Orally administered peptides to ameliorate atherosclerosis

1. A peptide that ameliorates a symptom of atherosclerosis, wherein said peptide:

ranges in length up to 30 amino acids;

comprises at least one class A amphipathic helix;

protects a phospholipid against oxidation by an oxidizing agent;

comprises the amino acid sequence-D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F(SEQ-ID-NO:5); and

bears at least one protecting group.

2. The peptide of claim 1 , wherein said protecting group is a protecting group selected from the group consisting of amide, 3 to 20 carbon alkyl groups, Fmoc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh), Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Bom), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO),t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), Acetyl (Ac), a carbobenzoxy group, a propyl group, a butyl group, a pentyl group, a hexyl group, and Trifluoroacetyl (TFA).

3. The peptide of claim 2 , wherein said peptide comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus.

4. The peptide of claim 1 , wherein said peptide is mixed with a pharmacologically acceptable excipient.

5. The peptide of claim 1 , wherein said peptide is mixed with a pharmacologically acceptable excipient suitable for oral administration to a mammal.

6. The peptide of claim 1 , wherein said peptide comprises a protecting group coupled to the amino terminus and said amino terminal protecting group is a protecting group selected from the group consisting of a benzoyl group, an acetyl, a propionyl, a carbobenzoxy, a propyl, a butyl, a pentyl, a hexyl, and a 3 to 20 carbon alkyl.

7. The peptide of claim 1 , wherein said peptide comprises a protecting group coupled to the carboxyl terminus and said carboxyl terminal protecting group is an amide.

8. The peptide of claim 1 , wherein said peptide comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus.

9. The peptide of claim 1 , wherein said peptide comprises:

a first protecting group coupled to the amino terminus wherein said protecting group is a protecting group selected from the group consisting of a benzoyl group, an acetyl, a propionyl, a carbobenzoxy, a propyl, a butyl, a pentyl, a hexyl, and a 3 to 20 carbon alkyl; and

a second protecting group coupled to the carboxyl terminus and said carboxyl terminal protecting group is an amide.

10. The peptide of claim 1 , wherein said oxidizing agent is selected from the group consisting of hydrogen peroxide, 13(S)-HPODE, 15(S)-HPETE, HPODE, HPETE, HODE, and HETE.

11. The peptide of claim 1 , wherein said phospholipid is selected from the group consisting of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (SAPC)), and 1-stearoyl-2-arachidonyl-sn-glycero-3-phosphorylethanolamine (SAPE).

12. A method of mitigating or preventing a coronary complication associated with an acute phase response to an inflammation in a mammal, wherein said coronary complication is a symptom of atherosclerosis, said method comprising administering to a mammal having said acute phase response, or at risk for said acute phase response, a peptide of any one of claims 2 , 3 , 4 , 5 , 1 , 6 , 7 , 8 , 9 , 10 and 11 .

13. The method of claim 12 , where said administration is by a route selected from the group consisting of oral administration, nasal administration, rectal administration, intraperitoneal injection, intravascular injection, subcutaneous injection, transcutaneous administration, and intramuscular injection.

14. The method of claim 12 , wherein said peptide is provided as a unit formulation in a pharmaceutically acceptable excipient.

15. The method of claim 12 , wherein said acute phase response is an inflammatory response associated with a recurrent inflammatory disease.

16. The method of claim 13 , wherein said acute phase response is associated with a disease selected from the group consisting of leprosy, tuberculosis, systemic lupus erythematosus, polymyalgia rheumatica, polyarteritis nodosa, scleroderma, idiopathic pulmonary fibrosis, chronic obstructive pulmonary disease, coronary calcification, calcific aortic stenosis, osteoporosis, and rheumatoid arthritis.

17. The method of claim 12 , wherein said acute phase response is an inflammatory response associated with a condition selected from the group consisting of a bacterial infection, a viral infection, a fungal infection, an organ transplant, a wound, an implanted prosthesis, parasitic infection, sepsis, endotoxic shock syndrome, and biofilm formation.

18. A method of mitigating or preventing a coronary complication associated with an acute phase response to an inflammation in a mammal, wherein said coronary complication is a symptom of atherosclerosis, said method comprising:

assaying said mammal for an acute phase protein (APP) level indicative of an acute phase response or a significant risk of an acute phase response; and

administering to a mammal showing an acute phase protein (APP) level indicative of an acute phase response a peptide of any one of claims 2 , 3 , 4 , 5 , 1 , 6 , 7 , 8 , 9 , 10 and 11 .

19. The method of claim 18 , wherein said acute phase protein (APP) is a positive APR selected from the group consisting of serum amyloid A, c-reactive protein, serum amyloid P component, C2 complement protein, C3 complement protein, C4 complement protein, C5 complement protein, C9 complement protein, B complement protein, C1 inhibitor, C4 binding protein, fibrinogen, von Willebrand factor, α1-antitrypsin, α1-antichymotrypsin, α2 antiplasmin, heparin cofactor II, plasminogen activator inhibitor I, haptoglobin, haemopexin, ceruloplasmin, manganese superoxide dismutase, α1-acid glycoprotein, haeme oxygenase, mannose binding protein, leukocyte protein I, lipoprotein (a), and lipopolysaccharide binding protein.

20. The method of claim 18 , wherein said acute phase protein (APP) is a negative APR selected from the group consisting of albumin, prealbumin, transferin, apoAI, apoAII, α2-HS glycoprotein, inter-α-trypsin inhibitor, and histidine-rich glycoprotein.

21. The peptide of claim 1 , wherein said peptide has the formula:

P 1 -D-W-F-K-A-F-Y-D-K-V-A-E-K-F-E-A-F-P 2 (SEQ ID NO:5)

wherein P 1 and P 2 are protecting groups.

22. The peptide of claim 21 , wherein:

P 1 is selected from the group consisting of a benzoyl group, an acetyl, a propionyl, a carbobenzoxy, a propyl, a butyl, a pentyl, a hexyl, and a 3 to 20 carbon alkyl; and

P 2 is an amide.

23. The peptide of claim 22 , wherein P 1 is an acetyl and P 2 is an amide.

24. The peptide of claim 22 , wherein said peptide is mixed with a pharmacologically acceptable excipient.

25. The peptide of claim 22 , wherein said peptide is mixed with a pharmacologically acceptable excipient for oral administration.

26. A method of ameliorating a symptom of atherosclerosis in a mammal, said method comprising administering to said mammal a peptide or a concatamer of a peptide that:

ranges in length up to about 30 amino acids;

comprises at least one class A amphipathic helix;

protects a phospholid against oxidation by an oxidizing agent; and

comprises the amino acid sequence D-W-F-K-A-F-Y-D-K-V-A-E-K-E-A-F (SEQ-ID-NO:5).

27. The method of claim 26 , wherein said administering comprises orally administering said peptide.

28. The method of claim 26 , wherein said mammal is a mammal diagnosed as having one or more symptoms of atherosclerosis.

29. The method of claim 26 , wherein said mammal is a mammal diagnosed as at risk for atherosclerosis.

30. The method of claim 26 , wherein said mammal is a human.

31. The method of claim 26 , wherein said mammal is non-human mammal.

32. The method of claim 26 , wherein said peptide is combined with a pharmacological excipient.

33. The method of claim 26 , wherein said peptide is combined with a pharmacological excipient suitable for oral administration to a mammal.

34. The method of claim 26 , wherein said peptide further comprises a protecting group coupled to the amino or carboxyl terminus.

35. The method of claim 34 , wherein said protecting group is a protecting group selected from the group consisting of amide, 3 to 20 carbon alkyl groups, Fmoc, 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group, Xanthyl (Xan), Trityl (Trt), 4-methyltrityl (Mtt), 4-methoxytrityl (Mmt), 4-methoxy-2,3,6-trimethyl-benzenesulphonyl (Mtr), Mesitylene-2-sulphonyl (Mts), 4,4-dimethoxybenzhydryl (Mbh),Tosyl (Tos), 2,2,5,7,8-pentamethyl chroman-6-sulphonyl (Pmc), 4-methylbenzyl (MeBzl), 4-methoxybenzyl (MeOBzl), Benzyloxy (BzlO), Benzyl (Bzl), Benzoyl (Bz), 3-nitro-2-pyridinesulphenyl (Npys), 1-(4,4-dimethyl-2,6-dioxocyclohexylidene)ethyl (Dde), 2,6-dichlorobenzyl (2,6-DiCl-Bzl), 2-chlorobenzyloxycarbonyl (2-Cl-Z), 2-bromobenzyloxycarbonyl (2-Br-Z), Benzyloxymethyl (Bom), t-butoxycarbonyl (Boc), cyclohexyloxy (cHxO),t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), Acetyl (Ac), a carbobenzoxy group, a propyl group, a butyl group, a pentyl group, a hexyl group, and Trifluoroacetyl (TFA).

36. The method of claim 34 , wherein said protecting group is a protecting group selected from the group consisting of acetyl, CH 3 —(CH 2 ) n —CO— where n ranges from 1 to 20, and an amide.

37. The method of claim 34 , wherein said peptide comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus.

38. The method of claim 26 , wherein said oxidizing agent is selected from the group consisting of hydrogen peroxide, 13(S)-HPODE, 15(S)-HPETE, HPODE, HPETE, HODE, and HETE.

39. The method of claim 26 , wherein said phospholipid is selected from the group consisting of 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (PAPC), 1-stearoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine (SAPC)), and 1-stearoyl-2-arachidonyl-sn-glycero-3-phosphorylethanolamine (SAPE).

40. A kit for ameliorating a symptom of atherosclerosis, said kit comprising a container containing a peptide that:

ranges in length up to about 30 amino acids;

comprises at least one class A amphipathic helix;

protects a phospholid against oxidation by an oxidizing agent;

comprises the amino acid sequence D-W-F-K-A-F-Y-D-K-V-A-E-K-E-A-F (SEQ-ID-NO:5); and

bears at least one protecting group.

41. The kit of claim 40 , wherein said peptide is combined with a pharmaceutically acceptable excipient in a unit dosage formulation.

42. The kit of claim 41 , wherein said unit dosage formulation is for oral administration.

43. The kit of claim 40 , further comprising instructional materials teaching the use of said peptide for ameliorating one or more symptoms of atherosclerosis.

44. The kit of claim 40 , wherein said peptide comprises a protecting group coupled to the amino or carboxyl terminus.

45. The kit of claim 44 , wherein said peptide comprises a protecting group coupled to the amino terminus and said amino terminal protecting group is a protecting group selected from the group consisting of a benzoyl group, an acetyl, a propionyl, a carbobenzoxy, a propyl, a butyl, a pentyl, a hexyl, and a 3 to 20 carbon alkyl.

46. The kit of claim 44 , wherein said peptide comprises a protecting group coupled to the carboxyl terminus and said carboxyl terminal protecting group is an amide.

47. The kit of claim 44 , wherein said peptide further comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus.

48. The kit of claim 44 , wherein said peptide comprises:

a first protecting group coupled to the amino terminus wherein said protecting group is a protecting group selected from the group consisting of a benzoyl group, an acetyl, a propionyl, a carbobenzoxy, a propyl, a butyl, a pentyl, a hexyl, and a 3 to 20 carbon alkyl; and

a second protecting group coupled to the carboxyl terminus and said carboxyl terminal protecting group is an amide.