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-?-peptides are effective HDL modulating agents. The abiotic structure of cyclic D,L-?-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-?-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.
There has been great interest in advancing HDL-targeted therapies to prevent and manage atherosclerosis. In recent progress, we have identified a novel class of HDL modulators based on amphiphilic cyclic D,L-?- peptides, which reduce dyslipidemia and prevent the development of atherosclerosis in vivo. Building on these exciting findings, this project seeks to advance such molecular entities as mechanistically novel therapeutic agents for treating atherosclerosis.
|Zhao, Yannan; Leman, Luke J; Search, Debra J et al. (2017) Self-Assembling Cyclic d,l-?-Peptides as Modulators of Plasma HDL Function. A Supramolecular Approach toward Antiatherosclerotic Agents. ACS Cent Sci 3:639-646|
|Leman, Luke J (2015) The potential of apolipoprotein mimetic peptides in the treatment of atherosclerosis. Clin Lipidol 10:215-217|
|Zhao, Yannan; Black, Audrey S; Bonnet, David J et al. (2014) In vivo efficacy of HDL-like nanolipid particles containing multivalent peptide mimetics of apolipoprotein A-I. J Lipid Res 55:2053-63|
|Leman, Luke J; Maryanoff, Bruce E; Ghadiri, M Reza (2014) Molecules that mimic apolipoprotein A-I: potential agents for treating atherosclerosis. J Med Chem 57:2169-96|
|Zhao, Yannan; Imura, Tomohiro; Leman, Luke J et al. (2013) Mimicry of high-density lipoprotein: functional peptide-lipid nanoparticles based on multivalent peptide constructs. J Am Chem Soc 135:13414-24|