Multi-domain amphipathic helical peptides and methods of their use
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-8835378-B2
Publication Date
2014-09-16
Expiration Date
2025-10-14
Interested in licensing this patent?
MTEC can help explore whether this patent might be available for licensing for your application.
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 disclosed are 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 in a non-cytotoxic manner. Methods for identifying substantially non-cytotoxic peptides that promote ABCA1-dependent lipid efflux from cells are also described, including cytotoxicity tests and lipid efflux tests on ABCA1-expressing and non-ABCA1-expressing cells.
The problem addressed is that existing short synthetic peptide mimics of apolipoproteins, while some having beneficial effects in preventing atherosclerosis, are potentially cytotoxic due to non-specific, ABCA1-independent lipid efflux from cells. This cytotoxicity limits their therapeutic use. There is a need for non-cytotoxic synthetic peptide mimics that promote specific lipid efflux from cells by an ABCA1-dependent pathway to effectively treat cardiovascular diseases such as atherosclerosis.
The disclosure identifies multi-domain peptides containing at least two amphipathic α-helical domains wherein a first domain exhibits higher lipid affinity relative to a second domain in the same peptide, measured for example by hydrophobic moment scores. This structural feature enables the peptides to promote lipid efflux specifically through the ABCA1 transporter, reducing cytotoxicity associated with ABCA1-independent pathways. Representative peptides and sequences are included, and the peptides can be modified with functional domains to enhance their activities or therapeutic efficacy.
Claims Coverage
The patent claims encompass two independent claims directed to isolated multi-domain peptides or peptide analogs promoting lipid efflux via an ABCA1-dependent pathway and methods of their use.
Multi-domain peptide sequence that promotes ABCA1-dependent lipid efflux
An isolated peptide or peptide analog consisting of the specific amino acid sequence set forth in SEQ ID NO: 7 that promotes lipid efflux from cells via an ABCA1-dependent pathway.
Multi-domain peptide with additional functional peptide domains
An isolated peptide or peptide analog comprising the sequence of SEQ ID NO: 7 coupled with at least one additional peptide domain, optionally including functional domains such as heparin binding site, integrin binding site, P-selectin site, TAT HIV sequence, panning sequence, penatratin sequence, serum amyloid A C- or N-terminus sequences, LDL receptor sequence, modified 18A sequence, apoA-I Milano sequence, 6×-His sequence, lactoferrin sequence, or combinations thereof.
Pharmaceutical composition containing multi-domain peptide and carrier
A pharmaceutical composition comprising an isolated peptide or peptide analog of the cited sequences and a pharmaceutically acceptable carrier.
Methods of treating dyslipidemic and vascular disorders
Methods of treating or inhibiting dyslipidemic or 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, vasculitis, inflammation, or combinations thereof, by administering therapeutically effective amounts of the pharmaceutical compositions containing the peptides or analogs.
Use of peptide-coated implants
Implants coated with the peptides or peptide analogs which, when implanted in heart or peripheral vasculature, treat or inhibit dyslipidemic and vascular disorders.
The claims cover isolated multi-domain amphipathic helical peptides that promote ABCA1-dependent lipid efflux, compositions containing these peptides, methods of treating various dyslipidemic and vascular disorders using these peptides and compositions, and the use of peptide-coated implants for treatment. The inventive features focus on the peptide sequences, functional modifications, pharmaceutical compositions, therapeutic methods, and delivery via implants.
Stated Advantages
The isolated multi-domain peptides promote lipid efflux from cells by an ABCA1-dependent pathway with reduced cytotoxicity compared to peptides that cause ABCA1-independent lipid efflux.
The peptides with appropriately designed amphipathic helices have high specificity for ABCA1-mediated lipid removal, which enhances therapeutic effectiveness for dyslipidemic and vascular disorders.
The ability to modify peptides with additional functional domains potentially enhances cell targeting, uptake, anti-oxidant, or anti-inflammatory properties, improving therapeutic efficacy.
Documented Applications
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, vasculitis, inflammation, and combinations thereof.
Use in pharmaceutical compositions for administration via injection, implant, or other delivery methods to subjects suffering from the aforementioned disorders.
Use of peptide-coated implants, including those implanted in the heart or peripheral vasculature, to treat or inhibit dyslipidemic or vascular disorders.
Interested in licensing this patent?