US2010272817A1PendingUtilityA1

Compositions and Methods for Treating Atherosclerosis

18
Individually held — no corporate assignee on recordPriority: Mar 31, 2006Filed: Feb 8, 2010Published: Oct 28, 2010
Est. expiryMar 31, 2026(expired)· nominal 20-yr term from priority
Inventors:Perry Kim
A61P 9/10C07K 14/47A61P 3/00C07K 14/4711A61P 29/00A61K 38/00C07K 7/08
18
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Claims

Abstract

Reverse peptides and mimetics of a mammalian serum amyloid A isoform 2.1 (SAA2.1) domain or a portion thereof and compositions and pharmaceutical compositions thereof are provided that enhance the effect on macrophage cholesterol ester hydrolase activity. Methods of using these reverse peptides, mimetics thereof and compositions in the treatment and/or prevention of atherosclerosis as well as coronary heart disease and cardiovascular disease are also provided.

Claims

exact text as granted — not AI-modified
1 . A reverse peptide or a mimetic thereof which enhances cholesterol ester hydrolase activity, said reverse peptide comprising the formula:
 X 18 X 17 X 16 X 15 X 14 X 13 X 12 X 11 X 10 X 9 X 8 X 7 X 6 X 5 X 4 X 3 X 2 X 1  (SEQ ID NO: 1) or a portion thereof   wherein   X 1  and X 9 , X 12  or X 18  are amino acids capable of forming a salt bridge;   X 6  is glutamic acid or lysine or an amino acid which is a conservative substitution thereof;   X 2 , X 3  X 4 , x 5 , x 7 , X 8 , X 10 , X 11 , X 13 , X 14 , X 15 , X 16 , and X 17  are independently any amino acid.   
     
     
         2 . The reverse peptide or a mimetic thereof of  claim 1  wherein
 X 2  is glutamine or an amino acid which is a conservative substitution thereof;   X 3  and X 4  are independently alanine or an amino acid which is a conservative substitution thereof;   X 5  and X 15  are independently asparagine or an amino acid which is a conservative substitution thereof;   X 7  is tryptophan or an amino acid which is a conservative substitution thereof;   X 8  and X 11  are independently glycine or an amino acid which is a conservative substitution thereof;   X 10  is serine or an amino acid which is a conservative substitution thereof;   X 13  is aspartic acid or an amino acid which is a conservative substitution thereof;   X 14  is proline or an amino acid which is a conservative substitution thereof;   X 16  is histidine or an amino acid which is a conservative substitution thereof; and/or   X 17  is phenylalanine or an amino acid which is a conservative substitution thereof.   
     
     
         3 . The reverse peptide or mimetic thereof of  claim 1  which has less than 80 amino acid residues. 
     
     
         4 . The reverse peptide or mimetic thereof of  claim 1  which has 18 to 79 amino acid residues. 
     
     
         5 . The reverse peptide or mimetic thereof of  claim 1  comprising RFHNPDKGSRGWENAAQDA (SEQ ID NO:2); RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3);
 YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4);   YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);   YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         6 . The reverse peptide or mimetic thereof of  claim 1  comprising the retroinversal peptide RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3) or a portion thereof. 
     
     
         7 . The reverse peptide or mimetic thereof of  claim 1  which has at least 80% sequence identity with RFHNPDKGSRGWENAAQDA (SEQ ID NO:2); RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3); YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4); YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);
 YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         8 . The reverse peptide or mimetic thereof of  claim 1  which has at least 90% sequence identity with RFHNPDKGSRGWENAAQDA (SEQ ID NO:2); RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3); YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4); YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);
 YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         9 . The reverse peptide or mimetic thereof of  claim 1  which has at least 95% sequence identity with RFHNPDKGSRGWENAAQDA (SEQ ID NO:2); RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3); YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4); YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);
 YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         10 . The reverse peptide or mimetic thereof of  claim 1  which has at least 99% sequence identity with RFHNPDKGSRGWENAAQDA (SEQ ID NO:2); RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3); YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4); YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);
 YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         11 . The reverse peptide or mimetic thereof of  claim 1  which has one or more conservative amino acid substitutions in the amino acid sequence of the peptide comprising: RFHNPDKGSRGWENAAQDA (SEQ ID NO:2);
 RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3);   YKDPLGPPRYYNPDKGSRGHRNAEQDAITD(SEQ ID NO:4);   YKDPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:5);   YKAPLGPPRYYNPDKGSRGHRNAEQDA(SEQ ID NO:6);   YKEPLGAPRFHNPDKGSRGWENAAQDA(SEQ ID NO:7);   RYYNPDKGSRGHRNAEQDA (SEQ ID NO:8);   RFHNPDRGSRGWKNAAQDA (SEQ ID NO:9); or   RFHNPDRGSRGWKNAAQD(SEQ ID NO:10) or a portion thereof.   
     
     
         12 . The reverse peptide or mimetic thereof of  claim 1  wherein one or more amino acids is a D amino acid. 
     
     
         13 . A composition having a formula:
 Y-Z   wherein Y comprises a reverse peptide or a mimetic thereof that enhances cholesterol ester hydrolase activity; and   wherein Z comprises a compound linked to Y that enhances the performance of Y.   
     
     
         14 . The composition of  claim 13  wherein Y comprises a reverse peptide or a mimetic thereof which enhances cholesterol ester hydrolase activity, said reverse peptide comprising a formula:
 X 18 X 17 X 16 X 15 X 14 X 13 X 12 X 11 X 10 X 9 X 8 X 7 X 6 X 5 X 4 X 3 X 2 X 1  (SEQ ID NO: 1) or a portion thereof   wherein   X 1  and X 9 , X 12  or X 18  are amino acids capable of forming a salt bridge;   X 6  is glutamic acid or lysine or an amino acid which is a conservative substitution thereof;   X 2 , X 3 , X 4 , X 5 , X 7 , X 8 , X 10 , X 11 , X 13 , X 14 , X 15 , X 16 , and X 17      are independently any amino acid.   
     
     
         15 . The composition of  claim 13  wherein Z comprises a targeting agent, a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease, an agent which enhances solubility, absorption, distribution, half-life, bioavailability, stability, activity and/or efficacy, or an agent which reduces toxicity or side effects of the compound. 
     
     
         16 . The composition of  claim 13  further comprising Q linked to Y-Z wherein Q is identical to Z or different from Z and wherein Q comprises a targeting agent, a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease, an agent which enhances solubility, absorption, distribution, half-life, bioavailability, stability, activity and/or efficacy, or an agent which reduces toxicity or side effects of the compound. 
     
     
         17 . A pharmaceutical composition comprising the reverse peptide or mimetic thereof of  claim 1  or a composition having a formula:
 Y-Z   wherein Y comprises a reverse peptide or a mimetic thereof that enhances cholesterol ester hydrolase activity; and   wherein Z comprises a compound linked to Y that enhances the performance of Y;   and a pharmaceutically acceptable vehicle.   
     
     
         18 . The pharmaceutical composition of  claim 17  further comprising a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease. 
     
     
         19 . The pharmaceutical composition of  claim 17  wherein the pharmaceutically acceptable vehicle is suitable for oral, intravenous, intramuscular, intraperitoneal, topical, subcutaneous, rectal, dermal, sublingual, buccal, intranasal or inhalation administration. 
     
     
         20 . The pharmaceutical composition of  claim 17  wherein the reverse peptide or mimetic thereof or the composition is complexed with a lipid. 
     
     
         21 . The pharmaceutical composition of  claim 17  wherein the reverse peptide or mimetic thereof or the composition is enclosed in a phospholipid vesicle. 
     
     
         22 . A method for modulating an activity of a cholesterol metabolizing enzyme in a subject comprising administering to the subject the pharmaceutical composition of  claim 17 . 
     
     
         23 . The method of  claim 22  wherein the cholesterol metabolizing enzyme is cholesterol ester hydrolase and its activity is enhanced. 
     
     
         24 . The method of  claim 22  wherein the cholesterol metabolizing enzyme is in a macrophage. 
     
     
         25 . The method of  claim 22  further comprising administering a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease. 
     
     
         26 . The method of  claim 25  wherein the second agent is an acyl CoA:cholesterol acyl transferase inhibitor, an apolipoprotein free cholesterol acceptor, a statin, a resin, a bile acid sequestrant, niacin, a liver X receptor agonist, a calcium antagonist or a modulator of peroxisome proliferator-activated receptors. 
     
     
         27 . The method of  claim 25  wherein the cholesterol metabolizing enzyme is cholesterol ester hydrolase and its activity is enhanced. 
     
     
         28 . The method of  claim 25  wherein the cholesterol metabolizing enzyme is in a macrophage. 
     
     
         29 . A method for treating atherosclerosis or regressing or decreasing formation of arterial atherosclerotic lesions in a subject comprising administering to the subject the pharmaceutical composition of  claim 17 . 
     
     
         30 . The method of  claim 29  further comprising administering a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease. 
     
     
         31 . The method of  claim 30  wherein the second agent is an acyl CoA:cholesterol acyl transferase inhibitor, an apolipoprotein free cholesterol acceptor, a statin, a resin, a bile acid sequestrant, niacin, a liver X receptor agonist, a calcium antagonist or a modulator of peroxisome proliferator-activated receptors. 
     
     
         32 . A method for treating coronary heart disease or cardiovascular disease in a subject comprising administering to the subject the pharmaceutical composition of  claim 17 . 
     
     
         33 . The method of  claim 32  further comprising administering a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease. 
     
     
         34 . The method of  claim 33  wherein the second agent is an acyl CoA:cholesterol acyl transferase inhibitor, an apolipoprotein free cholesterol acceptor, a statin, a resin, a bile acid sequestrant, niacin, a liver X receptor agonist, a calcium antagonist or a modulator of peroxisome proliferator-activated receptors. 
     
     
         35 . A method for preventing or inhibiting inflammation in a subject comprising administering to the subject the pharmaceutical composition of  claim 17 . 
     
     
         36 . A reverse peptide comprising RFHNPDKGSRGWENAAQDA (SEQ ID NO:2) or RFHNPDKGSRGWENAAQDA (D-form; SEQ ID NO:3).

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