广泛的HIV分离株具有强大活性的第二代MI，ii)描述最有希望的第二代MI的开发概况，以及iii)选择一种药物开发候选药物，以进入临床前研究。

DESCRIPTION (provided by applicant): Despite advances in the development of HIV drugs there remains a need for new therapies. Toxicities associated with long term use of many of the approved HIV drugs coupled with the development of resistance drives the need for new and novel antivirals. Maturation inhibitors (MIs) represent one such class of HIV therapies. HIV maturation inhibitors 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 formation of non-infectious viral particles. Unlike protease inhibitors that bind to and inhibit the action of the vral protease, MIs directly target the HIV-1 Gag protein. This novel mechanism of action allows MIs to retain full activity against viruses that have developed resistance to approved classes of HIV drugs. Clinical proof-of-concept for maturation inhibitors 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. As a result of this observation, clinical development of BVM was terminated. DFH Pharma is focusing on the identification of next generation MIs with broad anti-HIV activity including BVM-resistant isolates. This work has led to the discovery of bevirimat analogs that are highly active against both BVM-sensitive virus and those exhibiting polymorphic-mediated resistance. While similar in structure to bevirimat, these 2nd generation MIs are modified at the C-28 position. The most potent of the newly identified inhibitors exhibit nM IC50 values against both BVM-sensitive virus and resistant A7 polymorphs. The enhanced activity against the A7 virus exhibited by these compounds represents a 100-fold increase in over that observed with BVM. Importantly, efforts to date suggest that these 2nd generation MIs will retain the promising drug development profile observed with bevirimat. The goal of the proposed research is to continue the identification of 2nd generation MIs suitable for advancement as drug development candidates. Specifically, DFH Pharma will; i) continue to identify 2nd generation MIs with potent activity against the broad spectrum of HIV isolates, ii) characterize the development profiles of the most promising 2nd generation MIs and iii) select a drug development candidate to advance into pre-clinical studies.