Multi-domain amphipathic helical peptides and methods of their use
Inventors
Remaley, Alan T. • Demosky, Stephen J. • Stonik, John A. • AMAR MARCELO J A, null • Amar, Marcele J. A. • Neufeld, Edward B. • Brewer, H. Bryan • Thomas, Fairwell
Assignees
US Department of Health and Human Services
Publication Number
US-7572771-B1
Publication Date
2009-08-11
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 discloses isolated peptides and peptide analogs containing multiple amphipathic α-helical domains that promote lipid efflux from cells via an ABCA1-dependent pathway. These multi-domain peptides feature a first amphipathic α-helical domain with higher lipid affinity relative to a second amphipathic α-helical domain within the same peptide, resulting in promotion of lipid efflux specifically through the ABCA1 transporter while maintaining low cytotoxicity. The peptides include sequences as exemplified in SEQ ID NOs: 3-45 and can further comprise additional functional domains to enhance activity or therapeutic efficacy.
The problem addressed by the invention arises from the limitations of existing synthetic apolipoprotein mimetic peptides that, while promoting lipid efflux and showing potential in treating atherosclerosis and related cardiovascular disorders, often exert cytotoxic effects due to non-specific, ABCA1-independent lipid efflux pathways. Such cytotoxicity is linked to detergent-like actions that disrupt cell membranes, reducing therapeutic efficacy and causing undesirable cell damage. There is a need for non-cytotoxic synthetic peptides that specifically promote lipid efflux through the ABCA1-dependent pathway to provide safer and more effective treatment for dyslipidemic and vascular disorders.
Claims Coverage
The claims present five main inventive features focusing on a specific isolated peptide and its pharmaceutical uses, including its sequence, functional properties, and therapeutic applications.
Isolated peptide comprising two amphipathic α-helical domains with a defined amino acid sequence
An isolated peptide or peptide analog comprising two amphipathic α-helical domains, specifically including the amino acid sequence set forth in SEQ ID NO: 3.
Promotion of ABCA1-dependent lipid efflux and substantially non-cytotoxic nature
The isolated peptide promotes lipid efflux from cells via the ABCA1-dependent pathway and is substantially non-cytotoxic, enabling safe therapeutic application.
Inclusion of additional functional peptide domains
The peptide can be further modified to include additional peptide domains such as heparin binding sites, integrin binding sites, P-selectin sites, TAT HIV sequences, panning sequences, penatratin sequences, serum amyloid A sequences, LDL receptor sequences, modified 18A sequences, apoA-I Milano sequences, 6×-His sequences, lactoferrin sequences, or combinations thereof.
Pharmaceutical compositions comprising the peptide
Pharmaceutical compositions including the isolated peptide or peptide analog and a pharmaceutically acceptable carrier for administration to subjects.
Therapeutic methods for dyslipidemic and vascular disorders and implant applications
Methods for treating or inhibiting dyslipidemic or vascular disorders by administering therapeutically effective amounts of the pharmaceutical composition containing the peptide, use of implants coated with the peptide for treatment, and implants capable of treating such disorders when implanted in heart or peripheral vasculature.
The claims focus on specific isolated multi-domain amphipathic α-helical peptides defined by sequence and function, their compositions, and therapeutic methods including treatments of dyslipidemic and vascular disorders, emphasizing ABCA1-dependent lipid efflux promotion, non-cytotoxicity, and implant-based delivery.
Stated Advantages
The peptides promote lipid efflux from cells specifically via an ABCA1-dependent pathway, maintaining cell membrane integrity and avoiding cytotoxicity.
The dual-domain structure with differing lipid affinities confers selectivity and reduces non-specific lipid extraction, enhancing therapeutic efficacy in dyslipidemic and vascular disorders.
Modifications and peptide analogs improve stability, lipid affinity, and potentially therapeutic function, including anti-inflammatory and anti-oxidant properties.
Pharmaceutical formulations including implants enable targeted delivery to affected tissues, expanding clinical applications and improving treatment outcomes.
Documented Applications
Treatment or inhibition of dyslipidemic and vascular disorders such as hyperlipidemia, hyperlipoproteinemia, hypercholesterolemia, hypertriglyceridemia, HDL deficiency, apoA-I deficiency, coronary artery disease, atherosclerosis, thrombotic stroke, peripheral vascular disease, restenosis, acute coronary syndrome, post-perfusion myocardial injury, and vasculitis.
Use in pharmaceutical compositions for administration via implants, injections, or formulations in combination with other lipid-lowering or anti-inflammatory agents.
Research and screening methods to identify non-cytotoxic peptides that promote ABCA1-dependent lipid efflux by performing cytotoxicity and lipid efflux tests on cells with or without ABCA1 expression.
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