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.

项目总结/文摘