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近五分之一的人类死亡的致病因素。对抗动脉粥样硬化的一个有前景的策略是调节高密度脂蛋白（HDL）以促进胆固醇反向转运（RCT）过程，从而从外周组织中去除多余的胆固醇并消除。然而，最近提高血浆总 HDL 水平的化合物的临床试验失败，凸显了需要更好地了解 HDL 的动脉粥样硬化机制，以及改善 HDL 功能的新方法。越来越明显的是，提高 HDL 质量（即功能）比简单增加 HDL 数量更重要。拟议的研究计划是建立在我们最近成功推进一类新型载脂蛋白 A-I (apoA-I) 模拟物的基础上的，该模拟物可在体外和体内增强 HDL 的 RCT 功能。 ApoA-I 在启动 RCT 中发挥着关键作用，其抗动脉粥样硬化特性已在包括人体临床试验在内的众多研究中得到证实。然而，apoA-I 的高生产成本和缺乏口服生物利用度使其无法长期用于动脉粥样硬化的治疗。我们设计了基于短的、合成的、两亲性的螺旋肽的多价呈现的新型apoA-I模拟物，这些肽可以被塑造成盘状HDL样纳米脂肽结构。这些构建体与人和小鼠血浆 HDL 相互作用并进行重塑，增加前 β HDL 颗粒（被认为最具抗动脉粥样硬化作用的 HDL 亚种）的水平，并增强巨噬细胞的胆固醇流出。此外，在 LDLr-/- 小鼠（类似于人类高脂血症的动脉粥样硬化动物模型）中进行的为期 10 周的研究中，三聚体构建体在体内预防动脉粥样硬化病变的进展非常有效。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，从而为未来治疗药物的开发提供了一条有希望的道路。简而言之，我们迄今为止的研究为拟议的研究提供了坚实的基础，该研究旨在开发安全的、口服生物可利用的 apoA-I 模拟物来治疗动脉粥样硬化。我们的首要目标是优化先导构建体的合成效率、口服生物利用度、药代动力学特征和体内功效（目标 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通过使用天然和重构的 HDL 颗粒进行一系列拟议的生物物理和酶学分析，更好地了解载脂蛋白模拟肽调节 HDL 功能的基本机制（目标 3）。我们组建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，非常适合开展拟议的研究。我们希望这些研究能够更详细地了解如何最好地调节 HDL 并确定候选药物以开发为口服生物可利用的抗动脉粥样硬化药物。