Managing Atherosclerosis by Modulating HDL Function

通过调节 HDL 功能来治疗动脉粥样硬化

• 批准号: 8480969
• 负责人: M. Reza Ghadiri
• 金额: $ 63.14万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-06-01 至 2017-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8480969
• 关键词: Amino Acids; Animal Model; Antiatherogenic; Apolipoprotein A-I; Apolipoproteins; Arterial Fatty Streak; Atherosclerosis; Basic Science; Bioavailable; Biological Availability; Cardiovascular Diseases; Cessation of life; Chemistry; Cholesterol; Chronic; Clinical Trials; Development; Diet; Drug Formulations; Drug Kinetics; Enzymes; Exhibits; Failure; Fatty acid glycerol esters; Funding; Future; Generations; Grant; Health; Heart Diseases; High Density Lipoproteins; Human; Hyperlipidemia; In Vitro; Kinetics; Knowledge; Lead; Length; Lipids; Liver; Molecular; Mus; National Heart, Lung, and Blood Institute; Oral; Pathway interactions; Peptides; Peripheral; Plasma; Play; Prevention therapy; Process; Production; Property; Research; Role; Series; Solid; Therapeutic; Therapeutic Agents; Tissues; absorption; atheroprotective; base; combat; cost; design; drug candidate; drug development; high density lipoprotein-2; improved; improved functioning; in vivo; interest; macrophage; mimetics; mouse model; novel; novel strategies; novel therapeutics; particle; pre-beta high-density lipoprotein; prevent; programs; public health relevance; reconstitution; research study; reverse cholesterol transport; success; synthetic construct

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.

描述（由申请人提供）：动脉粥样硬化是全世界所有人类死亡的近五分之一的原因。打击动脉粥样硬化的一种有希望的策略涉及调节高密度脂蛋白（HDLS），以促进反向胆固醇转运（RCT）的过程，从而从外周组织中去除多余的胆固醇以消除。但是，升高总等离子体HDL水平的化合物的最新临床试验失败强调了需要更好地了解HDLS的动脉保护机制，以及改善HDL功能的新方法。越来越清楚的是，提高HDL质量（即功能）比仅仅增加HDL数量更重要。拟议的研究计划是基于我们最近成功地推进一类新的载脂蛋白A-I（apoa-i）的模拟物的成功，从而增强了体外和体内HDLS的RCT功能。 APOA-I在启动RCT中起着关键作用，并且在包括人类临床试验在内的许多研究中都记录了其抗动脉粥样硬化特性。但是，Apoa-I的高生产成本和缺乏口服生物利用度使得长期使用动脉粥样硬化是不切实际的。我们设计了新颖的ApoA-I模拟物，基于短，合成，两亲性，螺旋肽的多价表示，这些肽可以被形成盘状HDL样的HDL样纳米二肽构建体。这些构建体与人类和小鼠血浆HDL相互作用并重塑，增加了β前HDL颗粒的水平（HDL的亚种，被认为是最抗动脉粥样硬化的亚种），并增强了巨噬细胞的胆固醇外排。此外，在LDLR - / - 小鼠（类似于人类中高脂血症的动脉粥样硬化动物模型）中，三聚体构建体在预防动脉粥样硬化病变的进展方面非常有效。重要的是，我们的Apoa-I模拟物在小鼠中表现出令人惊讶的高口服生物利用度，从而为未来治疗剂的发展提供了有希望的途径。简而言之，迄今为止，我们的研究为拟议的研究提供了良好的基础，旨在开发安全的，可生物利用的apoa-i mimetics来治疗动脉粥样硬化。我们的第一个目标是优化铅构建体，以提高合成效率，口服生物瓦利比利，药代动力学特征和体内功效（AIMS 1和2）。这些目标将通过一系列新设计，结构优化和功能分析来实现。我们的第二个目标是更好地理解载脂蛋白模拟肽通过用天然和重构的HDL颗粒进行一系列建议的生物物理和酶学分析来调节HDL功能的基本机制（AIM 3）。我们的组装团队包括生物活性肽设计和化学专家，动脉粥样硬化的小鼠模型以及药物开发，非常适合进行拟议的研究。我们希望这些研究能够更详细地了解如何最好地调节HDL并确定候选药物以形成可生物可用的抗动脉粥样硬化剂。