Novel Peptides that Promote Lipid Efflux

Abstract

Disclosed herein are peptides with domains that promote lipid efflux from cells and optionally possess at least one anti-inflammatory domain or a domain that stimulates LCAT activity. Provided herein are methods of using the peptides to treat or inhibit diseases including dyslipidemic disorders, stroke and myocardial infarction. Also provided are methods of detecting plaque in vessels using the labeled peptides of the present invention.

1 . An isolated peptide comprising Formula I
   (A-B-C) n , wherein  I   A comprises a modified form of Helix 8 of ApoA-I (Helix 8′);   C comprises Helix 8 of ApoA-I;   B comprises a linking group between A and C; and   n is an integer from 1 to 10.   
     
     
         2 . The isolated peptide of  claim 1 , wherein:
 A comprises SEQ ID NO: 2 Leu Glu Ser Ala Lys Val Ser Ala Leu Ser Ala Leu Glu Glu Ala Thr Lys Lys, a reverse orientation thereof (SEQ ID NO: 3 Lys Lys Thr Ala Glu Glu Leu Ala Ser Leu Ala Ser Val Lys Ala Ser Glu Leu), or a substitution of SEQ ID NO: 2 or SEQ ID NO: 3;   C comprises SEQ ID NO: 14 Leu Glu Ser Phe Lys Val Ser Phe Leu Ser Ala Leu Glu Glu Tyr Thr Lys Lys, a reverse orientation thereof (SEQ ID NO: 15 Lys Lys Thr Tyr Glu Glu Leu Ala Ser Leu Phe Ser Val Lys Phe Ser Glu Leu), or a substitution of SEQ ID NO: 14 or SEQ ID NO: 15;   B comprises Pro; SEQ ID NO: 4 Lys Leu Ser Pro Leu; SEQ ID NO: 5 Leu Ser Pro Leu; SEQ ID NO: 6 Ser Pro Leu; Pro Leu; SEQ ID NO: 7 Lys Leu Ser Pro; SEQ ID NO: 8 Leu Ser Pro; Ser Pro; SEQ ID NO: 9 Leu Pro Ser Leu Lys; SEQ ID NO: 10 Leu Pro Ser Leu; SEQ ID NO: 11 Leu Pro Ser; Leu Pro; SEQ ID NO: 12 Pro Ser Leu Lys; SEQ ID NO: 13 Pro Ser Leu; or Pro Ser; and   n is 1.   
     
     
         3 . The isolated peptide of  claim 1 , further comprising at least one of G and H to form subgeneric Formula II
   G-(A-B-C) n —H wherein  II   G is absent or present and comrprises SEQ ID NO: 6 Ser Pro Leu; Pro Leu; Leu; Ser Pro; Ser; Pro; SEQ ID NO: 11 Leu Pro Ser; Pro Ser; Leu Pro; or a substitution thereof; and   H is absent or present and comprises SEQ ID NO: 16 Leu Asn Thr Gln; SEQ ID NO: 17 Asn Thr Gln; Thr Gln; Gln; SEQ ID NO: 18 Leu Asn Thr; Leu Asn; Leu; SEQ ID NO: 19 Gln Thr Asn Leu; SEQ ID NO: 20 Thr Asn Leu; Asn Leu; SEQ ID NO: 21 Gln Thr Asn; Gln Thr; or a substitution thereof.   
     
     
         4 . The isolated peptide of  claim 3 , wherein:
 A comprises SEQ ID NO: 2 Leu Glu Ser Ala Lys Val Ser Ala Leu Ser Ala Leu Glu Glu Ala Thr Lys Lys;   B comprises SEQ ID NO: 4 Lys Leu Ser Pro Leu;   C comprises SEQ ID NO: 14 Leu Glu Ser Phe Lys Val Ser Phe Leu Ser Ala Leu Glu Glu Tyr Thr Lys Lys;   G comprises SEQ ID NO: 6 Ser Pro Leu;   H comprises SEQ ID NO: 16 Leu Asn Thr Gln; and   n is 1.   
     
     
         5 . The isolated peptide of  claim 3 , wherein the peptide comprises SEQ ID NO: 142 Ser Pro Leu Leu Glu Ser Ala Lys Val Ser Ala Leu Ser Ala Leu Glu Glu Ala Thr Lys Lys Lys Leu Ser Pro Leu Leu Glu Ser Phe Lys Val Ser Phe Leu Ser Ala Leu Glu Glu Tyr Thr Lys Lys Leu Asn Thr Gln or a substitution thereof. 
     
     
         6 . The isolated peptide of  claim 1 , wherein an N-terminal amino acid is acetylated and/or a C-terminal amino acid is amidated. 
     
     
         7 . The isolated peptide of  claim 3 , wherein an N-terminal amino acid is acetylated and/or a C-terminal amino acid is amidated. 
     
     
         8 . The isolated peptide of  claim 7 , wherein said isolated peptide comprises SEQ ID NO: 602 Ac-Ser Pro Leu Leu Glu Ser Ala Lys Val Ser Ala Leu Ser Ala Leu Glu Glu Ala Thr Lys Lys Lys Leu Ser Pro Leu Leu Glu Ser Phe Lys Val Ser Phe Leu Ser Ala Leu Glu Glu Tyr Thr Lys Lys Leu Asn Thr Gln-NH 2  or a substitution thereof 
     
     
         9 . The isolated peptide of  claim 1 , wherein the isolated peptide contains at least one D-amino acid. 
     
     
         10 . The isolated peptide of  claim 3 , wherein the isolated peptide contains at least one D-amino acid. 
     
     
         11 . The isolated peptide of  claim 1 , further comprising a label. 
     
     
         12 . The isolated peptide of  claim 3 , further comprising a label. 
     
     
         13 . A pharmaceutical composition comprising the isolated peptide of  claim 1  and a pharmaceutically acceptable carrier. 
     
     
         14 . A pharmaceutical composition comprising the isolated peptide of  claim 3  and a pharmaceutically acceptable carrier. 
     
     
         15 . A method of treating disease in a human or non-human animal, comprising administering to the human or non-human animal the pharmaceutical composition of  claim 13 , thereby treating disease in the human or non-human animal. 
     
     
         16 . A method of treating disease in a human or non-human animal, comprising administering to the human or non-human animal the pharmaceutical composition of  claim 14 , thereby treating disease in the human or non-human animal. 
     
     
         17 . A method of treating or inhibiting a dyslipidemic disorder or a vascular disorder in a human or non-human animal, comprising administering to the animal or the human a therapeutically effective amount of the pharmaceutical composition of  claim 13 , thereby treating or inhibiting the dyslipidemic disorder or vascular disorder in the human or non-human animal. 
     
     
         18 . A method of treating or inhibiting a dyslipidemic disorder or a vascular disorder in a human or non-human animal, comprising administering to the animal or the human a therapeutically effective amount of the pharmaceutical composition of  claim 14 , thereby treating or inhibiting the dyslipidemic disorder or vascular disorder in the human or non-human animal. 
     
     
         19 . A method of visualizing plaque comprising:
 a) administering the labeled peptide of  claim 11  in an acceptable carrier to a vascular system of human or non-human animal; and   b) detecting the labeled peptide bound to the plaque within the vascular system of the animal or the human.   
     
     
         20 . A method of visualizing plaque comprising:
 a) administering the labeled peptide of  claim 12  in an acceptable carrier to a vascular system of human or non-human animal; and   b) detecting the labeled peptide bound to the plaque within the vascular system of the animal or the human.