# Managing Atherosclerosis by Modulating HDL Function

> **NIH NIH R01** · SCRIPPS RESEARCH INSTITUTE, THE · 2021 · $693,767

## Abstract

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 chem...

## Key facts

- **NIH application ID:** 10065511
- **Project number:** 5R01HL118114-08
- **Recipient organization:** SCRIPPS RESEARCH INSTITUTE, THE
- **Principal Investigator:** M. Reza Ghadiri
- **Activity code:** R01 (R01, R21, SBIR, etc.)
- **Funding institute:** NIH
- **Fiscal year:** 2021
- **Award amount:** $693,767
- **Award type:** 5
- **Project period:** 2013-06-01 → 2022-03-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10065511

## Citation

> US National Institutes of Health, RePORTER application 10065511, Managing Atherosclerosis by Modulating HDL Function (5R01HL118114-08). Retrieved via AI Analytics 2026-05-25 from https://api.ai-analytics.org/grant/nih/10065511. Licensed CC0.

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