Targeting HIV with Hydrocarbon-Stapled Fusion Helices

描述（由申请人提供）：病毒融合是一种有效的药物抑制HIV感染的机制靶点。虽然这一领域的原型治疗药物恩孚韦肽（fufuvirtide, Fuzeon, T20）能够抑制接受过治疗的患者的HIV病毒载量，但这种肽类药物存在传统肽类药物的普遍缺陷。这些包括生物相关二级结构的丧失，由此导致的生物活性下降，以及对蛋白质水解降解的易感性。由于这些和其他挑战，包括商品成本和皮下给药途径，药物治疗HIV融合抑制的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，随着恩富韦肽治疗纳入抗hiv武库，耐药性突变已经出现。在这里，我们提出使用我们的新化学策略，称为碳氢化合物钉接，来产生“稳定的gp41 α螺旋”（SAH-gp41）化合物，用于研究和靶向HIV融合，并克服恩氟韦肽耐药性。具体而言，我们的目标是(1)合成多种碳氢钉接的gp41结构域，以优化其生物物理性质；(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，但本文所描述的合成方法和实验策略在多种类型病毒感染的分析、预防和治疗中具有广泛应用的潜力。

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.