Managing Atherosclerosis by Modulating HDL Function

项目摘要/摘要 动脉粥样硬化是世界范围内导致人类死亡的主要原因。人们对……一直很感兴趣 开发治疗这种疾病的新疗法，其作用机制与目前 可获得的药物。一个有希望的策略是增强高密度脂蛋白(HDL)的功能。高密度脂蛋白 促进胆固醇反向转运的过程，将多余的胆固醇从外周组织转移到 排出的肝脏。拟议的研究计划，由强大的概念验证初步支持 结果，试图提出一种新的超分子策略来改善体内的高密度脂蛋白功能以对抗 动脉硬化。 建议的研究建立在我们的研究计划的成功基础上，该计划由NHLBI R01拨款资助 在过去的3年里。尽管在过去30年中，载脂蛋白A-I的设计研究取得了实质性进展 模拟多肽，通常与线性多肽相关的固有药理缺陷有 是推动高密度脂蛋白调节剂进入临床的主要障碍。拟议的研究 该计划寻求开发一类新的化学类型，该类型可以概括 螺旋apoA-I模拟，但没有其固有的局限性。我们在这里第一次描述了 适当设计八个残基自组装的环D，L-α-肽是有效的高密度脂蛋白调节 探员们。环D，L-α-肽的非生物结构克服了通常与 线性多肽，如血清/血浆稳定性低，口服生物利用度低，生产成本高等。 我们发现，环D，L-α-肽在体外重塑人和小鼠血浆高密度脂蛋白，增加前-高密度脂蛋白水平 β-高密度脂蛋白颗粒(高密度脂蛋白的亚种被认为是最抗动脉粥样硬化的)，并提高胆固醇 培养的巨噬细胞的外流。在体内，口服给药后，环肽增加了Pre-Pre-2水平 β-高密度脂蛋白颗粒，降低血浆低密度脂蛋白-胆固醇和甘油三酯水平，提高高密度脂蛋白水平，并促进抗 炎症效应伴随而来的动脉粥样硬化斑块的预防。 本研究项目旨在开发安全有效的环肽类化合物，以防止糖尿病的发生。 通过改善高密度脂蛋白功能来增强RCT，从而导致动脉粥样硬化。我们正在遵循一种综合的方法，从 我们的药物化学优化导致体内机制研究、药理学、毒理学和 功效。我们的目标是在初步发现的基础上，探索体内的作用机制 以及它可能如何根据给药途径而不同(目标1)，优化并更好地理解 使用一系列基于机理的功能分析(目标2)的多肽结构-活性关系，并 确定优化化合物的口服有效性和安全性(目标3)。这些研究将推动 开发口服和肠外有效化合物并为治疗提供新的化学框架 开发高密度脂蛋白调节疗法。

PROJECT SUMMARY/ABSTRACT Atherosclerosis is the leading cause of human mortality worldwide. There has been a great interest in developing novel therapeutics for this disease that function via an orthogonal mechanism of action to currently available drugs. One promising strategy is to enhance the function of high-density lipoproteins (HDLs). HDLs facilitate the process of reverse cholesterol transport to transfer excess cholesterol from peripheral tissues to the liver for elimination. The proposed research program, supported by strong proof-of-concept preliminary results, seeks to advance a novel supramolecular strategy for improving HDL function in vivo to combat atherosclerosis. The proposed studies build on the successes of our research program, funded by an NHLBI R01 grant over the past 3 years. Despite substantial progress over the past 30 years of research in the design of apoA-I mimetic peptides, the inherent pharmacological shortcomings typically associated with linear peptides have been a major impediment to advancing HDL-modulating agents through the clinic. The proposed research program seeks to develop a novel class of chemotypes that could recapitulate the functional attributes of helical apoA-I mimetics but without their inherent limitations. We describe here for the first time that appropriately designed eight-residue self-assembling cyclic D,L-α-peptides are effective HDL modulating agents. The abiotic structure of cyclic D,L-α-peptides overcome many of the shortcomings typically associated with linear peptides, such as low serum/plasma stability, lack of oral bioavailability, high production costs, etc. We show that cyclic D,L-α-peptides remodel human and mouse plasma HDLs in vitro, increase the level of pre- beta HDL particles (subspecies of HDLs considered to be the most anti-atherogenic), and enhance cholesterol efflux from cultured macrophages. In vivo, with oral administration, the cyclic peptides increase the level of pre- beta HDL particles, reduce plasma LDL-cholesterol and triglyceride levels, raise HDL levels, and promote anti- inflammatory effects with concomitant prevention of atherosclerotic plaques. This research project aims to develop safe and efficacious cyclic peptides that prevent the development of atherosclerosis by enhancing RCT via improved HDL function. We are following an integrated approach, from medicinal chemistry optimization of our leads to in vivo mechanistic studies, pharmacology, toxicology, and efficacy. Our objectives, building on our preliminary findings, are to explore the in vivo mechanism of action and how it might differ depending on route of administration (Aim 1), optimize and better understand the peptide structure-activity relationship using a series of mechanism-based functional assays (Aim 2), and to determine the oral efficacy and safety of optimized compounds (Aim 3). These studies will advance the development of orally and parenterally efficacious compounds and provide a new chemical framework for developing HDL modulating therapeutics.