US2012245101A1PendingUtilityA1

Synthetic apolipoprotein e mimicking polypeptides and methods of use

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Individually held — no corporate assignee on recordPriority: Aug 28, 2007Filed: Mar 23, 2012Published: Sep 27, 2012
Est. expiryAug 28, 2027(~1.1 yrs left)· nominal 20-yr term from priority
Inventors:Gattadahalli M. AnantharamaiahDavid W. GarberGeeta DattaShaila P. HandattuVinod Kumar Mishra
A61P 5/00A61P 37/06A61P 3/06A61P 9/00A61P 37/08A61P 9/10A61P 7/00A61P 7/06A61P 31/04A61P 25/28A61P 35/00A61P 31/10A61P 25/00A61P 31/12A61P 33/00A61P 27/02A61P 25/16A61P 19/10A61P 21/04C07K 2319/03A61P 15/10A61P 17/00A61P 1/04A61P 17/04A61K 38/00A61P 11/06A61P 13/12C07K 14/775A61P 19/02A61P 15/00A61P 17/06
42
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Claims

Abstract

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.

Claims

exact text as granted — not AI-modified
1 . A method of treating cancer in a subject, comprising administering an effective amount of a synthetic apolipoprotein E-mimicking peptide to the subject. 
     
     
         2 . The method of  claim 1 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 11-14, 18-57, 60, 61, and 62-103. 
     
     
         3 . The method of  claim 1 , wherein the synthetic apolipoprotein E-mimicking peptide comprises the sequence of SEQ ID NO: 62 or SEQ ID NO: 12. 
     
     
         4 . The method of  claim 1 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a receptor binding domain peptide and a lipid-associating peptide, wherein the lipid-associating peptide is covalently linked to the receptor binding domain peptide. 
     
     
         5 . The method of  claim 4 , wherein the receptor binding domain peptide is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog. 
     
     
         6 . The method of  claim 4 , wherein the receptor binding domain peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-2, 3, 5-10, 15, and 58. 
     
     
         7 . The method of  claim 4 , wherein the receptor binding domain peptide is mutated 
     
     
         8 . The method of  claim 4 , wherein the receptor binding domain peptide is scrambled. 
     
     
         9 . The method of  claim 4 , wherein the receptor binding domain peptide is in a reversed orientation. 
     
     
         10 . The method of  claim 4 , wherein the lipid-associating peptide is model class A amphipathic helical peptide 18A. 
     
     
         11 . The method of  claim 4 , wherein the lipid-associating peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 16, 17, and 59. 
     
     
         12 . The method of  claim 4 , wherein the lipid-associating peptide is mutated. 
     
     
         13 . The method of  claim 4 , wherein the lipid-associating peptide is scrambled. 
     
     
         14 . The method of  claim 4 , wherein the lipid-associating peptide is in a reversed orientation. 
     
     
         15 . The method of  claim 4 , wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain switched orientation. 
     
     
         16 . The method of  claim 1 , wherein the synthetic apolipoprotein E-mimicking peptide is protected using acetyl and amide groups at the N- and C-terminus, respectively. 
     
     
         17 . The method of  claim 1 , wherein the synthetic apolipoprotein E-mimicking peptide is administered in a composition comprising a pharmaceutically acceptable carrier. 
     
     
         18 . A method of treating cancer in a subject, comprising administering an effective amount of a pharmaceutical composition comprising a synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier to the subject. 
     
     
         19 . The method of  claim 18 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 11-14, 18-57, 60, 61, and 62-103. 
     
     
         20 . The method of  claim 18 , wherein the synthetic apolipoprotein E-mimicking peptide comprises the sequence of SEQ ID NO: 62 or SEQ ID NO: 12. 
     
     
         21 . The method of  claim 18 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a receptor binding domain peptide and a lipid-associating peptide, wherein the lipid-associating peptide is covalently linked to the receptor binding domain peptide. 
     
     
         22 . The method of  claim 21 , wherein the receptor binding domain peptide is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog. 
     
     
         23 . The method of  claim 21 , wherein the receptor binding domain peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-2, 3, 5-10, 15, and 58. 
     
     
         24 . The method of  claim 21 , wherein the receptor binding domain peptide is mutated 
     
     
         25 . The method of  claim 21 , wherein the receptor binding domain peptide is scrambled. 
     
     
         26 . The method of  claim 21 , wherein the receptor binding domain peptide is in a reversed orientation. 
     
     
         27 . The method of  claim 21 , wherein the lipid-associating peptide is model class A amphipathic helical peptide 18A. 
     
     
         28 . The method of  claim 21 , wherein the lipid-associating peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 16, 17, and 59. 
     
     
         29 . The method of  claim 21 , wherein the lipid-associating peptide is mutated. 
     
     
         30 . The method of  claim 21 , wherein the lipid-associating peptide is scrambled. 
     
     
         31 . The method of  claim 21 , wherein the lipid-associating peptide is in a reversed orientation. 
     
     
         32 . The method of  claim 21 , wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain switched orientation. 
     
     
         33 . The method of  claim 18 , wherein the synthetic apolipoprotein E-mimicking peptide is protected using acetyl and amide groups at the N- and C-terminus, respectively. 
     
     
         34 . A method of treating a subject with cancer comprising:
 selecting a subject with cancer;   administering an effective amount of a synthetic apolipoprotein E-mimicking peptide to the subject, thereby treating cancer in the subject.   
     
     
         35 . The method of  claim 34 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 11-14, 18-57, 60, 61, and 62-103. 
     
     
         36 . The method of  claim 34 , wherein the synthetic apolipoprotein E-mimicking peptide comprises the sequence of SEQ ID NO: 62 or SEQ ID NO: 12. 
     
     
         37 . The method of  claim 34 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a receptor binding domain peptide and a lipid-associating peptide, wherein the lipid-associating peptide is covalently linked to the receptor binding domain peptide. 
     
     
         38 . The method of  claim 37 , wherein the receptor binding domain peptide is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog. 
     
     
         39 . The method of  claim 37 , wherein the receptor binding domain peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-2, 3, 5-10, 15, and 58. 
     
     
         40 . The method of  claim 37 , wherein the receptor binding domain peptide is mutated 
     
     
         41 . The method of  claim 37 , wherein the receptor binding domain peptide is scrambled. 
     
     
         42 . The method of  claim 37 , wherein the receptor binding domain peptide is in a reversed orientation. 
     
     
         43 . The method of  claim 37 , wherein the lipid-associating peptide is model class A amphipathic helical peptide 18A. 
     
     
         44 . The method of  claim 37 , wherein the lipid-associating peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 16, 17, and 59. 
     
     
         45 . The method of  claim 37 , wherein the lipid-associating peptide is mutated. 
     
     
         46 . The method of  claim 37 , wherein the lipid-associating peptide is scrambled. 
     
     
         47 . The method of  claim 37 , wherein the lipid-associating peptide is in a reversed orientation. 
     
     
         48 . The method of  claim 37 , wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain switched orientation. 
     
     
         49 . The method of  claim 34 , wherein the synthetic apolipoprotein E-mimicking peptide is protected using acetyl and amide groups at the N- and C-terminus, respectively. 
     
     
         50 . The method of  claim 34 , wherein the synthetic apolipoprotein E-mimicking peptide is administered in a composition comprising a pharmaceutically acceptable carrier. 
     
     
         51 . A method of treating cancer in a subject, comprising:
 selecting a subject with cancer; and   administering an effective amount of a pharmaceutical composition comprising a synthetic apolipoprotein E-mimicking peptide and a pharmaceutically acceptable carrier to the subject, thereby treating cancer in the subject.   
     
     
         52 . The method of  claim 51 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 11-14, 18-57, 60, 61, and 62-103. 
     
     
         53 . The method of  claim 51 , wherein the synthetic apolipoprotein E-mimicking peptide comprises the sequence of SEQ ID NO: 62 or SEQ ID NO: 12. 
     
     
         54 . The method of  claim 51 , wherein the synthetic apolipoprotein E-mimicking peptide comprises a receptor binding domain peptide and a lipid-associating peptide, wherein the lipid-associating peptide is covalently linked to the receptor binding domain peptide. 
     
     
         55 . The method of  claim 51 , wherein the receptor binding domain peptide is from a species selected from the group consisting of human, mouse, rabbit, monkey, rat, bovine, pig and dog. 
     
     
         56 . The method of  claim 54 , wherein the receptor binding domain peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 1-2, 3, 5-10, 15, and 58. 
     
     
         57 . The method of  claim 54 , wherein the receptor binding domain peptide is mutated 
     
     
         58 . The method of  claim 54 , wherein the receptor binding domain peptide is scrambled. 
     
     
         59 . The method of  claim 54 , wherein the receptor binding domain peptide is in a reversed orientation. 
     
     
         60 . The method of  claim 54 , wherein the lipid-associating peptide is model class A amphipathic helical peptide 18A. 
     
     
         61 . The method of  claim 54 , wherein the lipid-associating peptide comprises a sequence selected from the group consisting of SEQ ID NOs: 4, 16, 17, and 59. 
     
     
         62 . The method of  claim 54 , wherein the lipid-associating peptide is mutated. 
     
     
         63 . The method of  claim 54 , wherein the lipid-associating peptide is scrambled. 
     
     
         64 . The method of  claim 54 , wherein the lipid-associating peptide is in a reversed orientation. 
     
     
         65 . The method of  claim 54 , wherein the receptor binding domain is covalently linked to the lipid-associating peptide in a domain switched orientation. 
     
     
         66 . The method of  claim 51 , wherein the synthetic apolipoprotein E-mimicking peptide is protected using acetyl and amide groups at the N- and C-terminus, respectively.

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