Mechanism of action of an HIV-1 maturation inhibitor

描述(申请人提供)：迫切需要治疗艾滋病毒/艾滋病的新药，特别是发现和开发对目前批准的疗法具有抗药性的病毒分离株有效的化合物。在我毕业前的职业生涯中，我们报道了3-O-(3‘，3’-二甲基琥珀酰基)白桦酸(PA-457)，这是一类新的HIV-1成熟抑制剂，对目前治疗方法耐药的菌株有效。与蛋白酶抑制剂不同，PA-457阻止了病毒Gag蛋白加工的一个步骤：将Gag衣壳(CA)前体(CA-SP1)酶切成成熟的CA蛋白。这导致了未成熟的、非传染性的病毒颗粒的释放，也提出了几个有趣的问题，关于这种新型HIV-1抑制剂的作用机制、分子决定因素和分子靶标的一致性。我希望随着更多成熟抑制剂的开发，这些问题成为我职业研究的中心。我想确立自己在逆转录病毒成熟方面的多产科学家的地位，这是一个相对未被探索的研究领域。我们和其他人的工作表明，HIV-1Gag CA-SP1边界区域内的残基是PA-457活性的决定因素，而该区域内的基因变异使HIV-1能够逃避PA-457介导的抑制。最近的结果支持这样的理论，即该化合物与低聚形式的GAG之间的直接相互作用对PA-457的活性至关重要。虽然这些观察结果使人们得以深入了解PA-457的抗病毒作用，但PA-457的作用机制和耐药性仍有待充分确定。我们建议进一步研究PA-457活性的作用机制，并进一步阐明PA-457活性的分子决定因素。我们相信，我们的研究结果将对PA-457的作用和抗性机制以及PA-457活性的确切分子决定因素提供更深入的了解。由于PA-457‘S正在进行临床开发(目前处于2b期试验)，对这些问题的更好理解尤其相关。我们相信，这些研究的结果将有助于开发更多类别的HIV-1成熟抑制剂，并有助于阐明HIV-1成熟的基本机制。外行语言：抗药性是艾滋病毒治疗失败的主要原因。拟议研究的完成将有助于确定新的艾滋病毒成熟抑制剂，提供更多的治疗选择，并改善疾病结局。

DESCRIPTION (provided by applicant): There is an urgent need for new drugs to treat HIV/AIDS, particularly the discovery and development of compounds that are active against virus isolates resistant to currently approved therapies. During my pre-academic career, we reported on 3-O-(3',3'-dimethylsuccinyl) betulinic acid (PA-457), first in a new class of HIV-1 maturation inhibitors with efficacy against strains resistant to current therapies. Unlike protease inhibitors, PA-457 blocks a single step in the processing of the viral Gag protein: protease cleavage of the Gag capsid (CA) precursor (CA-SP1) to mature CA protein. This results in the release of immature, non-infectious viral particles, and also raises several interesting questions about the mechanism of action, molecular determinants, and identity of molecular target for this novel HIV-1 inhibitor. I would like these questions along with the development of additional maturation inhibitors to be the center of my career research. I would like to establish myself as a productive scientist in retrovirus maturation, a relatively unexplored research area. Work by our group and others has demonstrated that residues within the HIV-1 Gag CA-SP1 boundary region serve as determinants of PA-457 activity, and genetic variation within this region allows HIV-1 to escape PA-457-mediated inhibition. More 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 insight into the PA-457 antiviral effect, the mechanisms of action and resistance of PA-457 remain to be fully determined. We propose to further characterize the mechanism of action of PA-457 activity and further elucidate the molecular determinants of PA-457 activity. We believe that the results of our studies will provide greater insight into the mechanisms of action and resistance of PA-457 as well as into the precise molecular determinant of PA-457 activity. A better understanding of these issues is particularly relevant due to PA-457's ongoing clinical development (currently in Phase 2b trial). We are confident that the results of these studies will aid in the development of additional classes of HIV-1 maturation inhibitors and help elucidate the basic mechanism of HIV-1 maturation. Lay Language: Drug resistance is the leading reason for HIV treatment failure. Completion of the proposed research will help identify novel HIV maturation inhibitors, provide additional treatment options, and improve disease outcome.