Peptides promoting lipid efflux
Inventors
Remaley, Alan T. • Amar, Marcelo J. A.
Assignees
US Department of Health and Human Services
Publication Number
US-8936787-B2
Publication Date
2015-01-20
Expiration Date
2029-04-14
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Abstract
Disclosed herein are peptides and peptide analogs with multiple amphipathic α-helical domains that promote lipid efflux from cells via an ABCA1-dependent pathway, as well as peptides that activate lipoprotein lipase, and compositions comprising such peptides or combinations thereof. Also provided herein are methods of using multi-domain amphipathic α-helical peptides or peptide analogs to treat or inhibit dyslipidemic disorders. Methods for identifying non-cytotoxic peptides that promote ABCA1-dependent lipid efflux from cells and activate lipoprotein lipase within cells are also disclosed herein.
Core Innovation
The invention provides isolated peptides and peptide analogs comprising multiple amphipathic α-helical domains that specifically promote lipid efflux from cells via an ABCA1-dependent pathway. These peptides include domains exhibiting different lipid affinities, where a first amphipathic α-helical domain has higher lipid affinity than a second domain, and the peptides mediate lipid removal from cells in a substantially non-cytotoxic manner, such as without inducing significant hypertriglyceridemia. The peptides can also include domains capable of activating lipoprotein lipase, either covalently linked or as separate peptides combined in therapy.
The background identifies the problem that existing synthetic peptide mimics of apolipoproteins, particularly those with high lipid affinity, can promote lipid efflux from cells through an ABCA1-independent pathway. This non-specific pathway results in cytotoxicity and reduces therapeutic efficacy by indiscriminately removing lipid from cells that do not express ABCA1, diluting the peptide's capacity to remove cholesterol from cells involved in atherosclerosis. Therefore, there is a need for non-cytotoxic synthetic peptide mimics that specifically promote lipid efflux through an ABCA1-dependent pathway, preserving cell integrity and improving therapeutic potential against cardiovascular diseases.
The invention addresses this need by providing peptides containing multiple amphipathic α-helical domains with asymmetric lipid affinities—one domain having relatively high lipid affinity and another having relatively low lipid affinity—with a hydrophobic moment difference sufficient to enable specificity for ABCA1-dependent lipid efflux. Such peptides maintain cell membrane integrity and avoid cytotoxic lipid removal pathways. Additionally, peptides or mixtures combining ABCA1-dependent lipid efflux activity with lipoprotein lipase activation domains enhance treatment potential for dyslipidemic and vascular disorders by both promoting cholesterol clearance and reducing hypertriglyceridemia.
Claims Coverage
The patent includes two independent claims directed to isolated peptides comprising a first domain promoting ABCA1-dependent lipid efflux and a second domain activating lipoprotein lipase, along with related pharmaceutical compositions and methods of treatment.
Peptides containing dual functional domains
An isolated peptide comprises two domains: a first domain capable of promoting lipid efflux from cells via an ABCA1-dependent pathway, and a second domain capable of activating lipoprotein lipase.
Linker connecting functional domains
The peptide optionally includes a linker connecting the first and second domains, where the linker comprises amino acids such as glycine, alanine, or proline, with proline preferred.
Additional functional peptide domains
The peptide may further comprise additional peptide domains including but not limited to heparin binding sites, integrin binding sites, P-selectin sites, TAT HIV sequences, panning sequences, penatratin sequences, SAA C- or N-terminus sequences, LDL receptor sequences, modified 18A sequences, apoA-I Milano sequences, 6×-His sequences, and lactoferrin sequences.
Specific peptides exemplified by SEQ ID NOs: 70–75
The peptide may comprise any amino acid sequence as set forth in SEQ ID NOs: 70-75, which embody both activities of lipid efflux promotion and lipoprotein lipase activation.
Pharmaceutical compositions including the peptide
Pharmaceutical compositions comprising the isolated peptide and a pharmaceutically acceptable carrier are claimed.
Methods of treating lipid disorders using peptides
Methods directed to treating or inhibiting hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, or combinations thereof in subjects by administering therapeutically effective amounts of pharmaceutical compositions containing the peptides.
Use of implants coated with peptides
Implants, such as stents, coated with the peptide (optionally comprising additional functional domains as described) for localized treatment of dyslipidemic or vascular disorders are claimed.
Co-administration of peptides
Methods comprising co-administering isolated peptides comprising lipid efflux promoting sequences (SEQ ID NOs: 3-45) and peptides comprising lipoprotein lipase activating sequences (SEQ ID NOs: 63-69) to treat dyslipidemic disorders.
The claims cover isolated peptides with dual domains promoting ABCA1-dependent lipid efflux and activating lipoprotein lipase, pharmaceutical compositions including such peptides, their use in treating dyslipidemic and vascular disorders, implant coatings comprising the peptides, and methods involving co-administration of separate peptides with these functions.
Stated Advantages
Provides peptides that promote lipid efflux in an ABCA1-dependent and substantially non-cytotoxic manner, reducing adverse effects associated with non-specific lipid efflux.
Peptides combining lipid efflux promotion and lipoprotein lipase activation effectively treat dyslipidemic and vascular disorders, including atherosclerosis and hypertriglyceridemia.
Peptides and pharmaceutical compositions can be administered via implants or systemically, enabling versatile therapeutic applications.
Documented Applications
Treatment or inhibition of dyslipidemic and vascular disorders including hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, HDL deficiency, apoA-I deficiency, coronary artery disease, atherosclerosis, thrombotic stroke, peripheral vascular disease, restenosis, acute coronary syndrome, reperfusion myocardial injury, vasculitis, and inflammation.
Use in combination with lipid-lowering agents such as statins, fibrates, niacin, bile-acid resins, and other cholesterol-lowering therapies.
Use of peptides coated on implants such as stents for localized treatment of vascular disorders.
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