Mechanism of action of an HIV-1 maturation inhibitor

HIV-1 成熟抑制剂的作用机制

• 批准号: 7683909
• 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/7683909
• 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治疗具有耐药性的病毒分离株有效的化合物。在我的前学术生涯中，我们报道了3- o -（3',3'-二甲基琥珀酰）白桦树酸（PA-457），这是一种新型HIV-1成熟抑制剂中的第一种，对目前治疗的耐药菌株有效。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：蛋白酶将Gag衣壳（CA）前体（CA- sp1）裂解为成熟的CA蛋白。这导致未成熟的、非传染性的病毒颗粒的释放，也提出了关于这种新型HIV-1抑制剂的作用机制、分子决定因素和分子靶标的身份的几个有趣的问题。我希望这些问题以及其他成熟抑制剂的发展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卓有成效的科学家，这是一个相对未开发的研究领域。我们和其他人的研究表明，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。虽然这些观察结果使我们能够深入了解PA-457的抗病毒作用，但PA-457的作用机制和耐药性仍有待完全确定。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深入了解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见解。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。抗药性是HIV治疗失败的主要原因。完成拟议的研究将有助于确定新的HIV成熟抑制剂，提供额外的治疗选择，并改善疾病结果。