Mechanism of action of the HIV-1 maturation inhibitor PA-457

描述（由申请人提供）：迫切需要新的药物来治疗艾滋病毒/艾滋病。特别重要的是发现和开发对目前批准的疗法具有抗性的病毒分离株有活性的化合物。我们最近报道了3-O-（3 '，3'-二甲基琥珀酰基）桦木酸（PA-457），这是一类新的HIV-1抑制剂，通过破坏病毒成熟来阻断病毒复制。与蛋白酶抑制剂不同，PA-457阻断了病毒Gag蛋白加工过程中的一个步骤。具体而言，PA-457破坏Gag衣壳（CA）前体（CA-SP1）裂解为成熟CA蛋白，导致释放未成熟的非感染性病毒颗粒。重要的是，PA-457独特的作用机制使该化合物能够保持对HIV-1菌株的有效活性，这些HIV-1菌株对目前批准的药物具有耐药性。我们小组和其他人的工作表明，HIV-1 Gag CA-SP1结构域内的残基是PA-457活性的决定因素，该结构域内的遗传变异使HIV-1能够逃避PA-457介导的抑制。最新结果支持以下理论，即化合物与Gag的低聚物形式之间的直接相互作用对PA-457活性至关重要。虽然这些观察结果使人们对PA-457的抗病毒作用有了一些了解，但PA-457的作用机制和耐药性仍有待完全确定。为了解决这些问题，我们提出了以下具体目标：（1）进一步表征PA-457活性的作用机制，（2）进一步表征PA-457活性的分子决定因素。我们相信这些研究的结果将为PA- 457的作用机制和耐药性提供见解。由于PA-457正在进行临床开发，因此更好地了解这两个问题尤为重要。我们也相信，这些研究的结果将直接适用于设计其他广泛活性的HIV-1成熟抑制剂，这些抑制剂对WT HIV-1毒株和PA-457治疗患者中出现的耐药病毒分离株均有效。耐药性是艾滋病毒治疗失败的主要原因。成功完成拟议的研究将有助于确定和设计额外的艾滋病毒成熟抑制剂，这将提供额外的治疗选择，并改善疾病的结果。

DESCRIPTION (provided by applicant): There is an urgent need for new drugs to treat HIV/AIDS. Of particular importance is the discovery and development of compounds that are active against virus isolates resistant to currently approved therapies. We recently reported on 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457), first in a new class of HIV-1 inhibitors that block virus replication by disrupting virus maturation. Unlike protease inhibitors, PA-457 blocks a single step in the processing of the viral Gag protein. Specifically, PA-457 disrupts the cleavage of the Gag capsid (CA) precursor (CA-SP1) to mature CA protein resulting in the release of immature, non-infectious viral particles. Importantly, PA-457's distinct mechanism of action allows the compound to retain potent activity against HIV-1 strains resistant to the current classes of approved drugs. Work by our group and others suggest that residues within the HIV-1 Gag CA-SP1 domain serve as determinants of PA-457 activity and genetic variation within this domain allows HIV-1 to escape PA-457- mediated inhibition. Most recent results support the theory that a direct interaction between the compound and an oligomeric form of Gag is critical to PA-457 activity. While these observations allow some insights into the PA-457 antiviral effect, the mechanisms of action and resistance to PA-457 remain to be fully determined. To address these issues, we propose the following specific aims: (1) To further characterize the mechanism of action of PA-457 activity, and (2) To further characterize the molecular determinants of PA-457 activity. We believe that the results of these studies will provide insights into the mechanisms of action and resistance of PA- 457. A better understanding of both of these issues is particularly relevant due to PA-457's ongoing clinical development. We are also confident that the results of these studies will be directly applicable to the design of additional broadly active HIV-1 maturation inhibitors effective against both WT HIV-1 strains and the resistant virus isolates that emerge in PA-457-treated patients. Drug resistance is the leading reason for HIV treatment failure. Successful completion of the proposed research will help identify and design additional HIV maturation inhibitors that will provide additional treatment options and improve disease outcome.