Managing Atherosclerosis by Modulating HDL Function

描述（由申请人提供）：动脉粥样硬化是全世界近五分之一的人类死亡的一个致病因素。一种很有前景的对抗动脉粥样硬化的策略包括调节高密度脂蛋白（hdl），以促进逆向胆固醇运输（RCT）过程，从而从外周组织中清除多余的胆固醇。然而，最近提高血浆总HDL水平的化合物的临床试验失败，突出了对HDL的动脉粥样硬化保护机制的更好理解和对改善HDL功能的新方法的需要。越来越清楚的是，提高HDL的质量（即功能）比简单地增加HDL的数量更重要。拟议的研究计划建立在我们最近成功推进一类新的载脂蛋白a - i （apoA-I）模拟物的基础上，该模拟物可增强hdl在体外和体内的RCT功能。apoa - 1在启动随机对照试验中起着关键作用，其抗动脉粥样硬化特性已在许多研究中得到证实，包括人体临床试验。然而，高生产成本和缺乏口服生物利用度使得apoa - 1在动脉粥样硬化管理中的长期使用不切实际。我们设计了新型的apoA-I模拟物，基于短的、合成的、两亲性的、螺旋状肽的多价呈现，这些肽可以塑造成盘状高密度脂蛋白样的纳米脂肽结构。这些构建体与人和小鼠血浆HDL相互作用并重塑，增加β - HDL颗粒（HDL的亚种被认为是最抗动脉粥样硬化的）的水平，并增强巨噬细胞的胆固醇外排。此外，在一项为期10周的LDLr-/-小鼠（一种类似于人类高脂血症的动脉粥样硬化动物模型）体内研究中，三聚体结构在预防动脉粥样硬化病变进展方面非常有效。重要的是，我们的apoA-I模拟物在小鼠中表现出惊人的高口服生物利用度，从而为未来治疗剂的开发提供了一条有希望的途径。总之，我们迄今为止的研究为旨在开发安全的、口服生物可利用的apoa - 1模拟物来治疗动脉粥样硬化的拟议研究提供了强有力的基础。我们的第一个目标是优化先导结构的合成效率、口服生物利用度、药代动力学特征和体内疗效（目标1和2）。这些目标将通过一系列新的设计、结构优化和功能分析来实现。我们的第二个目标是通过对天然和重组HDL颗粒进行一系列生物物理和酶学分析，更好地理解载脂蛋白模拟肽调节HDL功能的基本机制（目标3）。我们的团队包括生物活性肽设计和化学、动脉粥样硬化小鼠模型和药物开发方面的专家，他们非常适合开展拟议的研究。我们希望这些研究将导致更详细的知识如何最好地调节hdl和确定候选药物开发作为口服生物可利用的抗动脉粥样硬化药物。

DESCRIPTION (provided by applicant): Atherosclerosis is a causative factor in nearly one fifth of all human deaths worldwide. A promising strategy for combating atherosclerosis involves modulating high-density lipoproteins (HDLs) to facilitate the process of reverse cholesterol transport (RCT) and thereby remove excess cholesterol from peripheral tissues for elimination. However, recent clinical trial failures of compounds that elevate total plasma HDL levels highlight the need for a better understanding of the atheroprotective mechanisms of HDLs, and for new approaches to improve HDL function. It is becoming increasingly clear that improving HDL quality (i.e., function) is more important than simply increasing HDL quantity. The proposed research program is built on our recent success in advancing a new class of apolipoprotein A-I (apoA-I) mimetics that enhance the RCT function of HDLs both in vitro and in vivo. ApoA-I plays a key role in initiating RCT and its anti-atherogenic properties have been documented in numerous studies, including human clinical trials. However, the high production costs and lack of oral bioavailability of apoA-I have made it impractical for chronic use in the management of atherosclerosis. We have designed novel apoA-I mimetics based on multivalent presentation of short, synthetic, amphiphilic, helical peptides that can be fashioned into discoidal HDL-like nanolipopeptide constructs. These constructs interact with and remodel human and mouse plasma HDLs, increase the level of pre-beta HDL particles (the subspecies of HDLs considered to be the most anti-atherogenic), and enhance cholesterol efflux from macrophages. Moreover, a trimeric construct is remarkably effective in vivo in preventing the progression of atherosclerotic lesions in a 10-week study in LDLr-/- mice (an animal model of atherosclerosis that resembles hyperlipidemia in humans). Importantly, our apoA-I mimetics exhibit surprisingly high oral bioavailability in mice, thus providing a promising path toward the development of future therapeutic agents. In short, our studies to date provide a strong basis for the proposed research aimed at developing safe, orally bioavailable apoA-I mimetics to treat atherosclerosis. Our first objective is to optimize the lead constructs for synthetic efficiency, oral bioavailabiliy, pharmacokinetic profile, and in vivo efficacy (Aims 1 and 2). These aims will be achieved through a series of new designs, structural optimizations, and functional analyses. Our second objective is to better understand the basic mechanisms by which apolipoprotein mimetic peptides modulate HDL function by performing a series of proposed biophysical and enzymological analyses with native and reconstituted HDL particles (Aim 3). Our assembled team, which includes experts in bioactive peptide design and chemistry, mouse models of atherosclerosis, and drug development, is uniquely suited to carry out the proposed studies. We hope that these studies will result in a more detailed knowledge of how best to modulate HDLs and identify drug candidates to develop as orally bioavailable anti-atherosclerotic agents.