Mechanism of action of an HIV-1 maturation inhibitor

描述（由申请人提供）：迫切需要治疗HIV/AIDS的新药，特别是发现和开发对目前批准的疗法耐药的病毒分离株有活性的化合物。在我的预学术生涯中，我们报道了3-O-（3 '，3'-二甲基琥珀酰基）桦木酸（PA-457），这是一类新的HIV-1成熟抑制剂中的第一个，对目前治疗耐药的菌株有效。与蛋白酶抑制剂不同，PA-457阻断病毒Gag蛋白加工中的一个步骤：Gag衣壳（CA）前体（CA-SP1）被蛋白酶切割为成熟CA蛋白。这导致未成熟的非感染性病毒颗粒的释放，并且还提出了关于这种新型HIV-1抑制剂的作用机制、分子决定簇和分子靶点的身份的几个有趣的问题。我希望这些问题沿着其他成熟抑制剂的开发成为我职业研究的中心。我想在逆转录病毒成熟方面成为一名多产的科学家，这是一个相对未开发的研究领域。我们小组和其他人的工作表明，HIV-1 Gag CA-SP1边界区域内的残基是PA-457活性的决定因素，该区域内的遗传变异使HIV-1能够逃避PA-457介导的抑制。最近的结果支持了以下理论，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。虽然这些观察结果可以深入了解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。我们建议进一步表征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，我们的研究结果将为PA-457的作用机制和耐药性以及PA-457活性的精确分子决定因素提供更深入的了解。由于PA-457正在进行临床开发（目前处于2b期试验），因此更好地了解这些问题尤为重要。我们相信，这些研究的结果将有助于开发其他类型的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：耐药性是艾滋病毒治疗失败的主要原因。这项研究的完成将有助于确定新的HIV成熟抑制剂，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, 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.