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

描述（由申请人提供）：目前迫切需要治疗艾滋病的新药。特别重要的是发现和开发对目前批准的疗法有耐药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）白桦酸（PA-457），这是一种新的HIV-1抑制剂，通过破坏病毒成熟来阻止病毒复制。与蛋白酶抑制剂不同，PA-457阻断病毒Gag蛋白加工过程中的一个步骤。具体来说，PA-457破坏Gag衣壳（CA）前体（CA- sp1）到成熟CA蛋白的裂解，导致未成熟的非感染性病毒颗粒的释放。重要的是，PA-457独特的作用机制使这种化合物对HIV-1毒株保持有效的活性，这些毒株对目前批准的药物具有耐药性。我们和其他人的研究表明，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允许HIV-1逃避PA-457介导的抑制。最近的研究结果支持这一理论，即化合物与Gag的低聚形式之间的直接相互作用对PA-457的活性至关重要。虽然这些观察结果让我们对PA-457的抗病毒作用有了一些了解，但对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。我们相信这些研究结果将为深入了解PA- 457的作用机制和耐药性提供新的思路。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，对WT HIV-1毒株和pa -457治疗患者中出现的耐药病毒分离株都有效。耐药性是艾滋病治疗失败的主要原因。拟议研究的成功完成将有助于确定和设计更多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.