US2008221028A1PendingUtilityA1
Compositions and Methods for Treating Atherosclerosis
Est. expiryJun 12, 2023(expired)· nominal 20-yr term from priority
A61P 9/10A61P 3/06A61P 9/00A61P 43/00C07K 7/08A61P 29/00A61K 38/00C07K 14/775
49
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Claims
Abstract
Peptides and mimetics of selected domains of mammalian serum amyloid A isoform 2.1 (SAA2.1) and compounds and compositions thereof are provided that enhance the effect on macrophage cholesterol ester hydrolase activity and/or inhibit acyl CoA:cholesterol acyl transferase activity. Methods of using these 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-modified1 - 106 . (canceled)
107 . A method for treating coronary heart disease or cardiovascular disease in a subject comprising administering to the subject a pharmaceutical composition comprising:
an isolated peptide or mimetic thereof, said isolated peptide comprising a formula: X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 (SEQ ID NO:29) 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; and 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; wherein said isolated peptide or mimetic thereof enhances cholesterol ester hydrolase activity so that coronary heart disease or cardiovascular disease is treated in the subject, with the proviso that said pharmaceutical composition does not comprise a full length mammalian serum amyloid A 1.1 or a full length mammalian serum amyloid A 2.1.
108 . The method of claim 107 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.
109 . The method of claim 107 wherein the isolated peptide or mimetic thereof has less than 80 amino acid residues.
110 . The method of claim 107 wherein the isolated peptide or mimetic thereof has 18 to 79 amino acid residues.
111 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof comprising:
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a peptide variant of one of these peptides or a portion thereof.
112 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof which has at least 68% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
113 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof which has at least 80% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
114 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof which has at least 90% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
115 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof which has at least 95% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
116 . The method of claim 107 wherein the pharmaceutical composition comprises an isolated peptide or mimetic thereof which has at least 99% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
117 . The method of claim 107 wherein the pharmaceutical composition is administered to the subject daily, every other day or semi-weekly.
118 . The method of claim 107 wherein the isolated peptide or mimetic thereof has 18 to 30 amino acid residues.
119 . The method of claim 107 wherein the isolated peptide or mimetic thereof is completed with a lipid.
120 . The method of claim 107 wherein the isolated peptide or mimetic thereof is enclosed in a phospholipid vesicle.
121 . The method of claim 107 wherein the pharmaceutical composition is administered orally, intravenously, intramuscularly, intraperitoneally, topically, rectally, dermally, sublingually, buccally, intranasally or via inhalation.
122 . The method of claim 107 further comprising administering a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease.
123 . The method of claim 122 wherein said second agent is linked to said isolated peptide or mimetic thereof.
124 . The method of claim 107 further comprising administering a second agent comprising 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.
125 . The method of claim 124 wherein the apolipoprotein free cholesterol acceptor is cyclodextrin.
126 . The method of claim 124 wherein said second agent is linked to said isolated peptide or mimetic thereof.
127 . The method of claim 107 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity is linked to Z, wherein Z is a targeting agent, an 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 pharmaceutical composition.
128 . A method for treating coronary heart disease or cardiovascular disease in a subject comprising administering to the subject a pharmaceutical composition comprising a first isolated peptide or mimetic thereof and a second isolated peptide or mimetic thereof, wherein said first isolated peptide or mimetic thereof enhances cholesterol ester hydrolase activity and said second isolated peptide or mimetic thereof inhibits acyl CoA:cholesterol acyl transferase activity so that coronary heart disease or cardiovascular disease is treated in the subject, with the proviso that said pharmaceutical composition does not comprise a full length mammalian serum amyloid A 1.1 or a full length mammalian serum amyloid A 2.1.
129 . The method of claim 128 wherein the pharmaceutical composition is administered to the subject daily, every other day or semi-weekly.
130 . The method of claim 128 wherein the pharmaceutical composition is administered orally, intravenously, intramuscularly, intraperitoneally, topically, rectally, dermally, sublingually, buccally, intranasally or via inhalation.
131 . The method of claim 128 wherein said first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity is linked to said second isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase activity.
132 . The method of claim 128 wherein the first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity comprises a formula:
X 1 X 2 X 3 X 4 X 5 X 6 X 7 X 8 X 9 X 10 X 11 X 12 X 13 X 14 X 15 X 16 X 17 X 18 (SEQ ID NO:29) 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; and 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.
133 . The method of claim 132 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.
134 . The method of claim 128 wherein said first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity comprises:
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or is a peptide variant of one of these peptides or a portion thereof.
135 . The method of claim 128 wherein said pharmaceutical composition comprises a first isolated peptide or mimetic thereof having at least 68% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
136 . The method of claim 128 wherein said pharmaceutical composition comprises a first isolated peptide or mimetic thereof having at least 80% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
137 . The method of claim 128 wherein said pharmaceutical composition comprises a first isolated peptide or mimetic thereof having at least 90% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
138 . The method of claim 128 wherein said pharmaceutical composition comprises a first isolated peptide or mimetic thereof having at least 95% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
139 . The method of claim 128 wherein said pharmaceutical composition comprises a first isolated peptide or mimetic thereof having at least 99% sequence identity with
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 4)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form;
SEQ ID NO: 10)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 24)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 25)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 11)
ADQAANEWGRSGKDPNHFR;
(SEQ ID NO: 12)
or
DQAANKWGRSGRDPNHFR,
(SEQ ID NO: 26)
or a portion thereof.
140 . The method of claim 128 wherein the first isolated peptide or mimetic thereof has 18 to 30 amino acid residues.
141 . The method of claim 128 wherein said first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity and said second isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase activity are formulated together in a lipid complex or each formulated separately in a lipid complex.
142 . The method of claim 128 wherein said first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity and said second isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase activity are enclosed together in a phospholipid vesicle or each enclosed separately in a phospholipid vesicle.
143 . The method of claim 128 wherein said pharmaceutical composition further comprises Z, wherein Z is a targeting agent, an 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 pharmaceutical composition.
144 . The method of claim 143 wherein said first isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity and/or said second isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase activity is linked to Z.Cited by (0)
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