Orally administered peptides synergize statin activity
View Patent ↗This invention provides novel peptides that ameliorate one or more symptoms of atherosclerosis. In certain embodiments, the peptides comprise an 18 amino acid class A amphipathic helix with protecting groups on the amino and the carboxyl terminus. The peptides are highly stable, readily administered via an oral route, and effective to stimulate the formation and cycling of pre-beta high density lipoprotein-like particles, and/or to promote lipid transport and detoxification. When administered with a statin, the peptides enhance the activity of the statin permitting the statin to be used at significantly lower dosages and/or cause the statins to be significantly more anti-inflammatory at any given dose.
1. A peptide that is an enantiomer of 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), wherein said peptide:
comprises a first protecting group coupled to the amino terminus; and
comprises a second protecting group coupled to the carboxyl terminus.
2. The peptide of claim 1 , wherein said peptide comprises at least three D form amino acids.
3. The peptide of claim 1 , wherein said peptide comprises at least six D form amino acids.
4. The peptide of claim 1 , wherein said peptide comprises at least eight D form amino acids.
5. The peptide of claim 1 , wherein said first protecting group and said second protecting group are independently selected from the group consisting of acetyl (Ac), amide, 3 to 20 carbon alkyl groups, Fmoc, t-butoxycarbonyl (Tboc), 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, 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), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and Trifluoroacetyl (TFA).
6. The peptide of claim 1 , wherein said first protecting group is selected from the group consisting of acetyl, propionyl, and a 3 to 20 carbon alkyl.
7. The peptide of claim 1 , wherein said second protecting group is an amide.
8. The peptide of claim 6 , wherein said second protecting group is an amide.
9. The peptide of any one of claims 1 , 6 , or 7 , wherein said peptide is mixed with a pharmacologically acceptable excipient.
10. The peptide of claim 9 , wherein said pharmacologically acceptable excipient is an excipient suitable for oral administration to a mammal.
11. A method of ameliorating a symptom of atherosclerosis, said method comprising orally administering to a mammal a peptide that is an enantiomer of 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), wherein said peptide:
comprises a first protecting group coupled to the amino terminus; and
comprises a second protecting group coupled to the carboxyl terminus.
12. The method of claim 11 , wherein said mammal is a mammal diagnosed as having one or more symptoms of atherosclerosis.
13. The method of claim 11 , wherein said mammal is a mammal diagnosed as being at risk for atherosclerosis.
14. The method of claim 11 , wherein said mammal is a human.
15. The method of claim 11 , wherein said mammal is a non-human mammal.
16. The method of claim 11 , wherein said peptide is orally administered to said mammal.
17. The method of claim 11 , wherein said mammal is injected with said peptide.
18. The method of claim 11 , wherein said peptide comprises at least four D form amino acids.
19. The method of claim 11 , wherein said peptide comprises at least six D form amino acids.
20. The method of claim 11 , wherein said peptide comprises at least eight D form amino acids.
21. The method of claim 11 , wherein said first protecting group and said second protecting group are independently selected from the group consisting of acetyl (Ac), amide, 3 to 20 carbon alkyl groups, Fmoc, t-butoxycarbonyl (Tboc), 9-fluoreneacetyl group, 1-fluorenecarboxylic group, 9-fluorenecarboxylic group, 9-fluorenone-1-carboxylic group, benzyloxycarbonyl, 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), cyclohexyloxy (cHxO), t-butoxymethyl (Bum), t-butoxy (tBuO), t-Butyl (tBu), and Trifluoroacetyl (TFA).
22. The method of claim 11 , wherein said first protecting group is selected from the group consisting of acetyl, propionyl, and a 3 to 20 carbon alkyl.
23. The method of claim 11 , wherein said second protecting group is an amide.
24. The method of claim 22 , wherein said second protecting group is an amide.
25. The method of any one of claims 11 , 22 , or 24 , wherein said peptide is mixed with a pharmacologically acceptable excipient.
26. The method of claim 25 , wherein said pharmacologically acceptable excipient is an excipient suitable for oral administration to a mammal.