Mechanism of action of an HIV-1 maturation inhibitor

HIV-1 成熟抑制剂的作用机制

• 批准号: 7899718
• 负责人: FENG LI
• 金额: $ 9.81万
• 依托单位: SOUTH DAKOTA STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-09-01 至 2013-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7899718
• 关键词: AIDS/HIV problem; Adverse effects; Affect; African; Amino Acid Substitution; Antiviral Agents; Area; Asians; Betulinic Acid; Binding; Biophysics; Bovine Immunodeficiency Virus; Capsid; Capsid Proteins; Chemicals; Chimera organism; Clinical; Development; Disease Outcome; Drug resistance; Equine Infectious Anemia Virus; Exhibits; Feline Immunodeficiency Virus; Funding; Future; Gagging; Genes; Genetic Polymorphism; Genetic Variation; Genomics; Geographic Locations; Goals; Grant; HIV; HIV-1; Human; Kinetics; Knowledge; Laboratories; Language; Maps; Mediating; Molecular; Molecular Cloning; Molecular Mechanisms of Action; Molecular Target; Mutation; National Institute of Allergy and Infectious Disease; North America; Patients; Pattern; Peptide Hydrolases; Pharmaceutical Chemistry; Pharmaceutical Preparations; Phase; Play; Positioning Attribute; Primate Lentiviruses; Process; Property; Protease Inhibitor; RNA Viruses; Reagent; Reporting; Research; Research Personnel; Resistance; Resistance development; Resources; Retroviridae; Role; Scientist; Serum Proteins; Site-Directed Mutagenesis; Subfamily lentivirinae; System; Techniques; Toxic effect; Treatment Failure; Viral; Virion; Virus; Virus Replication; Western Europe; Work; analog; base; career; career development; design; drug development; gag Gene Products; improved; inhibitor/antagonist; insight; interest; mutant; novel; particle; programs; resistant strain; structural biology; theories

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.

描述（由申请人提供）：迫切需要新药来治疗艾滋病毒/艾滋病，尤其是发现和开发具有对当前批准疗法具有耐药性病毒分离株有效的化合物。在我的学术前职业生涯中，我们报道了3-O-（3'，3'-二甲基羟基甲基）β（PA-457），首先是一种新的HIV-1成熟抑制剂，具有抗抗性菌株对当前疗法的有效性。与蛋白酶抑制剂不同，PA-457阻止了病毒GAG蛋白质加工中的一个步骤：Gag Capsid（CA）前体（CA-SP1）的蛋白酶切割到成熟的Ca蛋白。这导致了未成熟，非感染病毒颗粒的释放，并且还提出了有关这种新型HIV-1抑制剂的作用机理，分子决定因素和分子靶标的身份的一些有趣问题。我希望这些问题以及开发额外的成熟抑制剂成为我职业研究的中心。我想确定自己是逆转录病毒成熟的生产科学家，这是一个相对尚未开发的研究领域。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，并且该区域内的遗传变异使HIV-1允许HIV-1逃脱PA-457介导的抑制作用。最新的结果支持这样的理论，即GAG的化合物和寡聚形式之间的直接相互作用对于PA-457活性至关重要。尽管这些观察结果可以深入了解PA-457抗病毒效应，但PA-457的作用和抗性机理仍有待完全确定。我们建议进一步表征PA-457活性的作用机理，并进一步阐明PA-457活性的分子决定因素。我们认为，我们的研究结果将为PA-457的作用和抗性以及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的持续临床开发（目前正在2B期试验中），对这些问题的更好理解尤其重要。我们相信这些研究的结果将有助于开发其他类别的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：耐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型的HIV成熟抑制剂，提供其他治疗选择并改善疾病结果。