Multi-domain amphipathic helical peptides and methods of their use
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.
1. An isolated peptide or peptide analog, wherein the peptide or peptide analog promotes lipid efflux from cells by an ATP-binding cassette transporter one (ABCA1)-dependent pathway, and wherein the sequence of the peptide or peptide analog consists of the sequence set forth as SEQ ID NO: 7.
2. An isolated peptide or peptide analog comprising the isolated peptide or peptide analog of claim 1 and at least one additional peptide domain.
3. The isolated peptide or peptide analog of claim 2 , wherein the additional peptide domain comprises a heparin binding site, an integrin binding site, a P-selectin site, a TAT HIV sequence, a panning sequence, a penatratin sequence, a serum amyloid A (SAA) C-terminus sequence, a SAA N-terminus sequence, a LDL receptor sequence, a modified 18A sequence, an apoA-I Milano sequence, a 6×-His sequence, a lactoferrin sequence, or combinations of two or more thereof.
4. A pharmaceutical composition, comprising:
an isolated peptide or peptide analog of claim 1 ; and
a pharmaceutically acceptable carrier.
5. A method of treating or inhibiting a dyslipidemic or vascular disorder in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 4 .
6. The method of claim 5 , wherein the dyslipidemic or vascular disorder comprises 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 of two or more thereof.
7. The method of claim 6 , wherein the dyslipidemic or vascular disorder is hypercholesterolemia.
8. The method of claim 7 , further comprising administering an additional lipid lowering composition.
9. The method of claim 5 , wherein the pharmaceutical composition is delivered on an implant.
10. A method of treating or inhibiting inflammation, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 4 .
11. The method of claim 10 , wherein the method is of use to treat or inhibit inflammation and one or more additional disorders comprising 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 a combination thereof.
12. The method of claim 11 , wherein the dyslipidemic or vascular disorder is hypercholesterolemia.
13. The method of claim 10 , wherein the pharmaceutical composition is delivered on an implant.
14. An implant coated with the peptide or peptide analog of claim 1 .
15. The implant of claim 14 which, when implanted in a heart or peripheral vasculature, treats or inhibits a dyslipidemic or vascular disorder.
16. A pharmaceutical composition, comprising:
an isolated peptide or peptide analog of claim 2 ; and
a pharmaceutically acceptable carrier.
17. A method of treating or inhibiting a dyslipidemic or vascular disorder in a subject, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition according to claim 16 .
18. The method of claim 17 , wherein the dyslipidemic or vascular disorder comprises 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 of two or more thereof.
19. The method of claim 18 , wherein the dyslipidemic or vascular disorder is hypercholesterolemia.
20. The method of claim 19 , further comprising administering an additional lipid lowering composition.
21. The method of claim 17 , wherein the pharmaceutical composition is delivered on an implant.
22. A method of treating or inhibiting inflammation, comprising administering to the subject a therapeutically effective amount of the pharmaceutical composition of claim 16 .
23. The method of claim 22 , wherein the method is of use to treat or inhibit inflammation and one or more additional disorders comprising 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 a combination thereof.
24. The method of claim 23 , wherein the dyslipidemic or vascular disorder is hypercholesterolemia.
25. The method of claim 22 , wherein the pharmaceutical composition is delivered on an implant.
26. An implant coated with the peptide or peptide analog of claim 2 .
27. The implant of claim 26 which, when implanted in a heart or peripheral vasculature, treats or inhibits a dyslipidemic or vascular disorder.
28. An implant coated with the peptide or peptide analog of claim 3 .
29. The implant of claim 27 which, when implanted in a heart or peripheral vasculature, treats or inhibits a dyslipidemic or vascular disorder.