Targeting HIV with Hydrocarbon-Stapled Fusion Helices

用碳氢化合物固定的融合螺旋靶向艾滋病毒

• 批准号: 7727361
• 负责人: Gregory Howard Bird
• 金额: $ 5.35万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2008
• 资助国家: 美国
• 起止时间: 2008-07-01 至 2011-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7727361
• 关键词: Affinity; Binding; Biochemical; Biodistribution; Biology; C-terminal; Chemicals; Drug Kinetics; Fuzeon; HIV; HIV Infections; Hydrocarbons; Investigation; Life; Life Cycle Stages; Methodology; Patients; Peptide Library; Peptides; Personal Satisfaction; Pharmaceutical Preparations; Predisposition; Prevention; Property; Public Health; Refractory; Resistance; Route; Structure; T-20; Therapeutic; Viral; Viral Load result; Virus Diseases; alpha helix; cost; economic impact; experience; in vivo; interdisciplinary approach; novel; novel strategies; prevent; prototype; public health relevance; resistance mutation; subcutaneous; virology

DESCRIPTION (provided by applicant): Viral fusion is a validated mechanistic target for pharmacologic inhibition of HIV infection. Although the prototype therapeutic in this arena, enfuvirtide (Fuzeon, T20),is capable of suppressing HIV viral load in treatment-experienced patients, this peptidic drug suffers from the general drawbacks of traditional peptide therapeutics. These include loss of biologically-relevant secondary structure, a resultant decrease in bioactivity, and susceptibility to proteolytic degradation. Due to these and other challenges, including cost of goods and subcutaneous route of administration, pharmacologic approaches to HIV fusion inhibition are only deployed in refractory patients, rather than as an upfront approach to blocking viral infection. In addition, with incorporation of enfuvirtide therapy into the anti-HIV arsenal, resistance mutations have emerged. Here we propose the use of our novel chemical strategy, termed hydrocarbon-stapling, to generate "Stabilized Alpha Helices of gp41" (SAH-gp41) compounds for the investigation and targeting of HIV fusion, and for overcoming enfuvirtide resistance. Specifically, we aim to (1) synthesize diversified hydrocarbon- stapled gp41domains to optimize their biophysical properties, and (2) evaluate and optimize the capacity of SAH-gp41 compounds to target and inhibit HIV fusion. Although we choose gp41 as our prototype for fusion helix stabilization, the synthetic methodology and experimental strategies described herein have the potential for broad application in the analysis, prevention, and treatment of many types of viral infections. PUBLIC HEALTH RELEVANCE: HIV infection has created a public health crisis that threatens the lives of people across the globe and impacts the economic and societal well-being of world nations. There is an urgent need for new approaches to prevent and disrupt ongoing HIV infection. We propose an interdisciplinary approach that combines chemical biology and virology to generate a "chemical toolbox" to investigate and neutralize viral fusion, a critical step in the life cycle of the HIV virus.

描述（由申请人提供）：病毒融合是一种经过验证的药理学抑制HIV感染的机制靶点。虽然在这个竞技场中的原型治疗剂恩夫韦肽（Fuzeon，T20）能够抑制治疗经验丰富的患者中的HIV病毒载量，但是这种肽药物遭受传统肽治疗剂的一般缺点。这些包括生物学相关二级结构的丧失、生物活性的降低和对蛋白水解降解的敏感性。由于这些和其他挑战，包括商品成本和皮下给药途径，HIV融合抑制的药理学方法仅用于难治性患者，而不是作为阻断病毒感染的前期方法。此外，随着恩夫韦肽治疗纳入抗艾滋病毒药物库，出现了耐药性突变。在这里，我们提出了使用我们的新的化学策略，称为烃钉合，以产生“稳定的α螺旋的gp 41”（SAH-gp 41）的化合物的调查和靶向HIV融合，并克服恩夫韦肽耐药性。具体而言，我们的目标是（1）合成多样化的烃钉合gp 41结构域以优化其生物物理性质，以及（2）评估和优化SAH-gp 41化合物靶向和抑制HIV融合的能力。虽然我们选择gp 41作为融合螺旋稳定化的原型，但本文所述的合成方法和实验策略具有广泛应用于分析、预防和治疗许多类型的病毒感染的潜力。 公共卫生相关性：艾滋病毒感染造成了一场公共卫生危机，威胁着地球仪各地人民的生命，影响着世界各国的经济和社会福祉。迫切需要采取新的方法来预防和阻断艾滋病毒的持续感染。我们提出了一种跨学科的方法，结合化学生物学和病毒学，以产生一个“化学工具箱”来调查和中和病毒融合，这是HIV病毒生命周期中的一个关键步骤。