US2011268768A1PendingUtilityA1
Compositions and Methods for Treating Atherosclerosis
Est. expiryJun 12, 2023(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/00A61P 9/10A61P 3/06C07K 14/775A61P 29/00C07K 7/08A61K 38/00
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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 . An isolated peptide or a mimetic thereof which enhances cholesterol ester hydrolase activity, 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 has less than 80 amino acid residues; and with the proviso that said isolated peptide does not consist of:
(SEQ ID NO: 18)
GFFSFIGEAFQGAGDMWRAYTDMKEAGWKDGDKYFHARGNYDAAQRGPGG
VWAAEKISDARESFQEFFGRGHEDTMADQEANRHGRSGKDPNYYRPPGLP
AKY;
(SEQ ID NO: 19)
GFFSFVHEAFQGAGDMWRAYTDMKEANWKNSDKYFHARGNYDAAQRGPGG
VWAAEKISDGREAFQEFFGRGHEDTIADQEANRHGRSGKDPNYYRPPGLP
DKY;
(SEQ ID NO: 20)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GVWAAEAISDARENIQRFFGHGAEDSLADQAANEWGRSGKDPNHFRPAGL
PEKY;
(SEQ ID NO: 21)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GAWAAEVISNARENIQRLTGHGAEDSLADQAANKWGRSGRDPNHFRPAGL
PEKY;
(SEQ ID NO: 22)
KEAGWKDGDKYFHARGNYDAAQRGPGGVWAAEKISDARESFQEFFGRGHE
DTMADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 23)
KEANWKNSDKYFHARGNYDAAQRGPGGVWAAEKISDGREAFQEFFGRGHE
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
or
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY.
2 . The isolated 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 . (canceled)
4 . The isolated peptide or mimetic thereof of claim 1 which has 18 to 79 amino acid residues.
5 . The isolated peptide or mimetic thereof of claim 1 comprising:
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a peptide variant of one of these peptides or a portion thereof.
6 . The isolated peptide or mimetic thereof of claim 5 which has at least 80% sequence identity with
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a portion thereof.
7 . The isolated peptide or mimetic thereof of claim 5 which has at least 90% sequence identity with
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a portion thereof.
8 . The isolated peptide or mimetic thereof of claim 5 which has at least 95% sequence identity with
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a portion thereof.
9 . The isolated peptide or mimetic thereof of claim 5 which has at least 99% sequence identity with
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a portion thereof.
10 . The isolated peptide or mimetic thereof of claim 5 which has one or more conservative amino acid substitutions in the amino acid sequence of the peptide comprising:
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 9)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(D-form; SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 24)
ADQAANEWGRSGKDPNHFRPAGLPEKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR;
or a portion thereof.
11 . The isolated peptide or mimetic thereof of claim 1 wherein the mimetic is a small organic molecule.
12 . The isolated peptide or mimetic thereof of claim 1 which is prepared synthetically or recombinantly.
13 . A compound having a formula:
Y—Z
wherein Y comprises a 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; with the proviso that Y—Z does not consist of
(SEQ ID NO: 18)
GFFSFIGEAFQGAGDMWRAYTDMKEAGWKDGDKYFHARGNYDAAQRGPGG
VWAAEKISDARESFQEFFGRGHEDTMADQEANRHGRSGKDPNYYRPPGLP
AKY;
(SEQ ID NO: 19)
GFFSFVHEAFQGAGDMWRAYTDMKEANWKNSDKYFHARGNYDAAQRGPGG
VWAAEKISDGREAFQEFFGRGHEDTIADQEANRHGRSGKDPNYYRPPGLP
DKY;
(SEQ ID NO: 20)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GVWAAEAISDARENIQRFFGHGAEDSLADQAANEWGRSGKDPNHFRPAGL
PEKY;
or
(SEQ ID NO: 21)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GAWAAEVISNARENIQRLTGHGAEDSLADQAANKWGRSGRDPNHFRPAGL
PEKY.
14 . The compound of claim 13 wherein Y comprises a cholesterol ester hydrolase enhancing peptide domain of a serum amyloid A protein.
15 . The compound of claim 13 wherein Y comprises a peptide or a mimetic thereof which enhances cholesterol ester hydrolase activity, said peptide comprising a formula:
(SEQ ID NO: 29)
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
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.
16 . The compound 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.
17 . The compound 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.
18 . A pharmaceutical composition comprising the isolated peptide or mimetic thereof of claim 1 and a pharmaceutically acceptable vehicle.
19 . The pharmaceutical composition of claim 18 further comprising a second agent for treatment of atherosclerosis, cardiovascular disease or coronary heart disease.
20 . The pharmaceutical composition of claim 18 wherein the isolated peptide or mimetic thereof is complexed with a lipid.
21 . The pharmaceutical composition of claim 18 wherein the isolated peptide or mimetic thereof is enclosed in a phospholipid vesicle.
22 - 78 . (canceled)
79 . A pharmaceutical composition comprising an isolated peptide or a mimetic thereof which enhances cholesterol ester hydrolase activity and an isolated peptide or a mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase.
80 . The pharmaceutical composition of claim 79 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity is linked to the isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase with the proviso that the linked isolated peptides or mimetics thereof do not consist of:
(SEQ ID NO: 18)
GFFSFIGEAFQGAGDMWRAYTDMKEAGWKDGDKYFHARGNYDAAQRGPGG
VWAAEKISDARESFQEFFGRGHEDTMADQEANRHGRSGKDPNYYRPPGLP
AKY;
(SEQ ID NO: 19)
GFFSFVHEAFQGAGDMWRAYTDMKEANWKNSDKYFHARGNYDAAQRGPGG
VWAAEKISDGREAFQEFFGRGHEDTIADQEANRHGRSGKDPNYYRPPGLP
DKY;
(SEQ ID NO: 20)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GVWAAEAISDARENIQRFFGHGAEDSLADQAANEWGRSGKDPNHFRPAGL
PEKY;
or
(SEQ ID NO: 21)
RSFFSFLGEAFDGARDMWRAYSDMREANYIGSDKYFHARGNYDAAKRGPG
GAWAAEVISNARENIQRLTGHGAEDSLADQAANKWGRSGRDPNHFRPAGL
PEKY.
81 . The pharmaceutical composition of claim 79 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase comprises a formula:
(SEQ ID NO: 29)
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
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.
82 . The pharmaceutical composition of claim 81 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.
83 . The pharmaceutical composition of claim 79 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase comprises:
(SEQ ID NO: 4)
DTIADQEANRHGRSGKDPNYYRPPGLPDKY;
(SEQ ID NO: 8)
ADQEANRHGRSGKDPNYYRPPGLPDKY;
(D-form;SEQ ID NO: 10)
ADQEANRHGRSGKDPNYYRPPGLPAKY;
(SEQ ID NO: 25)
ADQEANRHGRSGKDPNYYR;
(SEQ ID NO: 11)
ADQAANKWGRSGRDPNHFR;
(SEQ ID NO: 12)
ADQAANEWGRSGKDPNHFR;
or
(SEQ ID NO: 26)
DQAANKWGRSGRDPNHFR,
or a peptide variant of one of these peptides or a portion thereof.
84 - 85 . (canceled)
86 . The pharmaceutical composition of claim 79 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity and the isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase are formulated together in a lipid complex or each formulated separately in a lipid complex and mixed together prior to administration.
87 . The pharmaceutical composition of claim 79 wherein the isolated peptide or mimetic thereof which enhances cholesterol ester hydrolase activity and/or the isolated peptide or mimetic thereof which inhibits acyl CoA:cholesterol acyl transferase is linked to Z and wherein Z is a targeting agent, a second agent for treatment of atherosclerosis, cardiovascular disease, or coronary heart disease, or an agent which enhances solubility, absorption, distribution, half-life, bioavailability, stability, activity and/or efficacy of the compound.
88 . A pharmaceutical composition comprising the compound Y—Z of claim 13 and and a pharmaceutically acceptable vehicle.
89 - 105 . (canceled)
106 . An isolated peptide comprising RGFFSFIGEAFQGAGDMWRAY (SEQ ID NO:7).Cited by (0)
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