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: 10065511
• 负责人: M. Reza Ghadiri
• 金额: $ 69.38万
• 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 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10065511
• 关键词: Abate; Advanced Development; Adverse effects; Amino Acids; Antiatherogenic; Antiinflammatory Effect; Apolipoprotein A-I; Arterial Fatty Streak; Atherosclerosis; Biological Assay; Biological Availability; Biophysics; Chemicals; Cholesterol; Clinic; Cyclic Peptides; Data; Development; Dietary Cholesterol; Disease; Dose; Dyslipidemias; Funding; Gene Expression; Goals; Grant; Heart Valves; High Density Lipoproteins; Human; In Vitro; Intestines; Knockout Mice; LDL Cholesterol Lipoproteins; Lead; Lipids; Liver; Low-Density Lipoproteins; Measures; Molecular; Molecular Structure; Mus; National Heart, Lung, and Blood Institute; Oral; Oral Administration; Outcome Study; Peptide Nanotubes; Peptides; Periodicity; Peripheral; Pharmaceutical Chemistry; Pharmaceutical Preparations; Pharmacology; Pharmacology and Toxicology; Plasma; Play; Population; Prevention; Process; Production; Research; Research Project Grants; Route; Safety; Series; Side; Structure; Structure-Activity Relationship; Therapeutic; Therapeutic Agents; Time; Tissues; Toxic effect; Toxicology; Triglycerides; absorption; amphiphilicity; aortic arch; base; combat; cost; design; efficacy study; human mortality; improved; in vitro Assay; in vivo; inhibitor/antagonist; interest; intraperitoneal; lead optimization; macrophage; mimetics; novel; novel therapeutics; particle; peptide structure; peptidomimetics; pre-beta high-density lipoprotein; prevent; programs; reverse cholesterol transport; success; targeted treatment; transcriptome sequencing

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.

项目概要/摘要 动脉粥样硬化是全世界人类死亡的主要原因。人们对此产生了极大的兴趣 开发针对这种疾病的新疗法，通过目前的正交作用机制发挥作用 可用药物。一种有前途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过程，将多余的胆固醇从周围组织转移到 肝脏用于消除。拟议的研究计划得到了强有力的初步概念验证的支持 结果，寻求推进一种新的超分子策略，以改善体内 HDL 功能以对抗 动脉粥样硬化。 拟议的研究建立在我们研究计划的成功之上，该计划由 NHLBI R01 拨款资助 过去3年。尽管过去 30 年的 apoA-I 设计研究取得了实质性进展 模拟肽，通常与线性肽相关的固有药理学缺点 是 HDL 调节剂在临床上推广的主要障碍。拟议的研究 该计划旨在开发一类新颖的化学型，可以概括的功能属性 螺旋 apoA-I 模拟物，但没有其固有的局限性。我们在这里第一次描述 适当设计的八残基自组装环状 D,L-α-肽是有效的 HDL 调节 代理。环状 D,L-α-肽的非生物结构克服了许多通常相关的缺点 线性肽存在血清/血浆稳定性低、口服生物利用度不足、生产成本高等问题。 我们发现，环状 D,L-α-肽可在体外重塑人和小鼠血浆 HDL，提高前- β HDL 颗粒（HDL 亚种被认为是最具抗动脉粥样硬化作用的），并增强胆固醇 从培养的巨噬细胞流出。在体内，通过口服给药，环肽可增加前体的水平。 β-HDL 颗粒，降低血浆 LDL-胆固醇和甘油三酯水平，提高 HDL 水平，并促进抗- 炎症作用并同时预防动脉粥样硬化斑块。 该研究项目旨在开发安全有效的环肽，以预防 通过改善 HDL 功能增强 RCT 来治疗动脉粥样硬化。我们正在遵循一种综合方法，从 我们的药物化学优化可用于体内机制研究、药理学、毒理学和 功效。基于我们的初步发现，我们的目标是探索体内作用机制 以及它如何根据给药途径而有所不同（目标 1），优化并更好地了解 使用一系列基于机制的功能测定（目标 2）来确定肽的结构-活性关系，并 确定优化化合物的口服功效和安全性（目标 3）。这些研究将推进 开发口服和肠胃外有效的化合物，并提供新的化学框架 开发 HDL 调节疗法。