Hepcidin analogues and uses thereof
First Claim
Patent Images
1. A peptide having the following structural formula I′
-
R1′
-X′
-Y′
-R2′
(I′
) (SEQ ID NO;
21)or a pharmaceutically acceptable salt or solvate thereof,whereinR1′
is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl or pGlu;
R2′
is —
NH2 or —
OH;
X′
is a peptide sequence having the formula Ia′
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10
(Ia′
) (SEQ ID NO;
13)whereinX1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent;
X2 is Thr, Ala, Aib, D-Thr, Arg or absent;
X3 is His, Ala, D-His or Lys;
X4 is Phe, Ala, Dpa, bhPhe or D-Phe;
X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent;
X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala;
X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys;
X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or Dapa;
X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and
X10 is Lys, Phe or absent;
Y′
is a peptide having the formula IIa′
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15
(IIa′
) (SEQ ID NO;
16)whereinY1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent;
Y2 is Pro, Ala, Cys, Gly or absent;
Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent;
Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent;
Y5 is Lys, Met, Arg, Ala or absent;
Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala Ile, Val or absent;
Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent;
Y9 is Cys, Tyr or absent;
Y10 is Met, Lys, Arg, Tyr or absent;
Y11 is Arg, Met, Cys, Lys or absent;
Y12 is Arg, Lys, Ala or absent;
Y13 is Arg, Cys, Lys, Val or absent;
Y14 is Arg, Lys, Pro, Cys, Thr or absent; and
Y15 is Thr, Arg or absent;
wherein at least one of Y1, Y2, Y8, Y9, Y11, Y13, or Y14 is Cys;
wherein said compound of formula I′
is optionally PEGylated on X′
, or Y′
; and
wherein when said compound of formula I′
comprises two or more cysteine residues, at least two of said cysteine residues being linked via a disulfide bond.
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Accused Products
Abstract
The present invention relates, inter alia, to certain hepcidin peptide analogs, including peptides and dimers thereof, and to the use of the peptides and peptide dimers in the treatment and/or prevention of a variety of diseases, conditions or disorders, including treatment and/or prevention of iron overload diseases, which include hereditary hemochromatosis and iron-loading anemias, and other conditions and disorders described herein.
98 Citations
19 Claims
-
1. A peptide having the following structural formula I′
-
R1′
-X′
-Y′
-R2′
(I′
) (SEQ ID NO;
21)or a pharmaceutically acceptable salt or solvate thereof, wherein R1′
is hydrogen, C1-C6 alkyl, C6-C12 aryl, C6-C12 aryl C1-C6 alkyl, C1-C20 alkanoyl or pGlu;R2′
is —
NH2 or —
OH;X′
is a peptide sequence having the formula Ia′
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10
(Ia′
) (SEQ ID NO;
13)wherein X1 is Asp, Glu, Ala, Gly, Thr, Ida, pGlu, bhAsp, D-Asp, Tyr, Leu or absent; X2 is Thr, Ala, Aib, D-Thr, Arg or absent; X3 is His, Ala, D-His or Lys; X4 is Phe, Ala, Dpa, bhPhe or D-Phe; X5 is Pro, Glu, Ser, Gly, Arg, Lys, Val, Ala, D-Pro, bhPro, Sarc, Abu or absent; X6 is Ile, Cys, Arg, Leu, Lys, His, Glu, D-Ile, D-Arg, D-Cys, Val, Ser or Ala; X7 is Cys, Ile, Ala, Leu, Val, Ser, Phe, Dapa, D-Ile or D-Cys; X8 is Ile, Lys, Arg, Ala, Gln, Phe, Glu, Asp, Tyr, Ser, Leu, Val, D-Ile, D-Lys, D-Arg, or Dapa; X9 is Phe, Ala, Ile, Tyr, Lys, Arg, bhPhe or D-Phe; and X10 is Lys, Phe or absent; Y′
is a peptide having the formula IIa′
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15
(IIa′
) (SEQ ID NO;
16)wherein Y1 is Gly, Cys, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, Ser or absent; Y2 is Pro, Ala, Cys, Gly or absent; Y3 is Arg, Lys, Pro, Gly, His, Ala, Trp or absent; Y4 is Ser, Arg, Gly, Trp, Ala, His, Tyr or absent; Y5 is Lys, Met, Arg, Ala or absent; Y6 is Gly, Ser, Lys, Ile, Ala, Pro, Val or absent; Y7 is Trp, Lys, Gly, Ala Ile, Val or absent; Y8 is Val, Thr, Gly, Cys, Met, Tyr, Ala, Glu, Lys, Asp, Arg or absent; Y9 is Cys, Tyr or absent; Y10 is Met, Lys, Arg, Tyr or absent; Y11 is Arg, Met, Cys, Lys or absent; Y12 is Arg, Lys, Ala or absent; Y13 is Arg, Cys, Lys, Val or absent; Y14 is Arg, Lys, Pro, Cys, Thr or absent; and Y15 is Thr, Arg or absent; wherein at least one of Y1, Y2, Y8, Y9, Y11, Y13, or Y14 is Cys; wherein said compound of formula I′
is optionally PEGylated on X′
, or Y′
; andwherein when said compound of formula I′
comprises two or more cysteine residues, at least two of said cysteine residues being linked via a disulfide bond. - View Dependent Claims (2, 3, 4, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19)
-
-
5. The peptide of formula or I′
- pharmaceutically acceptable salt or solvate thereof according to claim h, wherein X′
is a peptide having formula Ic′
X1-Thr-His-X4-X5-Cys-Ile-X8-Phe-X10
(Ic′
) (SEQ ID NO;
15)wherein X1 is Asp, Ida, pGlu, bhAsp or absent; X4 is Phe or Dpa; X5 is Pro or bhPro; X8 is Ile, Lys, Glu, Phe, Gln or Arg; and X10 is Lys or absent.
- pharmaceutically acceptable salt or solvate thereof according to claim h, wherein X′
Specification