Method of treating or inhibiting inflammation by multi-domain amphipathic helical peptides
Inventors
Remaley, Alan T. • Demosky, Stephen J. • Stonik, John A. • Amar, Marcelo J. A. • Neufeld, Edward B. • Brewer, H. Bryan • Thomas, Fairwell
Assignees
US Department of Health and Human Services
Publication Number
US-8148323-B2
Publication Date
2012-04-03
Expiration Date
2025-10-14
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Abstract
Disclosed herein are peptides or peptide analogs with multiple amphipathic α-helical domains that promote lipid efflux from cells via an ABCA1-dependent pathway. 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 are also disclosed herein.
Core Innovation
The invention relates to isolated peptides or peptide analogs with multiple amphipathic α-helical domains that promote lipid efflux from cells via an ABCA1-dependent pathway. These multi-domain amphipathic α-helical peptides or peptide analogs can be used to treat or inhibit dyslipidemic and vascular disorders by promoting lipid efflux through ABCA1 transporter facilitation. The peptides include at least two amphipathic α-helices where one domain exhibits higher lipid affinity than the other, enabling specificity for ABCA1-dependent lipid efflux while minimizing cytotoxicity.
The problem being addressed is the need for non-cytotoxic synthetic peptide mimics of apolipoproteins that promote lipid efflux specifically by the ABCA1-dependent pathway. Previous peptides with high lipid affinity showed cytotoxicity due to ABCA1-independent lipid efflux, which is a passive, detergent-like extraction process leading to cell damage and reduced therapeutic efficacy. Non-specific lipid removal from non-ABCA1-expressing cells reduces the peptides’ effectiveness. Therefore, there is a need to develop peptides that selectively efflux lipid from ABCA1-expressing cells without cytotoxic effects.
Claims Coverage
The claims include one independent claim focused on a therapeutic method using a specific peptide sequence to treat or inhibit inflammation. The claim covers additional features such as inclusion of extra peptide domains and combinational therapies.
Method of treating or inhibiting inflammation using a specific peptide sequence
Administering to a subject a therapeutically effective amount of a pharmaceutical composition comprising an isolated peptide or peptide analog comprising the amino acid sequence set forth in SEQ ID NO: 3 to treat or inhibit inflammation.
Use of additional peptide domains in the therapeutic composition
Inclusion of at least one additional peptide domain to the peptide sequence, wherein the additional domain can be a heparin binding site, integrin binding site, P-selectin site, TAT HIV sequence, panning sequence, penatratin sequence, serum amyloid A (SAA) C- or N-terminus sequences, LDL receptor sequence, modified 18A sequence, apoA-I Milano sequence, 6×-His sequence, lactoferrin sequence, or combinations thereof.
Peptide promotes ABCA1-dependent lipid efflux and is substantially non-cytotoxic
The peptide or peptide analog administered promotes ATP-binding cassette transporter A1 (ABCA1)-dependent lipid efflux from cells and is substantially non-cytotoxic.
Combination therapy with additional therapeutic agents
Administration of the peptide can be combined with an additional therapeutic agent such as a lipid lowering agent, anti-microbial agent, additional anti-inflammatory agent, or combinations thereof.
Various modes of administration including implant
Administration of the peptide can be performed by delivery of a pharmaceutical composition comprising the peptide on an implant.
Treatment of multiple related disorders
The method is applicable to treating or inhibiting inflammation and additional 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, or combinations thereof.
The claims cover methods of treating inflammation using multi-domain amphipathic α-helical peptides with specific sequences, their pharmaceutical compositions optionally including additional functional peptide domains, their substantial non-cytotoxicity and ABCA1-dependent lipid efflux activity, combination with other therapeutics, diverse administration modes, and treatment of a broad group of dyslipidemic and vascular disorders.
Stated Advantages
The peptides promote lipid efflux specifically via an ABCA1-dependent pathway, thereby enhancing specificity and reducing cytotoxicity.
Multi-domain peptides with a combination of a high lipid affinity helix and a low lipid affinity helix achieve ABCA1-mediated lipid efflux while avoiding ABCA1-independent cytotoxic lipid removal.
Reduced cytotoxicity makes the peptides safer and more therapeutically effective in the treatment and prevention of cardiovascular and dyslipidemic disorders.
Inclusion of additional functional peptide domains can enhance lipid efflux, therapeutic efficacy, cellular targeting, and potential anti-inflammatory and antioxidant properties.
Documented Applications
Treatment and inhibition of inflammation.
Treatment and prevention 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, and vasculitis.
Use in combination therapies with lipid lowering agents, anti-microbial agents, and/or other anti-inflammatory agents.
Administration of the peptides or compositions via implants, injections, or other pharmaceutical formulations for treating the above disorders.
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