Synthetic apolipoprotein E mimicking polypeptides and methods of use
The present invention provides novel synthetic apolipoprotein E (ApoE)-mimicking peptides wherein the receptor binding domain of apolipoprotein E is covalently linked to 18A, the well characterized lipid-associating model class A amphipathic helical peptide, or a modified version thereof. Such peptides enhance low density lipoprotein (LDL) and very low density lipoprotein (VLDL) binding to and degradation by fibroblast or HepG2 cells. Also provided are possible applications of the synthetic peptides in lowering human plasma LDL/VLDL cholesterol levels, thus inhibiting atherosclerosis. The present invention also relates to synthetic peptides that can improve HDL function and/or exert anti-inflammatory properties.
1. A synthetic apolipoprotein E-mimicking peptide, consisting of: a receptor binding domain of apolipoprotein E comprising the amino acid sequence of SEQ ID NO: 15; and a lipid-associating peptide wherein said receptor binding domain is covalently linked to said lipid-associating peptide, wherein the lipid-associating peptide comprises a class A amphipathic-helical domain.
2. The synthetic apolipoprotein E-mimicking peptide of claim 1 , wherein said lipid-associating peptide is SEQ ID NO: 4.
3. The synthetic apolipoprotein E-mimicking peptide of claim 1 , wherein said lipid-associating peptide comprises the amino acid sequence of SEQ ID NO: 16.
4. The synthetic apolipoprotein E-mimicking peptide of claim 1 , wherein said lipid-associating peptide comprises the amino acid sequence of SEQ ID NO: 17.
5. The synthetic apolipoprotein E-mimicking peptide of claim 1 , wherein said synthetic peptide is protected using acetyl and amide groups at the N- and C-terminus, respectively.
6. A pharmaceutical composition, comprising the synthetic apolipoprotein E-mimicking peptide of claim 1 and a pharmaceutically acceptable carrier.
7. An isolated nucleic acid encoding the polypeptide of claim 1 .
8. A vector comprising the nucleic acid of claim 7 .
9. A host cell comprising the nucleic acid of claim 7 .
10. An isolated nucleic acid encoding the polypeptide of claim 4 .
11. A vector comprising the nucleic acid of claim 10 .
12. A host cell comprising the nucleic acid of claim 10 .