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

第二代 HIV-1 成熟抑制剂药物的制备和表征

• 批准号: 8603183
• 负责人: Carl Wild
• 金额: $ 18.64万
• 依托单位: DFH PHARMA, INC.
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-08-01 至 2015-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8603183
• 关键词: Amino Acids; Antiviral Agents; Binding; Capsid; Clinical; Clinical Drug Development; Coupled; Development; Drug Interactions; Exhibits; Gagging; Generations; Genetic Polymorphism; Goals; HIV; HIV therapy; HIV-1; Half-Life; Individual; Inhibitory Concentration 50; Left; Mediating; Modification; Patients; Peptide Hydrolases; Pharmaceutical Preparations; Positioning Attribute; Preparation; Protease Inhibitor; Protein Precursors; Research; Resistance; Resistance development; SP1 gene; Series; Site; Structure; Therapeutic; Toxic effect; Viral; Viral Load result; Virus; Virus Replication; Work; analog; drug development; experience; gag Gene Products; in vivo; inhibitor/antagonist; neutrophil; next generation; novel; particle; pre-clinical; preclinical study; public health relevance; response

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.

描述（由申请人提供）：尽管HIV药物的开发取得了进展，但仍然需要新的治疗方法。与长期使用许多已批准的HIV药物相关的毒性以及耐药性的发展推动了对新的和新型抗病毒药物的需求。成熟抑制剂（MI）代表了一类这样的HIV疗法。HIV成熟抑制剂通过破坏衣壳前体蛋白CA-SP1（p25）向衣壳成熟形式CA（p24）的转化而阻断病毒复制，导致形成非感染性病毒颗粒。与蛋白酶抑制剂结合并抑制病毒蛋白酶的作用不同，MI直接靶向HIV-1 Gag蛋白。这种新的作用机制允许MI保留对已对批准的HIV药物类别产生耐药性的病毒的全部活性。成熟抑制剂的临床概念验证是用一流的MI，bevirimat（BVM）建立的。在一系列试验中，BVM被证明在降低感染者的HIV病毒载量方面是安全有效的，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区的单个氨基酸多态性是患者反应的主要决定因素。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，而其余50%含有A7，缺乏敏感性。由于这一观察结果，终止了BVM的临床开发。DFH Pharma专注于鉴定具有广泛抗HIV活性的下一代MI，包括BV耐药分离株。这项工作导致发现了对BVM敏感病毒和表现出多态性介导的抗性的病毒具有高度活性的贝韦瑞类似物。虽然与贝韦瑞的结构相似，但这些第二代MI在C-28位进行了修饰。新鉴定的最有效的抑制剂对BVM敏感病毒和耐药A7多晶型体均显示出nM IC 50值。这些化合物表现出的增强的抗A7病毒活性代表了比用BVM观察到的增加100倍。重要的是，迄今为止的努力表明，这些第二代MI将保留贝韦瑞马特观察到的有希望的药物开发概况。拟议研究的目标是继续鉴定适合作为药物开发候选药物的第二代MI。具体而言，DFH Pharma将：i）继续鉴定对广谱HIV分离株具有强效活性的第二代MI，ii）表征最有前途的第二代MI的开发概况，iii）选择药物开发候选药物以推进临床前研究。