Granted Patent B2

US 11,807,674 · App. 17/099,308 · Granted Nov 7, 2023

Inventors: Mark Leslie Smythe (Bardon, AU); Gregory Thomas Bourne (Brisbane, AU); Simone Vink (Taringa, AU); Brian Troy Frederick (Ben Lomand, CA); Praveen Madala (Brisbane, AU); Anne Pernille Tofteng Shelton (Valby, DK); Jacob Ulrik Fog (Bagsvaerd, DK)

Assignee: Protagonist Therapeutics, Inc.

C07K14/575A61K38/00

Abstract

Claims (120)

1. A method of treating a disease of iron metabolism in a subject, comprising administering to the subject in need thereof an effective amount of at least one peptide according to formula I′:

R1′—X′—Y′—R2′  (I′)(SEQ ID NO:21)

or a pharmaceutically acceptable salt thereof, wherein

R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu;

R2′ is —NH 2 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, Ida, pGlu, bhAsp, or absent;

X2 is Thr;

X3 is His;

X4 is Phe or Dpa;

X5 is Pro or bhPro;

X6 is Ile, Cys, or Arg;

X7 is Cys, Ile, Leu, Val, Phe, D-Ile or D-Cys;

X8 is Ile, Arg, Phe, Gln, Lys, or Glu;

X9 is Phe; and

X10 is Lys or absent;

and

Y′ is a peptide sequence 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 or Val;

Y2 is Pro, Ala, Cys, Gly, or absent;

Y3 is Arg, Lys, Pro, Gly, 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, or absent;

Y7 is Trp, Lys, Gly, Ala, Ile, or absent;

Y8 is Val, Thr, Ala, Glu, Lys, or absent;

Y9 is Cys, Tyr, or absent;

Y10 is Met, Lys, Tyr, or absent;

Y11 is Arg, Met, Cys, Lys, or absent;

Y12 is Arg, Ala, or absent;

Y13 is Cys, Val, or absent;

Y14 is Arg, Cys, Thr, or absent; and

Y15 is Thr, Arg, or absent;

wherein the peptide of formula I′ comprises two cysteine residues linked via a disulfide bond, wherein the peptide is optionally PEGylated on R1′, X′, or Y′;

wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety; and

wherein the disease of iron metabolism is selected from the group consisting of hereditary hemochromatosis, iron hemochromatosis, human factors engineering (HFE) mutation hemochromatosis, ferroportin mutation hemochromatosis, transferrin receptor 2 mutation hemochromatosis, hemojuvelin mutation hemochromatosis, hepcidin mutation hemochromatosis, juvenile hemochromatosis, neonatal hemochromatosis, hepcidin deficiency, transfusional iron overload, and thalassemia.

2. A composition comprising a peptide according to formula I′:

R1′—X′—Y′—R2′  (I′)(SEQ ID NO:21)

or a pharmaceutically acceptable salt thereof, wherein

R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu;

R2′ is —NH 2 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, Ida, pGlu, bhAsp, or absent;

X2 is Thr;

X3 is His;

X4 is Phe or Dpa;

X5 is Pro or bhPro;

X6 is Ile, Cys, or Arg;

X7 is Cys, Ile, Leu, or Val;

X8 is Ile, Arg, Phe, Gln, Lys, or Glu;

X9 is Phe; and

X10 is Lys or absent;

and

Y′ is a peptide sequence 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, Glu, Lys, or Val;

Y2 is Pro, Ala, Cys, Gly, or absent;

Y3 is Arg, Lys, Pro, Gly, 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, or absent;

Y7 is Trp, Lys, Gly, Ala, Ile, or absent;

Y8 is Val, Thr, Ala, Glu, Lys, or absent;

Y9 is Cys, Tyr, or absent;

Y10 is Met, Lys, Tyr, or absent;

Y11 is Arg, Met, Cys, Lys, or absent;

Y12 is Arg, Ala, or absent;

Y13 is Cys, Val, or absent;

Y14 is Arg, Cys, Thr, or absent; and

Y15 is Thr, Arg, or absent;

wherein the peptide of formula I′ comprises two cysteine residues linked via a disulfide bond, wherein the peptide is optionally PEGylated on R1′, X′, or Y′; and

wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety.

3. A method of manufacturing a peptide according to formula I′:

R1′—X′—Y′—R2′  (I′)(SEQ ID NO:21)

or a pharmaceutically acceptable salt thereof, wherein

R1′ is hydrogen, a C1-C6 alkyl, a C6-C12 aryl, a C1-C20 alkanoyl or pGlu;

R2′ is —NH 2 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, Ala, Ida, pGlu, bhAsp, Leu, D-Asp, or absent;

X2 is Thr, Ala, or D-Thr;

X3 is His, D-His, or Lys;

X4 is Phe, Ala, Dpa, or D-Phe;

X5 is Pro, Gly, Arg, Lys, Ala, D-Pro, or bhPro;

X6 is Ile, Cys, Arg, Lys, D-Ile, or D-Cys;

X7 is Cys, Ile, Leu, Val, Phe, D-Ile, or D-Cys;

X8 is Ile, Arg, Phe, Gln, Lys, Glu, Val, Leu, or D-Ile;

X9 is Phe or bhPhe; and

X10 is Lys, Phe, or absent;

and

Y′ is a peptide sequence 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, Ala, Phe, Pro, Glu, Lys, D-Pro, Val, or Ser;

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 the peptide of formula I′ comprises two cysteine residues linked via a disulfide bond, wherein the peptide is optionally PEGylated on R1′, X′, or Y′; and

wherein a side chain of an amino acid of the peptide is optionally conjugated to a lipophilic substituent or a polymeric moiety,

wherein the method comprises synthesizing the peptide of formula (I′) using solid phase peptide synthesis protocols.

4. The method of claim 1 , wherein the disease of iron metabolism is selected from the group consisting of thalassemia intermedia, alpha thalassemia, and β-thalassemia.

Assignments (3)

Continuity (10)

Cited By (2)

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