# US 10,501,515 B2 · Hepcidin analogues and uses thereof

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- Number: US 10,501,515 B2
- Document ID: US10501515B2
- Status: Granted
- Kind: B2
- Application number: 16/289,451
- Filed: 2019-02-28
- Published: 2019-06-20
- Granted: 2019-12-10
- Earliest claimed: 2013-03-15
- Assignees: Protagonist Therapeutics, Inc.
- Applicants: Protagonist Therapeutics, Inc.
- Inventors: Mark Leslie Smythe; Gregory Thomas Bourne; Simone Vink; Brian Troy Frederick; Praveen Madala; Anne Pernille Tofteng Shelton; Jacob Ulrik Fog
- Web page: https://patentgrep.com/patent/US10501515B2

## CPC

- C07K 14/575: Hormones (derived from pro-opiomelanocortin, pro-enkephalin or pro-dynorphin C07K14/665, e.g. corticotropin C07K14/695)
- A61P 3/00: Drugs for disorders of the metabolism (of the blood or the extracellular fluid A61P7/00)
- A61P 3/12: for electrolyte homeostasis
- A61K 38/00: Medicinal preparations containing peptides (peptides containing beta-lactam rings A61K31/00; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, A61K31/00; ergot alkaloids of the cyclic peptide type A61K31/48; containing macromolecular compounds having statistically distributed amino acid units A61K31/74; medicinal preparations containing antigens or antibodies A61K39/00; medicinal preparations characterised by the non-active ingredients, e.g. peptides as drug carriers, A61K47/00)
- C07K: PEPTIDES (peptides in foodstuffs A23; obtaining protein compositions for foodstuffs, working-up proteins for foodstuffs A23J; preparations for medicinal purposes A61K; peptides containing beta-lactam rings C07D; cyclic dipeptides not having in their molecule any other peptide link than those which form their ring, e.g. piperazine-2,5-diones, C07D; ergot alkaloids of the cyclic peptide type C07D519/02; macromolecular compounds having statistically distributed amino acid units in their molecules, i.e. when the preparation does not provide for a specific; but for a random sequence of the amino acid units, homopolyamides and block copolyamides derived from amino acids C08G69/00; macromolecular products derived from proteins C08H1/00; preparation of glue or gelatine C09H; single cell proteins, enzymes C12N; genetic engineering processes for obtaining peptides C12N15/00; compositions for measuring or testing processes involving enzymes C12Q; investigation or analysis of biological material G01N33/00)
- A61P: SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61K: PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES (devices or methods specially adapted for bringing pharmaceutical products into particular physical or administering forms A61J3/00; chemical aspects of, or use of materials for deodorisation of air, for disinfection or sterilisation, or for bandages, dressings, absorbent pads or surgical articles A61L; soap compositions C11D)

## Abstract

The present invention relates, inter alia, to certain hepcidin peptide analogues, 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.

## Claims

### Claim 1

A method of treating a disease of iron metabolism in a subject, comprising administering to the subject an effective amount of at least one peptide according to formula I′:
(I′)
(SEQ ID NO: 21)
R1′-X′-Y′-R2′
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 —NH2 or —OH;
X′ is a peptide sequence having the formula Ia′
(Ia′)
(SEQ ID NO: 13)
X1-X2-X3-X4-X5-X6-X7-X8-X9-X10
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, IIe, Leu, or Val;
X8 is Ile, Arg, Phe, Gln, Lys, or Glu;
X9 is Phe or bhPhe; and
X10 is Lys, Phe or absent;
wherein if Y′ is absent, X7 is Ile; and
Y′ is a peptide sequence having the formula IIa′
(IIa′)
(SEQ ID NO: 16)
Y1-Y2-Y3-Y4-Y5-Y6-Y7-Y8-Y9-Y10-Y11-Y12-Y13-Y14-Y15
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, IIe, Ala, Pro, Val or absent;
Y7 is Trp, Lys, Gly, Ala, IIe, 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′;
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 hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia.

### Claim 2 (depends on 1)

The method of claim 1, wherein the peptide of Formula I′ is PEGylated on R1′, X′, or Y′, or wherein a side chain of an amino acid of the peptide of Formula I′ is conjugated to a lipophilic substituent or a polymeric moiety.

### Claim 3 (depends on 1)

The method of claim 1, wherein R1′ is hydrogen, isovaleric acid, isobutyric acid or acetyl.

### Claim 4 (depends on 1)

The method of claim 1, wherein X′ is a peptide sequence having formula Ib′
(Ib′)
(SEQ ID NO: 14)
X1-Thr-His-X4-X5-X6-X7-X8-Phe-X10
wherein
X1 is Asp, Ida, pGlu, bhAsp or absent;
X4 is Phe or Dpa;
X5 is Pro or bhPro;
X6 is Ile, Cys or Arg;
X7 is Cys, IIe, Leu or Val;
X8 is Ile, Lys, Glu, Phe, Gln or Arg; and
X10 is Lys or absent;
or having formula Ic′
(Ic′)
(SEQ ID NO: 15)
X1-Thr-His-X4-X5-Cys-I1e-X8-Phe-X10
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.

### Claim 5 (depends on 1)

The method of claim 1, wherein X1 is Asp, X4 is Phe, and X5 is Pro.

### Claim 6 (depends on 1)

The method of claim 1, wherein the peptide of Formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
DTHFPICIFGPRSKGWVC;
(SEQ ID NO: 38)
DTHFPCIIFGPRSKGWVCK;
(SEQ ID NO: 128)
DTHFPCIIFEPRSKGWVCK;
(SEQ ID NO: 164)
DTHFPCIIFGPRSKGWACK;
(SEQ ID NO: 168)
DTHFPCIIFGPRSKGWVCKK;
(SEQ ID NO: 57
DTHFPCIIFVCHRPKGCYRRVCR;
(SEQ ID NO: 125)
DTHFPCIKFGPRSKGWVCK;
(SEQ ID NO: 173)
DTHFPCIKFKPRSKGWVCK;
(SEQ ID NO: 106)
DTHFPCIIFGPRSRGWVCK;
(SEQ ID NO: 135)
DTHFPCIKFGPKSKGWVCK;
(SEQ ID NO: 207)
DTHFPCIKFEPRSKGCK;
(SEQ ID NO: 265)
DTHFPCIKFEPKSKGWECK;
(SEQ ID NO: 245)
DTHFPCIKFEPRSKKCK;
(SEQ ID NO: 247)
DTHFPCIKFEPRSKGCKK;
(SEQ ID NO: 249)
DTHFPCIKFKPRSKGCK;
or
(SEQ ID NO: 250)
DTHFPCIKFEPKSKGCK,
or a pharmaceutically acceptable salt thereof.

### Claim 7 (depends on 1)

The method of claim 1, wherein the peptide of Formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
Isovaleric acid-DTHFPICIFGPRSKGWVC-NH2;
(SEQ ID NO: 38)
Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2;
(SEQ ID NO: 128)
Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2;
(SEQ ID NO: 164)
Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH2;
(SEQ ID NO: 168)
Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH2;
(SEQ ID NO: 57)
Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH2;
(SEQ ID NO: 172)
Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2;
(SEQ ID NO: 173)
Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2;
(SEQ ID NO: 199)
Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH2;
(SEQ ID NO: 200)
Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH2;
(SEQ ID NO: 201)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH2;
(SEQ ID NO: 202)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH2;
(SEQ ID NO: 203)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2;
(SEQ ID NO: 183)
Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2;
(SEQ ID NO: 217)
Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2;
(SEQ ID NO: 219)
Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2;
(SEQ ID NO: 220)
Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2;
(SEQ ID NO: 221)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH2;
(SEQ ID NO: 222)
Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-
NH2;
(SEQ ID NO: 223)
Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-
NH2;
(SEQ ID NO: 224)
Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-
NH2;
(SEQ ID NO: 225)
Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-
NH2;
(SEQ ID NO: 226)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-
NH2;
(SEQ ID NO: 176)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2;
(SEQ ID NO: 241)
Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-
NH2;
(SEQ ID NO: 242)
Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-
NH2;
(SEQ ID NO: 243)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-
NH2;
(SEQ ID NO: 265)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-
NH2;
(SEQ ID NO: 244)
Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-
NH2;
(SEQ ID NO: 245)
Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-
NH2;
(SEQ ID NO: 246)
Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-
NH2;
(SEQ ID NO: 248)
Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2;
(SEQ ID NO: 249)
Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2;
(SEQ ID NO: 250)
Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2;
(SEQ ID NO: 251)
Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2;
(SEQ ID NO: 252)
Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2;
(SEQ ID NO: 253)
Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K-
NH2;
or
(SEQ ID NO: 254)
Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2,
or a pharmaceutically acceptable salt thereof, wherein the peptide of Formula I′ comprises two cysteine residues linked via a disulphide bond.

### Claim 8 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ comprises one of the following sequences:
(SEQ ID NO: 29)
DTHFPICIFGPRSKGWVC;
(SEQ ID NO: 38)
DTHFPCIIFGPRSKGWVCK;
(SEQ ID NO: 128)
DTHFPCIIFEPRSKGWVCK;
(SEQ ID NO: 164)
DTHFPCIIFGPRSKGWACK;
(SEQ ID NO: 168)
DTHFPCIIFGPRSKGWVCKK;
(SEQ ID NO: 57
DTHFPCIIFVCHRPKGCYRRVCR;
(SEQ ID NO: 125)
DTHFPCIKFGPRSKGWVCK;
(SEQ ID NO: 173)
DTHFPCIKFKPRSKGWVCK;
(SEQ ID NO: 106)
DTHFPCIIFGPRSRGWVCK;
(SEQ ID NO: 135)
DTHFPCIKFGPKSKGWVCK;
(SEQ ID NO: 207)
DTHFPCIKFEPRSKGCK;
(SEQ ID NO: 265)
DTHFPCIKFEPKSKGWECK;
(SEQ ID NO: 245)
DTHFPCIKFEPRSKKCK;
(SEQ ID NO: 247)
DTHFPCIKFEPRSKGCKK;
(SEQ ID NO: 249)
DTHFPCIKFKPRSKGCK;
or
(SEQ ID NO: 250)
DTHFPCIKFEPKSKGCK.

### Claim 9 (depends on 1)

The method of claim 1, wherein the peptide comprises one of the following sequences:
(SEQ ID NO: 29)
Isovaleric acid-DTHFPICIFGPRSKGWVC-NH2;
(SEQ ID NO: 38)
Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2;
(SEQ ID NO: 128)
Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2;
(SEQ ID NO: 164)
Isovaleric acid-DTHFPCIIFGPRSKGWACK-NH2;
(SEQ ID NO: 168)
Isovaleric acid-DTHFPCIIFGPRSKGWVCKK-NH2;
(SEQ ID NO: 57)
Isovaleric acid-DTHFPCIIFVCHRPKGCYRRVCR-NH2;
(SEQ ID NO: 172)
Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2;
(SEQ ID NO: 173)
Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2;
(SEQ ID NO: 199)
Isovaleric acid-DTHFPICIFGPRS(K(PEG8))GWVCNH2;
(SEQ ID NO: 200)
Isovaleric acid-DTHFPICIFGPRS(K(PEG4))GWVCNH2;
(SEQ ID NO: 201)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))-NH2;
(SEQ ID NO: 202)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG4))-NH2;
(SEQ ID NO: 203)
Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG2))-NH2;
(SEQ ID NO: 183)
Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2;
(SEQ ID NO: 217)
Isovaleric acid-DTHFPCIKF)K(Palm))PRSKGWVCK-NH2;
(SEQ ID NO: 219)
Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2;
(SEQ ID NO: 220)
Isovaleric acid-DTHFPCIKFGPRS(K(Palm))GWVCK-NH2;
(SEQ ID NO: 221)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))-NH2;
(SEQ ID NO: 222)
Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-
NH2;
(SEQ ID NO: 223)
Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-
NH2;
(SEQ ID NO: 224)
Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-
NH2;
(SEQ ID NO: 225)
Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-
NH2;
(SEQ ID NO: 226)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))-
NH2;
(SEQ ID NO: 176)
Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))-NH2;
(SEQ ID NO: 241)
Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-
NH2;
(SEQ ID NO: 242)
Isovaleric acid-DTHFPCIKF-K(isoGlu-Palm)-PRSKGCK-
NH2;
(SEQ ID NO: 243)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-
NH2;
(SEQ ID NO: 265)
Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGWECK-
NH2;
(SEQ ID NO: 244)
Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-
NH2;
(SEQ ID NO: 245)
Isovaleric acid-DTHFPCIKFEPRSK(K(isoGlu-Palm))CK-
NH2;
(SEQ ID NO: 246)
Isovaleric acid-DTHFPCIKFEPRSKGCK(K(isoGlu-Palm))-
NH2;
(SEQ ID NO: 248)
Isovaleric acid-DTHFPCI-K(Dapa-Palm)-FEPRSKGCK-NH2;
(SEQ ID NO: 249)
Isovaleric acid-DTHFPCIK(F(Dapa-Palm))PRSKGCK-NH2;
(SEQ ID NO: 250)
Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2;
(SEQ ID NO: 251)
Isovaleric acid-DTHFPCIKFEPRS(K(Dapa-Palm))GCK-NH2;
(SEQ ID NO: 252)
Isovaleric acid-DTHFPCIKFEPRSK(K(Dapa-Palm))CK-NH2;
(SEQ ID NO: 253)
Isovaleric acid-DTIFPCIKFEPRSKGC(K(Dapa-Palm))K-
NH2;
or
(SEQ ID NO: 254)
Isovaleric acid-DTHFPCIKFEPRSKGC(K(Dapa-Palm))-NH2,

### Claim 10 (depends on 1)

The method of claim 1, wherein the disease of iron metabolism is hereditary hemochromatosis, iron hemochromatosis, HFE (human factors engineering) mutation hemochromatosis, hepcidin deficiency, transfusional iron overload, or thalassemia.

### Claim 11 (depends on 1)

The method of claim 1, wherein the disease of iron metabolism is hereditary hemochromatosis (HH).

### Claim 12 (depends on 1)

The method of claim 1, wherein the disease of iron metabolism is a thalassemia, optionally thalassemia intermedia, alpha thalassemia, or β-thalassemia.

### Claim 13 (depends on 12)

The method of claim 12, wherein the disease of iron metabolism is β-thalassemia.

### Claim 14 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSKGWVCK-NH2 (SEQ ID NO:38) or Isovaleric acid-DTHFPCIIFEPRSKGWVCK-NH2 (SEQ ID NO:128).

### Claim 15 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG8))FGPRSKGWVCK-NH2 (SEQ ID NO:172) or Isovaleric acid-DTHFPCIKF(K(PEG8))PRSKGWVCK-NH2 (SEQ ID NO:173).

### Claim 16 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIIFGPRSRGWVC(K(PEG8))—NH2 (SEQ ID NO:201).

### Claim 17 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Palm))FGPRSKGWVCK-NH2 (SEQ ID NO:183).

### Claim 18 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(Palm))PRSKGWVCK-NH2 (SEQ ID NO:217).

### Claim 19 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(Palm))SKGWVCK-NH2(SEQ ID NO:219) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(Palm))—NH2 (SEQ ID NO:221).

### Claim 20 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(PEG3-Palm))FGPRSKGWVCK-NH2(SEQ ID NO:222).

### Claim 21 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(PEG3-Palm))PRSKGWVCK-NH2 (SEQ ID NO:223).

### Claim 22 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGP(K(PEG3-Palm))SKGWVCK-NH2(SEQ ID NO:224).

### Claim 23 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRS(K(PEG3-Palm))GWVCK-NH2(SEQ ID NO:225) or Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG3-Palm))—NH2(SEQ ID NO:226).

### Claim 24 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFGPRSKGWVC(K(PEG8))—NH2 (SEQ ID NO:176).

### Claim 25 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(isoGlu-Palm))FEPRSKGCK-NH2(SEQ ID NO:241).

### Claim 26 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKF(K(isoGlu-Palm))PRSKGCK-NH2(SEQ ID NO:242).

### Claim 27 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(isoGlu-Palm))SKGCK-NH2(SEQ ID NO:243).

### Claim 28 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEPRS(K(isoGlu-Palm))GCK-NH2(SEQ ID NO:244).

### Claim 29 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCI(K(Dapa-Palm))FEPRSKGCK-NH2(SEQ ID NO:248).

### Claim 30 (depends on 1)

The method of claim 1, wherein the peptide of formula I′ is: Isovaleric acid-DTHFPCIKFEP(K(Dapa-Palm))SKGCK-NH2(SEQ ID NO:250).