Targeting HIV with Hydrocarbon-Stapled Fusion Helices

描述(由申请人提供)：病毒融合是药物抑制艾滋病毒感染的有效机制靶点。尽管这一领域的原型治疗药物恩福韦肽(Fuzeon，T20)能够抑制有治疗经验的患者的HIV病毒载量，但这种多肽类药物存在传统多肽疗法的普遍缺陷。这些包括与生物相关的二级结构的丧失，由此导致的生物活性的降低，以及对蛋白质降解的敏感性。由于这些和其他挑战，包括商品成本和皮下给药途径，抑制艾滋病毒融合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，随着将恩福韦德疗法纳入抗艾滋病毒武器库，出现了耐药突变。在这里，我们建议使用我们的新的化学策略，称为碳氢化合物装订，以产生“稳定的gp41的阿尔法螺旋”(SAH-gp41)化合物，用于研究和靶向HIV融合，并克服环境耐药性。具体地说，我们的目标是(1)合成不同的碳氢化合物连接的gp41结构域，以优化其生物物理性质，以及(2)评估和优化SAH-gp41化合物靶向和抑制HIV融合的能力。虽然我们选择gp41作为融合螺旋稳定的原型，但这里描述的合成方法学和实验策略在分析、预防和治疗多种类型的病毒感染方面具有广泛的应用潜力。 公共卫生相关性：艾滋病毒感染造成了一场公共卫生危机，威胁着全球人民的生命，并影响到世界各国的经济和社会福祉。迫切需要新的方法来预防和阻断持续的艾滋病毒感染。我们提出了一种结合化学生物学和病毒学的跨学科方法，以产生一个“化学工具箱”来研究和中和病毒融合，这是艾滋病毒生命周期中的关键步骤。

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.