Helical synthetic peptides that stimulate cellular cholesterol efflux

1. An isolated peptide that has a cholesterol efflux mediating activity and an ABCA stabilization activity, comprising

an amphipathic alpha helix of 18-60 amino acids in length comprising an engineered helical segment, said engineered helical segment comprising: a polar face and a nonpolar face, wherein the polar face comprises an alignment of at least 3 acidic amino acids, wherein each of the at least 3 acidic amino acids is positioned at 2-3 helical turns from one another along the long-axis of the helix; and had the following characteristics in comparison to a helical segment of a native protein:

(a) said engineered helical segment comprises from 1 to 3 amino acid substitutions compared with the sequence of the helical segment of the native protein, and at least one of the substitutions creates the alignment of at least 3 acidic amino acids; or

(b) said helical segment comprises from 1 to 3 amino acid substitutions compared with the helical segment of the native protein and a deletion of 1 to 4 amino acid residues compared with the sequence of the helical segment of the native protein where the deletion creates the alignment of at least 3 acidic amino acids; and

said native protein is selected from the group consisting of human Apo A-I, human Apo A-II, human Apo A-IV, human Apo E, human Apo C-I, human Apo C-II, human Apo C-III, and human serum amyloid.

2. The peptide of claim 1 , wherein the ABCA stabilization activity is selected from the group consisting of ABCA1 and ABCA7.

3. The peptide of claim 1 , wherein said peptide has an antioxidant activity.

4. The peptide of claim 3 , wherein at least one native amino acid residue at or near the polar/nonpolar interface of the amphipathic alpha helix is substituted with a cysteine.

5. The peptide of claim 1 , wherein said peptide has an anti-inflammatory activity.

6. The peptide of claim 1 , wherein the peptide comprises at least one D amino acid.

7. The peptide of claim 1 , wherein the carboxy terminus of the peptide comprises a D amino acid and the amino terminus of the peptide comprises a D amino acid.

8. The peptide of claim 1 , wherein the peptide comprises all D amino acids.

9. The peptide of claim 1 , wherein the helical segment of the native protein is present in a sequence selected from the group consisting of: helix 1 (amino acids 44-65) of human Apo A-I, helix 10 (amino acids 220-238) of human Apo A-I, amino acids 1-51 of human Apo A-II, amino acids 5-32 of human Apo A-II, amino acids 62-94 of human Apo A-IV, amino acids 66-90 of human Apo A-IV, amino acids 183-204 of human Apo A-IV, amino acids 183-226 of human Apo A-IV, amino acids 205-226 of human Apo A-IV, amino acids 161-204 of human Apo A-IV, amino acids 161-182 of human Apo A-IV, amino acids 205-248 of human Apo A-IV, amino acids 227-248 of human Apo A-IV, amino acids 117-138 of human Apo A-IV, amino acids 138-160 of human Apo A-IV, amino acids of 25-57 human Apo C-I, amino acids 6-27 of human Apo C-I, amino acids 29-53 of human Apo C-I, amino acids 12-42 of human Apo C-II, amino acids 16-40 of human Apo C-II, amino acids 43-68 of human Apo C-II, amino acids 37-69 of human Apo C-III, amino acids 45-69 of human Apo C-III, the C terminal domain (amino acids 216-299) of human Apo E, amino acids 216-248 of human Apo E, amino acids 216-237 of human Apo E, amino acids 238-266 of human Apo E, amino acids 267-299 of human Apo E, amino acids 238-263 of human Apo E, amino acids 1-36 of human serum amyloid A, amino acids 1-34 of human serum amyloid A amino acids 5-29 of human serum amyloid A, and amino acids 53-78 of human serum amyloid A.

10. The peptide of claim 1 , wherein the helix comprises EVRAKLEEWFQQIRLQAEEFQARLKS (SEQ ID NO: 9).

11. The peptide of claim 1 , further comprising a second amphipathic alpha helix, wherein the second helix is from a human protein selected from the group consisting of Apo A-I, Apo C-II, Apo A-IV, Apo E, Apo C-I, Apo C-II, Apo C-III, serum amyloid A, and combinations thereof,

wherein said peptide has a cholesterol efflux mediating activity and an ABCA stabilization activity.

12. The peptide of claim 11 , wherein the second amphipathic alpha helix comprises a sequence selected from the group consisting of: helix 1 (amino acids 44-65) of Apo A-I, helix 6 (amino acids 145-162) of Apo A-I, helix 7 (amino acids 167-184) of Apo A-I, helix 9 (amino acids 209-219) of Apo A-I, helix 10 (amino acids 220-238) of Apo A-I, amino acids 1-51 of Apo A-II, amino acids 5-32 of Apo A-II, amino acids 62-94 of Apo A-IV, amino acids 66-90 of Apo A-IV, amino acids 183-204 of Apo A-IV, amino acids 183-226 of Apo A-IV, amino acids 205-226 of Apo A-IV, amino acids 161-204 of Apo A-IV, amino acids 161-182 of Apo A-IV, amino acids 205-248 of Apo A-IV, amino acids 227-248 of Apo A-IV, amino acids 117-138 of Apo A-IV, amino acids 138-160 of Apo A-IV, amino acids of 25-57 Apo C-I, amino acids 6-27 of Apo C-I, amino acids 29-53 of Apo C-I, amino acids 12-42 of Apo C-II, amino acids 16-40 of Apo C-II, amino acids 43-68 of Apo C-II, amino acids 37-69 of Apo C-III, amino acids 45-69 of Apo C-III, the C terminal domain (amino acids 216-299) of Apo E, amino acids 216-248 of Apo E, amino acids 216-237 of Apo E, amino acids 238-266 of Apo E, a amino acids 267-299 of Apo E, amino acids 238-263 of Apo E, amino acids 1-36 of serum amyloid A, amino acids 1-34 of serum amyloid A amino acids 5-29 of serum amyloid A, and amino acids 53-78 of serum amyloid A.

13. A pharmaceutical composition comprising a peptide of claim 1 and a pharmaceutically acceptable carrier.

14. The pharmaceutical composition of claim 13 , further comprising a therapeutic agent for treating cardiovascular disease.

15. The pharmaceutical composition of claim 14 , wherein the therapeutic agent is selected from the group consisting of: a statin, a bile acid binder, a platelet clumping inhibitor, nicotinamide, a PPAR activator, vitamin E, and combinations thereof.

16. The peptide of claim 1 , wherein the amphiphathic helix is from 20 to 44 amino acids in length.

17. The peptide of claim 1 , wherein the amphipathic helix is from 22 to 26 amino acids in length.

18. The peptide of claim 1 , wherein the helical segment of the native protein is present in the C terminal domain (amino acids 216-299) of human Apo E.

19. The peptide of claim 18 , wherein the helical segment of the native protein is present in a sequence selected from the group consisting of amino acids 216-248 of human Apo E, amino acids 216-237 of human Apo E, amino acids 238-266 of human Apo E, amino acids 267-299 of human Apo E, and amino acids 238-263 of human Apo E.