US2008050351A1PendingUtilityA1
Gene Therapy Approaches to Supply Apolipoprotein A-I Agonists and Their Use to Treat Dyslipidemic Disorder
Est. expirySep 29, 2017(expired)· nominal 20-yr term from priority
A61P 43/00A61P 9/00A61P 9/10A61P 3/06A61P 37/00A61K 48/00A61P 3/00A61P 31/04A61K 38/00A61K 48/005C07K 14/775A61K 51/08
62
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Claims
Abstract
The invention relates to genetic approaches to supply nucleotide sequences encoding modified forms of the native forms of apolipoprotein A-I (ApoA-I): mature ApoA-I, reproApoA-I and proApoA-I; including native ApoA-I modified to contain ApoA-I agonists, peptides which mimic the activity of ApoA-I; ApoA-I superagonists, peptides which exceed the activity of native ApoA-I; and modified native ApoA-I having one or more amphipathic helices replaced by the nucleotide sequences of one or more ApoA-I agonists; for the treatment of disorders associated with dyslipoproteinemia, including cardiovascular disease, atherosclerosis, restenosis, hyperlipidemia, and other disorders such as septic shock.
Claims
exact text as granted — not AI-modified1 . A nucleotide sequence encoding an ApoA-I agonist comprising:
(i) a 15 to 29-residue peptide or peptide analogue which forms an amphipathic α-helix in the presence of lipids and which comprises the structural formula (I): 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 —X 19 —X 20 —X 21 —X 22 —X 23 or a pharmaceutically acceptable salt thereof, wherein:
X 1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N) or Asp (D);
X 2 is an aliphatic residue;
X 3 is Leu (L) or Phe (F);
X 4 is an acidic residue;
X 5 is Leu (L) or Phe (F);
X 6 is Leu (L) or Phe (F);
X 7 is a hydrophilic residue;
X 8 is an acidic or a basic residue;
X 9 is Leu (L) or Gly (G);
X 10 is Leu (L), Trp (W) or Gly (G);
X 11 is a hydrophilic residue;
X 12 is a hydrophilic residue;
X 13 is Gly (G) or an aliphatic residue;
X 14 is Leu (L), Trp (W) or Gly (G);
X 15 is a hydrophilic residue;
X 16 is a hydrophobic residue;
X 17 is a hydrophobic residue;
X 18 His Gln (Q), Asn (N) or a basic residue;
X 19 is Gln (Q), Asn (N) or a basic residue;
X 20 is a basic residue;
X 21 is an aliphatic residue;
X 22 is a basic residue;
X 23 is absent or a basic residue; or
(ii) a deleted form of structural formula (I) in which at least one and up to eight of residues X 1 , X 2 , X 3 , X 4 , X 5 , X 6 , X 71 , X 8 , X 9 , X 10 , X 11 , X 12 , X 13 , X 14 , X 15 , X 16 , X 17 , X 18 , X 19 , X 20 , X 21 and X 22 are deleted; or (iii) an altered form of structural formula (I) in which at least one of residues 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 , X 19 , X 20 , X 21 , X 22 or X 23 is conservatively substituted with another residue.
2 . The ApoA-I agonist encoded by the nucleotide sequence of claim 1 which exhibits at least about 38% LCAT-activation activity as compared with human ApoA-I.
3 . The ApoA-I agonist encoded by the nucleotide sequence of claim 1 which is the altered form of structural formula (I).
4 . The ApoA-I agonist encoded by the nucleotide sequence of claim 3 in which the hydrophobic residues are fixed according to structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue.
5 . The ApoA-I agonist of claim 4 in which:
X 1 is Pro (P), Gly (G) or Ala (A); X 2 is Ala (A), Leu (L) or Val (V); X 3 is Leu (L) or Phe (F); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 9 is Leu (L) or Gly (G); X 10 is Leu (L), Trp (W) or Gly (G); X 13 is Leu (L) or Gly (G); X 14 is Leu (L), Trp (W) or Gly (G); X 16 is Ala (A), Trp (W), Gly (G), Leu (L) or Phe (F); X 17 is Leu (L) or Gly (G); X 21 is Leu (L); and at least one of X 4 , X 7 , X 8 , X 11 , X 12 , X 15 , X 18 , X 19 , X 20 , X 22 and X 23 is conservatively substituted with another residue.
6 . The ApoA-I agonist of claim 3 in which the hydrophilic residues are fixed according to structural formula (I) and at least one non-fixed residue is conservatively substituted with another residue.
7 . The ApoA-I agonist of claim 6 in which:
X 4 is Asp (D) or Glu (E); X 7 is Lys (K) or Arg (R); X 8 is Asp (D) or Glu (E); X 11 is Asn (N) or Gln (Q); X 12 is Glu (E) or Asp (D); X 15 is Asp (D) or Glu (E); X 18 is Gln (Q), Asn (N) or Lys (K); X 19 is Gln (Q), Asn (N) or Lys (K); X 20 is Lys (K); X 22 is Lys (K); X 23 is absent or Lys (K); and at least one of X 1 , X 2 , X 3 , X 5 , X 6 , X 9 , X 10 , X 13 , X 14 , X 16 , X 17 and X 21 is conservatively substituted with another residue.
8 . The ApoA-I agonist of claim 7 in which X 3 is Leu (L) or Phe (F), X 6 is Phe (F), X 9 is Leu (L) or Gly (G), X 10 is Leu (L) or Trp (W) or Gly (G) and at least one of X 1 , X 2 , X 5 , X 13 , X 14 , X 16 , X 17 and X 21 is conservatively substituted with another residue.
9 . The ApoA-I agonist of claim 5 or 7 in which the substituting residue is classified within the same sub-category as the substituted residue.
10 . The ApoA-I agonist encoded by the nucleotide sequence of claim 1 which is the deleted form of structural formula (I).
11 . The ApoA-I agonist of claim 10 in which one helical turn of the peptide or peptide analogue is deleted.
12 . The ApoA-I agonist encoded by the nucleotide sequence of claim 1 which is a 22-23 residue peptide or peptide analogue of structural formula (I).
13 . The ApoA-I agonist encoded by the nucleotide sequence of claim 1 , in which:
X 1 is Pro (P), Ala (A), Gly (G), Asn (N), Gln (Q) or Asp (D); X 2 is Ala (A), Val (V) or Leu (L); X 3 is Leu (L) or Phe (F); X 4 is Asp (D) or Glu (E); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 7 is Lys (K) or Arg (R); X 8 is Asp (D) or Glu (E); X 9 is Leu (L) or Gly (G); X 10 is Leu (L), Trp (W) or Gly (G); X 11 is Asn (N) or Gln (Q); X 12 is Glu (E) or Asp (D); X 13 is Gly (G) or Leu (L); X 14 is Leu (L) Trp (W) or Gly (G); X 15 is Asp (D) or Glu (E); X 16 is Ala (A), Trp (W), Leu (L), Phe (F) or Gly (G); X 17 is Gly (G) or Leu (L); X 18 is Gln (Q), Asn (N) or Lys (K); X 19 is Gln (Q), Asn (N) or Lys (K); X 20 is Lys (K); X 21 is Leu (L); X 22 is Lys (K); and X 23 is absent or Lys (K).
14 . The ApoA-I agonist of claim 13 , in which X 23 is absent.
15 . The ApoA-I agonist of claim 13 , in which one of X 18 or X 19 is Gln (Q) or Asn (N) and the other of X 18 or X 19 is Lys (K).
16 . The ApoA-I agonist of claim 13 in which each of X 9 , X 10 , X 13 , X 14 , X 15 and X 17 is other than Gly (G).
17 . The ApoA-I agonist of claim 13 in which one of X 9 , X 10 , X 13 , X 14 , X 15 and X 17 is Gly (G) and the others are other than Gly (G).
18 . The nucleotide sequence of claim 1 which encodes an ApoA-I agonist having an amino acid sequence selected from the group consisting of:
peptide 2
GVLDLFRELLNELLEALKQKLKK;
(SEQ ID NO:2)
peptide 3
PVLDLFRELLNELLEWLKQKLK;
(SEQ ID NO:3)
peptide 4
PVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:4)
peptide 7
PVLDLFKELLNELLEALKQKLK;
(SEQ ID NO:7)
peptide 8
PVLDLFRELLNEGLEALKQKLK;
(SEQ ID NO:8)
peptide 9
PVLDLFRELGNELLEALKQKLK;
(SEQ ID NO:9)
peptide 11
PVLDLFKELLQELLEALKQKLK;
(SEQ ID NO:11)
peptide 12
PVLDLFRELLNELLEAGKQKLK;
(SEQ ID NO:12)
peptide 13
GVLDLFRELLNEGLEALKQKLK;
(SEQ ID NO:13)
peptide 15
PVLDLFRELWNELLEALKQKLK;
(SEQ ID NO:15)
peptide 16
PVLDLLRELLNELLEALKQKLK;
(SEQ ID NO:16)
peptide 17
PVLELFKELLQELLEALKQKLK;
(SEQ ID NO:17)
peptide 18
GVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:16)
peptide 20
PVLDLFREGLNELLEALKQKLK;
(SEQ ID NO:20)
peptide 22
PVLDLFRELLNELLEGLKQKLK;
(SEQ ID NO:22)
peptide 23
PLLELFKELLQELLEALKQKLK;
(SEQ ID NO:23)
peptide 24
PVLDLFRELLNELLEALQKKLK;
(SEQ ID NO:24)
peptide 26
PVLDLFRELLNELLELLKQKLK;
(SEQ ID NO:26)
peptide 28
PVLDLFRELLNELWEALKQKLK;
(SEQ ID NO:28)
peptide 29
AVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:29)
peptide 123
QVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:123)
peptide 125
NVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:125)
peptide 126
PVLDLFRELLNELGEALKQKLK;
(SEQ ID NO:126)
peptide 127
PVLDLFRELLNELLELLKQKLK;
(SEQ ID NO:127)
peptide 128
PVLDLFRELLNELLEFLKQKLK;
(SEQ ID NO:128)
peptide 129
PVLELFNDLLRELLEALQKKLK;
(SEQ ID NO:129)
peptide 130
PVLELFNDLLRELLEALKQKLK;
(SEQ ID NO:130)
peptide 131
PVLELFKELLNELLDALRQKLK;
(SEQ ID NO:131)
peptide 132
PVLDLFRELLENLLEALQKKLK;
(SEQ ID NO:132)
peptide 133
PVLELFERLLEDLLQALNKKLK;
(SEQ ID NO:133)
peptide 134
PVLELFERLLEDLLKALNQKLK;
(SEQ ID NO:134)
peptide 135
DVLDLFRELLNELLEALKQKLK;
(SEQ ID NO:135)
peptide 136
PALELFKDLLQELLEALKQKLK;
(SEQ ID NO:136)
peptide 138
PVLDLFRELLNEGLEWLKQKLK;
(SEQ ID NO:138)
peptide 139
PVLDLFRELWNEGLEALKQKLK;
(SEQ ID NO:139)
peptide 141
PVLDFFRELLNEGLEALKQKLK;
(SEQ ID NO:141)
or
peptide 142
PVLELFRELLNEGLEALKQKLK.
(SEQ ID NO:142)
19 . A nucleotide sequence encoding an ApoA-I agonist comprising:
(i) a 15 to 29-residue peptide or peptide analogue which forms an amphipathic α-helix in the presence of lipids and which comprises the structural formula (II): 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 —X 19 —X 20 —X 21 —X 22 —X 23 or a pharmaceutically acceptable salt thereof, wherein:
X 1 is Pro (P), Ala (A), Gly (G), Gln (Q), Asn (N) or Asp (D);
X 2 is an aliphatic residue Val (v) or Len (L);
X 3 is Leu (L) or Phe (F);
X 4 is Glu (E);
X 5 is an aliphatic residue:
X 6 is Leu (L) or Phe (F);
X 7 is Glu (E) or Leu (L);
X 8 is Asn (N) or Gln (Q);
X 9 is Leu (L);
X 10 is Leu (L), Trp (W) or Gly (G);
X 11 is an acidic residue;
X 12 is Arg (R);
X 13 is Leu (L) or Gly (G);
X 14 is Leu (L), Phe (F) or Gly (G);
X 15 is Asp (D);
X 16 is Ala (A);
X 17 is Leu (L);
X 18 is Asn (N) or Gln (Q);
X 19 is a basic residue;
X 20 is a basic residue;
X 21 is Leu (L);
X 22 is a basic residue;
X 23 is absent or a basic residue; or
(ii) a deleted form of structural formula (II) in which at least one and up to eight of residues 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 , X 19 , X 20 , X 21 and X 22 are deleted; or (iii) an altered form of structural formula (II) in which at least one of residues X, 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 , X 19 , X 20 , X 21 , X 22 or X 23 is conservatively substituted with another residue.
20 . The ApoA-I agonist encoded by the nucleotide sequence of claim 18 which exhibits at least about 38% LCAT-activation activity as compared with human ApoA-I.
21 . The ApoA-I agonist encoded by the nucleotide sequence of claim 18 which is the altered form of structural formula (II).
22 . The ApoA-I agonist of claim 20 in which the hydrophobic residues are fixed according to structural formula (II) and at least one non-fixed residue is conservatively substituted with another residue.
23 . The ApoA-I agonist of claim 21 in which:
X 1 is Pro (P), Gly (G), Asn (N) or Ala (A); X 2 is Ala (A), Leu (L) or Val (V); X 3 is Leu (L) or Phe (F); X 5 is Leu (L); X 6 is Phe (F); X 9 is Leu (L); X 10 is Leu (L), Trp (W) or Gly (G); X 13 is Leu (L) or Gly (G); X 14 is Leu (L), Phe (F) or Gly (G); X 16 is Ala (A); X 17 is Leu (L); X 21 is Leu (L); and at least one of X 4 , X 7 , X 8 , X 11 , X 12 , X 15 , X 18 , X 19 , X 22 and X 23 is conservatively substituted with another residue.
24 . The ApoA-I agonist encoded by the nucleotide sequence of claim 20 in which the hydrophilic residues are fixed according to structural formula (II) and at least one non-fixed residue is conservatively substituted with another residue.
25 . The ApoA-I agonist of claim 23 in which:
X 4 is Glu (E); X 7 is Glu (E); X 8 is Asn (N) or Gln (Q); X 11 is Asp (D) or Glu (E); X 12 is Arg (R); X 15 is Asp (D); X 18 is Asn (N) or Gln (Q); X 19 is Lys (K); X 20 is Lys (K); X 22 is Lys (K); X 23 is absent or Lys (K); and at least one of X 1 , X 2 , X 3 , X 5 , X 6 , X 9 , X 10 , X 13 , X 14 , X 16 , X 17 and X 21 is conservatively substituted with another residue.
26 . The ApoA-I agonist of claim 23 in which X 3 is Leu (L) or Phe (F), X 6 is Phe (F), X 9 is Leu (L), X 10 is Leu (L), Trp (W) or Gly (G) and at least one of X 1 , X 2 , X 5 , X 13 , X 14 , X 16 , X 17 and X 21 is conservatively substituted with another residue.
27 . The ApoA-I agonist of claim 22 or 24 in which the substituting residue is classified within the same sub-category as the substituted residue.
28 . The ApoA-I agonist encoded by the nucleotide sequence of claim 18 which is the deleted form of structural formula (II).
29 . The ApoA-I agonist of claim 27 in which one helical turn of the peptide or peptide analogue is deleted.
30 . The ApoA-I agonist encoded by the nucleotide sequence of claim 18 which is a 22-23 residue peptide or peptide analogue of structural formula (II).
31 . The ApoA-I agonist encoded by the nucleotide sequence of claim 18 , in which:
X 1 is Pro (P), Ala (A), Gly (G) or Asn (N), X 2 is Ala (A), Val (V) or Leu (L); X 3 is Leu (L) or Phe (F); X 4 is Glu (E); X 5 is Leu (L); X 6 is Phe (F); X 7 is Leu (L) or Glu (E); X 8 is Asn (N) or Gln (Q); X 9 is Leu (L); X 10 is Leu (L), Trp (W) or Gly (G); X 11 , is Glu (E); X 12 is Arg (R); X 13 is Leu (L) or Gly (G); X 14 is Leu (L) Phe (F) or Gly (G); X 15 is Asp (D); X 16 is Ala (A); X 17 is Leu (L); X 18 is Asn (N) or Gln (Q); X 19 is Lys (K); X 20 is Lys (K); X 21 is Leu (L); X 22 is Lys (K); and X 23 is absent or Lys (K).
32 . The ApoA-I agonist of claim 30 , in which X 23 is absent.
33 . The ApoA-I agonist of claim 30 , in which each of X 10 , X 13 and X 14 is other than Gly (G).
34 . The ApoA-I agonist of claim 31 , in which one of X 10 , X 13 or X 14 is Gly (G) and the others are other than Gly (G).
35 . The nucleotide sequence of claim 18 which encodes an ApoA-I agonist having an amino acid sequence selected from the group consisting of:
(SEQ ID NO:145)
GVLELFENLLERLLDALQKKLK;
(SEQ ID NO:146)
PVLELFENLLERLLDALQKKLK;
(SEQ ID NO:147)
PVLELFENLLERLFDALQKKLK;
(SEQ ID NO:148)
PVLELFENLLERLGDALQKKLK;
(SEQ ID NO:149)
PVLELFENLWERLLDALQKKLK;
(SEQ ID NO:150)
PLLELFENLLERLLDALQKKLK;
(SEQ ID NO:151)
PVLELFENLGERLLDALQKKLK;
(SEQ ID NO:152)
PVFELFENLLERLLDALQKKLK;
(SEQ ID NO:153)
AVLELFENLLERLLDALQKKLK;
(SEQ ID NO:154)
PVLELFENLLERGLDALQKKLK;
(SEQ ID NO:155)
PVLELFLNLWERLLDALQKKLK;
(SEQ ID NO:186)
PVLELFEQLLERLLDALQKKLK;
(SEQ ID NO:187)
PVLELFENLLERLLDALNKKLK;
(SEQ ID NO:188)
PVLELFENLLDRLLDALQKKLK;
or
(SEQ ID NO:189)
DVLELFENLLERLLDALQKKLK.
36 . A nucleotide-sequence encoding an ApoA-I agonist comprising:
(i) a 14 to 22-residue peptide or peptide analogue which forms an amphipathic α-helix in the presence of lipids and which comprises the structural formula (III): 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 X 1 is Pro (P), Ala (A), Gly (G), Asn (N) or Gln (Q); X 2 is an aliphatic amino acid; X 3 is Leu (L); X 4 is an acidic amino acid; X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 7 is a basic amino acid; X 8 is an acidic amino acid; X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 11 is an acidic amino acid or Asn (N); X 12 is an acidic amino acid; X 13 is Leu (L), Trp (W) or Phe (F); X 14 is a basic amino acid or Leu (L); X 15 is Gln (Q) or Asn (N); X 16 is a basic amino acid; X 17 is Leu (L); X 18 is a basic amino acid; (ii) a deleted form of structural formula (III) in which at least one and up to eight of residues 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 , and X 18 are deleted; or (iii) an altered form of structural formula (III) in which at least one of residues 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 or X 18 is conservatively substituted with another residue.
37 . The ApoA-I agonist encoded by the nucleotide sequence of claim 36 which exhibits at least about 38% LCAT-activation activity as compared with human ApoA-I.
38 . The ApoA-I agonist encoded by the nucleotide sequence of claim 36 which is the altered form of structural formula (III).
39 . The ApoA-I agonist of claim 38 in which the hydrophobic residues are fixed according to structural formula (III) and at least one non-fixed residue is conservatively substituted with another residue.
40 . The ApoA-I agonist of claim 39 in which:
X 1 is Pro (P), Gly (G), Asn (N) or Ala (A); X 2 is Ala (A), Leu (L) or Val (V); X 3 is Leu (L); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 13 is Leu (L), Trp (W) or Phe (F); X 17 is Leu (L); and at least one of X 4 , X 7 , X 8 , X 11 , X 12 , X 14 , X 15 , X 16 and X 18 is conservatively substituted with another residue.
41 . The ApoA-I agonist of claim 38 in which the hydrophilic residues are fixed according to structural formula (III) and at least one non-fixed residue is conservatively substituted with another residue.
42 . The ApoA-I agonist of claim 41 in which:
X 4 is Asp (D) or Glu (E); X 7 is Arg (R) or Lys (K); X 8 is Asp (D) or Glu (E); X 11 is Asn (N) or Glu (E); X 12 is Glu (E); X 14 is Lys (K) or Arg (R); X 15 is Gln (Q) or Asn (N); X 16 is Lys (K) or Arg (R); X 18 is Asn (N) or Gln (Q); and at least one of X 1 , X 2 , X 3 , X 5 , X 6 , X 9 , X 10 , X 13 and X 17 is conservatively substituted with another residue.
43 . The ApoA-I agonist of claim 41 in which X 3 is Leu (L), X 6 is Phe (F), X, is Leu (L) or Trp (W), X 10 is Leu (L) or Trp (W) and at least one of X 1 , X 2 , X 1 , X 13 and X 10 is conservatively substituted with another residue.
44 . The ApoA-I agonist of claim 40 or 42 in which the substituting residue is classified within the same sub-category as the substituted residue.
45 . The ApoA-I agonist of claim 36 which is the deleted form of structural formula (III).
46 . The ApoA-I agonist of claim 45 in which one helical turn of the peptide or peptide analogue is deleted.
47 . The ApoA-I agonist of claim 36 which is an 18-residue peptide or peptide analogue of structural formula (III).
48 . The ApoA-I agonist encoded by the nucleotide sequence of claim 36 , in which:
X 1 is Pro (P), Ala (A), Gly (G) or Asn (N); X 2 is Ala (A), Val (V) or Leu (L); X 3 is Leu (L); X 4 is Asp (D) or Glu (E); X 5 is Leu (L) or Phe (F); X 6 is Leu (L) or Phe (F); X 7 is Arg (R) or Lys (K); X 8 is Asp (D) or Glu (E); X 9 is Leu (L) or Trp (W); X 10 is Leu (L) or Trp (W); X 11 is Glu (E) or Asn (N); X 12 is Glu (E); X 13 is Leu (L), Trp (W) or Phe (F); X 14 is Arg (R) or Lys (K); X 15 is Gln (Q) or Asn (N); X 16 is Arg (R) or Lys (K); X 17 is Leu (L); and X 18 is Arg (R) or Lys (K).
49 . The nucleotide sequence of claim 36 which encodes an ApoA-I agonist having an amino acid sequence selected from the group consisting of:
peptide 191
PVLDLLRELLEELKQKLK*;
(SEQ ID NO:191)
peptide 192
PVLDLFKELLEELKQKLK*;
(SEQ ID NO:192)
peptide 193
PVLDLFRELLEELKQKLK*;
(SEQ ID NO:193)
peptide 194
PVLELFRELLEELKQKLK*;
(SEQ ID NO:194)
peptide 195
PVLELFKELLEELKQKLK*;
(SEQ ID NO:195)
peptide 196
PVLDLFRELLEELKNKLK*;
(SEQ ID NO:196)
peptide 197
PLLDLFRELLEELKQKLK*;
(SEQ ID NO:197)
peptide 198
GVLDLFRELLEELKQKLK*;
(SEQ ID NO:198)
peptide 199
PVLDLFRELWEELKQKLK*;
(SEQ ID NO:199)
peptide 200
NVLDLFRELLEELKQKLK*;
(SEQ ID NO:200)
peptide 201
PLLDLFKELLEELKQKLK*;
(SEQ ID NO:201)
peptide 202
PALELFKDLLEELRQKLR*;
(SEQ ID NO:202)
peptide 203
AVLDLFRELLEELKQKLK*;
(SEQ ID NO:203)
peptide 204
PVLDFFRELLEELKQKLK*;
(SEQ ID NO:204)
peptide 205
PVLDLFREWLEELKQKLK*;
(SEQ ID NO:205)
peptide 206
PLLELLKELLEELKQKLK*;
(SEQ ID NO:206)
peptide 207
PVLELLKELLEELKQKLK*;
(SEQ ID NO:207)
peptide 208
PALELFKDLLEELRQRLK*;
(SEQ ID NO:208)
peptide 209
PVLDLFRELLNELLQKLK;
(SEQ ID NO:209)
peptide 210
PVLDLFRELLEELKQKLK;
(SEQ ID NO:210)
peptide 213
PALELFKDLLEEFRQRLK*;
(SEQ ID NO:213)
peptide 215
PVLDLFRELLEEWKQKLK*;
(SEQ ID NO:215)
peptide 229
PVLELFERLLEDLQKKLK;
(SEQ ID NO:229)
peptide 230
PVLDLFRELLEKLEQKLK;
(SEQ ID NO:230)
peptide 231
PLLELFKELLEELKQKLK*.
(SEQ ID NO:231)
50 . A nucleotide sequence encoding a multimeric ApoA-I agonist which exhibits at least about 38% LCAT activation activity as compared with human ApoA-I and which has the structural formula (IV):
HH LL m -HH n LL m -HH (IV) or a pharmaceutically acceptable salt thereof, wherein:
each m is independently an integer from 0 to 1;
n is an integer from 0 to 10;
each “HH” is independently a peptide or peptide
analogue according to claim 1 or 18 or 36 ; and;
each “LL” is independently a bifunctional linker.
51 . A host cell expressing a peptide encoded by the nucleotide sequence of claim 1 , 18 or 36 .
52 . A host cell expressing a peptide encoded by the nucleotide sequence of claim 17 , 35 or 49 .
53 . A host cell expressing a peptide encoded by the nucleotide sequence of claim 50 .
54 . A pharmaceutical composition comprising nucleotide sequences encoding an ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the ApoA-I agonist is encoded by the nucleotide sequences of claim 1 , 18 or 36 .
55 . A pharmaceutical composition comprising nucleotide sequences encoding an ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the ApoA-I agonist is encoded by the nucleotide sequences of claim 17 , 35 or 49 .
56 . A pharmaceutical composition comprising nucleotide sequences encoding an ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent, wherein the ApoA-I agonist is encoded by the nucleotide sequences of claim 50 .
57 . A pharmaceutical composition of claim 54 , in which the nucleotide sequence is in the form of a nucleotide lipid complex, said complex comprising the nucleotide sequences encoding an ApoA-I agonist and a lipid.
58 . A method of treating a subject suffering from a disorder associated with dyslipidemia, said method comprising the step of administrating to the subject an effective amount of a nucleotide sequence or a host cell expressing the nucleotide sequence of claims 1 , 18 or 36 .
59 . The method of claim 59 in which the ApoA-I agonist is in the form of an ApoA-I agonist-lipid complex, said complex comprising the ApoA-I agonist and a lipid.
60 . The method of claim 58 in which the ApoA-I agonist is in the form of a pharmaceutical composition, said composition comprising the ApoA-I agonist and a pharmaceutically acceptable carrier, excipient or diluent.
61 . The method of claim 58 in which the disorder associated with dyslipidemia is hypercholesterol.
62 . The method of claim 58 in which the disorder associated with dyslipidemia is cardiovascular disease.
63 . The method of claim 58 in which the disorder associated with dyslipidemia is atherosclerosis.
64 . The method of claim 58 in which the disorder associated with dyslipidemia is restenosis.
65 . The method of claim 58 in which the disorder associated with dyslipidemia is an HDL or ApoA-I deficiency.
66 . The method of claim 58 in which the disorder associated with dyslipidemia is hypertriglyceridemia.
67 . The method of claim 58 in which the disorder associated with dyslipidemia is a metabolic syndrome.
68 . The method of treating a subject suffering from a disorder associated with endotoxemia septic shock, said method comprising the step of administering to the subject an effective amount of a nucleotide sequence or a host cell expressing the nucleotide sequence of claims 1 , 18 or 36 .Join the waitlist — get patent alerts
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