Drug – bio-affecting and body treating compositions – Designated organic active ingredient containing – Peptide containing doai
Reexamination Certificate
2000-08-24
2003-12-16
Russel, Jeffrey E. (Department: 1654)
Drug, bio-affecting and body treating compositions
Designated organic active ingredient containing
Peptide containing doai
C514S012200, C514S014800, C514S015800, C530S324000, C530S325000, C530S326000, C530S327000, C530S328000, C530S345000
Reexamination Certificate
active
06664230
ABSTRACT:
FIELD OF THE INVENTION
This invention relates to the field of atherosclerosis. In particular, this invention pertains to the identification of a class of peptides that are orally administrable and that ameliorate one or more symptoms of atherosclerosis.
BACKGROUND OF THE INVENTION
Cardiovascular disease is a leading cause of morbidity and mortality, particularly in the United States and in Western European countries. Several causative factors are implicated in the development of cardiovascular disease including hereditary predisposition to the disease, gender, lifestyle factors such as smoking and diet, age, hypertension, and hyperlipidemia, including hypercholesterolemia. Several of these factors, particularly hyperlipidemia and hypercholesteremia (high blood cholesterol concentrations) provide a significant risk factor associated with atherosclerosis.
Cholesterol is present in the blood as free and esterified cholesterol within lipoprotein particles, commonly known as chylomicrons, very low density lipoproteins (VLDLs), low density lipoproteins (LDLs), and high density lipoproteins (HDLs). Concentration of total cholesterol in the blood is influenced by (1) absorption of cholesterol from the digestive tract, (2) synthesis of cholesterol from dietary constituents such as carbohydrates, proteins, fats and ethanol, and (3) removal of cholesterol from blood by tissues, especially the liver, and subsequent conversion of the cholesterol to bile acids, steroid hormones, and biliary cholesterol.
Maintenance of blood cholesterol concentrations is influenced by both genetic and environmental factors. Genetic factors include concentration of rate-limiting enzymes in cholesterol biosynthesis, concentration of receptors for low density lipoproteins in the liver, concentration of rate-limiting enzymes for conversion of cholesterols bile acids, rates of synthesis and secretion of lipoproteins and gender of person. Environmental factors influencing the hemostasis of blood cholesterol concentration in humans include dietary composition, incidence of smoking, physical activity, and use of a variety of pharmaceutical agents. Dietary variables include amount and type of fat (saturated and polyunsaturated fatty acids), amount of cholesterol, amount and type of fiber, and perhaps amounts of vitamins such as vitamin C and D and minerals such as calcium.
Epidemiological studies show an inverse correlation of high density lipoprotein (HDL) and apolipoprotein (apo) A-I levels with the occurrence of atherosclerotic events (Wilson et al. (1988)
Arteriosclerosis
8: 737-741). Injection of HDL into rabbits fed an atherogenic diet has been shown to inhibit atherosclerotic lesion formation (Badimon et al. (1990)
J. Clin. Invest
. 85: 1234-1241).
Human apo A-I has been a subject of intense study because of its anti-atherogenic properties. Exchangeable apolipoproteins, including apo A-I, possess lipid-associating domains (Brouillette and Anantharamaiah (1995)
Biochim. Biophys. Acta
1256:103-129; Segrest et al. (1974)
FEBS Lett
. 38: :247-253). Apo A-I has been postulated to possess eight tandem repeating 22 mer sequences, most of which have the potential to form class A amphipathic helical structures (Segrest et al. (1974)
FEBS Lett
. 38: 247-253). Characteristics of the class A amphipathic helix include the presence of positively charged residues at the polar-nonpolar interface and negatively charged residues at the center of the polar face (Segrest et al. (1974) FEBS Lett. 38: 247-253; Segrest et al. (1990)
Proteins: Structure, Function, and Genetics
8: 103-117). Apo A-I has been shown to strongly associate with phospholipids to form complexes and to promote cholesterol efflux from cholesterol-enriched cells. The delivery and maintenance of serum levels of apo A-I to effectively mitigate one or more symptoms of atherosclerosis has heretofore proven elusive.
SUMMARY OF THE INVENTION
This invention provides novel peptides administration of which mitigate one or more symptoms of atherosclerosis. In particular, it was a discovery of this invention that peptides comprising a class A amphipathic helix when formulated with “D” amino acid residue(s) and/or having protected amino and carboxyl termini can be orally administered to an organism, are readily taken up and delivered to the serum, and are effective to mitigate one or more symptoms of atherosclerosis.
Thus, in one embodiment, this invention provides a peptide that ameliorates a symptom of atherosclerosis, where the peptide ranges in length from about 10 to about 30 amino acids, comprises at least one class A amphipathic helix, comprises at least one “D” amino acid residue, protects a phospholipid against oxidation by an oxidizing agent, and is not the D-18A peptide (e.g. D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 1) having all D form amino acid residues). In particularly preferred embodiments, the peptide further comprises a protecting group coupled to the amino and/or carboxyl terminus. Preferred protecting groups include, but are not limited to acetyl, amide, and 3 to 20 carbon alkyl groups, Fmoc, 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-diaxocyclohexylidene)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), and Trifluoroacetyl (TFA). In certain particularly preferred embodiments the peptide further comprises a first protecting group coupled to the amino terminus and a second protecting group coupled to the carboxyl terminus. Particularly preferred peptides comprise greater than about 50% amino acid sequence identity with human or mouse apo A-I1 or with the polypeptide encoded by the. exon encoding a class A amphipathic helix of human or mouse apo A-I1. In certain preferred embodiments, at least 50%, more preferably at least 75%, and most preferably at least 90% and even 100% of the enantiomeric amino acids are “D” amino acids. The peptide may be combined with a pharmacologically acceptable excipient (e.g. an excipient suitable for oral administration to a mammal).
In certain particularly preferred embodiments, the peptide comprises one or more of the following amino acid sequences: D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO: 2), D-W-F-K-A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ-ID-NO:3), D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ-ID-NO:4), D-W-F-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F(SEQ-ID-NO:5), D-W-L-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F (SEQ-ID-NO:6), D-W-F-K-A-F-Y-D-K-F-F-E-K-F-K-E-F-F (SEQ-ID-NO:7), D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ-ID-NO:8), D-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F (SEQ-ID-NO:9), D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F (SEQ-ID-NO:10), D-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F (SEQ-ID-NO:11), D-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F (SEQ-ID-NO:12), D-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F (SEQ-ID-NO:13), E-W-L-K-L-F-Y-E-K-V-L-E-K-F-K-E-A-F (SEQ-ID-NO:14), E-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ-ID-NO:15), E-W-L-K-A-F-Y-D-K-V-A-E-K-L-K-E-F-F (SEQ-ID-NO:16), E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-A-F (SEQ-ID-NO:17), E-W-L-K-A-F-Y-D-K-V-F-E-K-L-K-E-F-F (SEQ-ID-NO:18), E-W-L-K-A-F-Y-D-K-V-A-E-K-F-K-E-F-F (SEQ-ID-NO:19), E-W-L-K-A-F-Y-D-K-V-F-E-K-F-K-E-F-F (SEQ ID NO:20), A-F-Y-D-K-V-A-E-K-L-K-E-A-F (SEQ ID NO:21), A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:22), A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:23), A-F-Y-D-K-F-F-E-K-F-K-E-F-F (SEQ ID NO:24), A-F-Y-D-K-F-F-E-K-F-K-E-F-F (SEQ ID NO:25), A-F-Y-D-K-V-A-E-K-F-K-E-A-F (SEQ ID NO:26), A-F-Y-D-K-V-A-E-K-L-K-E-F-F (SEQ ID NO:27), A-F-Y-D
Anantharamaiah Gattadahalli M.
Fogelman Alan M.
Navab Mohamad
Hunter Tom
Quine Intellectual Property Law Group, PC
Russel Jeffrey E.
The Regents of the University of California
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