MIC-1 compounds and uses thereof
The invention relates to MIC-1 compounds. More specifically it relates to compounds comprising a MIC-1 polypeptide with an N-terminal amino acid extension and a protractor wherein the amino acid extension comprises 3 to 36 amino acid residues and where the MIC-1 polypeptide and the N-terminal amino acid extension together have a calculated pI lower than 6.5. The compounds of the invention have MIC-1 activity. The invention also relates to pharmaceutical compositions comprising such compounds and pharmaceutically acceptable excipients, as well as the medical use of the compounds.
1. A MIC-1 compound, comprising
a MIC-1 polypeptide;
an amino acid extension attached to the N-terminal of the MIC-1 polypeptide; and
a protractor attached to the amino acid extension;
wherein the amino acid extension comprises 3 to 36 amino acid residues;
wherein one of the amino acid residues is a Cys and the remainder of the amino acid residues are selected from the group consisting of Ala, Glu, Gly, Pro, Ser, and Thr;
wherein the distance between the Cys residue and the N-terminal amino acid of the MIC-1 polypeptide is at least 3 amino acids;
wherein the protractor is attached to the amino acid extension at the Cys residue;
wherein the protractor comprises Chem. 1, Chem. 2, Chem. 3, and Chem. 4;
wherein Chem. 1 is selected from the group consisting of:
HOOC—(CH 2 ) x —CO—*, Chem. 1A:
HO—S(═O) 2 —(CH 2 ) x —CO—*, Chem. 1B:
HOOC-benzene-O—(CH 2 ) y —CO—*, and Chem. 1C:
(1H-tetrazol-5-yl)-(CH 2 ) x —CO—*, Chem. 1D:
wherein x is an integer in the range of 12-20, and
wherein y is an integer in the range of 5-15;
wherein Chem. 2 is selected from the group consisting of:
*—(NH—CH(COOH)—(CH 2 ) m —CO) k * and Chem. 2A:
*—(NH—S(═O) 2 —(CH 2 ) m —CO) k * Chem. 2B:
wherein m of Chem. 2 is an integer in the range of 1-5, and
wherein k of Chem. 2 is an integer in the range of 0-4;
wherein Chem. 3 is *(NH—(CH 2 ) 2 —[O—(CH 2 ) 2 ] k —O—[CH 2 ] n —CO—*) l ,
wherein k of Chem. 3 is an integer in the range of 1-10,
wherein n is an integer in the range of 1-5, and
wherein l is an integer in the range of 0-5;
wherein Chem. 4 is selected from the group consisting of:
*—NH—(CH 2 ) m —NH—CO—CH 2 —*, and Chem. 4A:
*—NH—CH(COOH)—(CH 2 ) m —NH—O—CH 2 —*, Chem. 4B:
wherein m of Chem. 4 is an integer in the range of 1-5;
wherein Chem. 1, Chem. 2, Chem. 3, and Chem. 4 are interconnected via amide bonds;
wherein Chem. 4 at its CH 2 —* end is connected to a sulphur atom of the Cys residue of the amino acid extension; and
wherein the MIC-1 polypeptide with the amino acid extension has a calculated pI lower than 6.5.
2. The MIC-1 compound according to claim 1 , wherein Chem. 1 is selected from the group consisting of:
HOOC—(CH 2 ) 16 —CO—*, Chem. 1a:
HO—S(═O) 2 —(CH 2 ) 15 —CO—*, and Chem. 1b:
HOOC-benzene-O—(CH 2 ) 9 —CO—*. Chem. 1c:
3. The MIC-1 compound according to claim 1 , wherein Chem. 2 is selected from the group consisting of:
*—NH—CH(COOH)—(CH 2 ) 2 —CO—* and Chem. 2a:
*—NH—S(═O) 2 —(CH 2 ) 3 —CO—*. Chem. 2b:
4. The MIC-1 compound according to claim 1 , wherein Chem. 4 is selected from the group consisting of:
*—NH—(CH 2 ) 2 —NH—CO—CH 2 —* and Chem. 4a:
*—NH—CH(COOH)—(CH 2 ) 4 —NH—CO—CH 2 —*. Chem. 4b:
5. The MIC-1 compound according to claim 1 , wherein Chem. 1 is selected from the group consisting of:
HOOC—(CH 2 ) 16 —CO—*, Chem. 1a:
HO—S(═O) 2 —(CH 2 ) 15 —CO—*, and Chem. 1b:
HOOC-benzene-O—(CH 2 ) 9 —CO—*; Chem. 1c:
wherein Chem. 2 is selected from the group consisting of:
*—NH—CH(COOH)—(CH 2 ) 2 —CO—* and Chem. 2a:
*—NH—S(═O) 2 —(CH 2 ) 3 —CO—*; and Chem. 2b:
wherein Chem. 4 is selected from the group consisting of:
*—NH—(CH 2 ) 2 —NH—CO—CH 2 —* and Chem. 4a:
*—NH—CH(COOH)—(CH 2 ) 4 —NH—CO—CH 2 —*. Chem. 4b:
6. The MIC-1 compound according to claim 1 , wherein the protractor is selected from the group consisting of Formula IX, Formula X, Formula XI, Formula XII, and Formula XIII:
7. The MIC-1 compound according to claim 1 , wherein the amino acid extension comprises a sequence selected from the group consisting of:
(SEQ ID NO: 223)
SEPATCGSETPGTSESATPESGPGTSTEPS,
(SEQ ID NO: 224)
SEPATSGCETPGTSESATPESGPGTSTEPS,
(SEQ ID NO: 225)
SEPCTSGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 226)
SEPATCGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 227)
SEPATSCSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 229)
SEPACSGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 230)
SEPATSGCETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 231)
SEPATSGSECPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 232)
SEPATSGSETPCTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 233)
SEPATSGSETPGTCESATPESGPGTSTEPSEG,
(SEQ ID NO: 234)
SEPATSGSETPGTSECATPESGPGTSTEPSEG,
(SEQ ID NO: 235)
SEPATSGSETPGTSESACPESGPGTSTEPSEG,
(SEQ ID NO: 236)
SEPATSGSETPGTSESATPECGPGTSTEPSEG,
and
(SEQ ID NO: 237)
SEPATSGSETPGTSESATPESCPGTSTEPSEG.
8. The MIC-1 compound according to claim 1 , wherein the MIC-1 polypeptide comprises at least one of M57L and M86L, when compared to SEQ ID NO: 1.
9. The MIC-1 compound according to claim 1 , wherein the MIC-1 polypeptide comprises a deletion of the first three residues or a deletion of N3 when compared to SEQ ID NO: 1.
10. The MIC-1 compound according to claim 1 , wherein the MIC-1 polypeptide comprises (i) at least one of M57L and M86L and (ii) a deletion of the first three residues or a deletion of N3, when compared to SEQ ID NO:1.
11. The MIC-1 compound according to claim 1 , wherein the combination of the MIC-1 polypeptide and the amino acid extension comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 100, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 164, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, and SEQ ID NO: 292.
12. The MIC-1 compound according to claim 1 , where the compound is selected from the group consisting of:
13. The MIC-1 compound according to claim 1 , wherein the compound is
14. The MIC-1 compound according to claim 1 , wherein the compound is
15. The MIC-1 compound according to claim 1 , wherein the compound is
16. The MIC-1 compound according to claim 1 , wherein the compound is
17. The MIC-1 compound according to claim 1 , wherein the compound is
18. The MIC-1 compound according to claim 1 , wherein the compound is
19. The MIC-1 compound according to claim 1 , wherein the compound is
20. The MIC-1 compound according to claim 1 , wherein the compound is
21. The MIC-1 compound according to claim 1 , wherein the compound is
22. The MIC-1 compound according to claim 1 , wherein the compound is
23. The MIC-1 compound according to claim 1 , wherein the compound is
24. A method for treating obesity, comprising administering a MIC-1 compound according to claim 1 to a subject in need thereof.
25. The method according to claim 24 , wherein Chem. 1 is selected from the group consisting of:
HOOC—(CH 2 ) 16 —CO—*, Chem. 1a:
HO—S(═O) 2 —(CH 2 ) 15 —CO—*, and Chem. 1b:
HOOC-benzene-O—(CH 2 ) 9 —CO—*; Chem. 1c:
wherein Chem. 2 is selected from the group consisting of:
*—NH—CH(COOH)—(CH 2 ) 2 —CO—* and Chem. 2a:
*—NH—S(═O) 2 —(CH 2 ) 3 —CO—*;and Chem. 2b:
wherein Chem. 4 is selected from the group consisting of:
*—NH—(CH 2 ) 2 —NH—CO—CH 2 —* and Chem. 4a:
*—NH—CH(COOH)—(CH 2 ) 4 —NH—CO—CH 2 —*. Chem. 4b:
26. The method according to claim 24 , wherein the amino acid extension comprises a sequence selected from the group consisting of:
(SEQ ID NO: 223)
SEPATCGSETPGTSESATPESGPGTSTEPS,
(SEQ ID NO: 224)
SEPATSGCETPGTSESATPESGPGTSTEPS,
(SEQ ID NO: 225)
SEPCTSGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 226)
SEPATCGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 227)
SEPATSCSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 229)
SEPACSGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 230)
SEPATSGCETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 231)
SEPATSGSECPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 232)
SEPATSGSETPCTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 233)
SEPATSGSETPGTCESATPESGPGTSTEPSEG,
(SEQ ID NO: 234)
SEPATSGSETPGTSECATPESGPGTSTEPSEG,
(SEQ ID NO: 235)
SEPATSGSETPGTSESACPESGPGTSTEPSEG,
(SEQ ID NO: 236)
SEPATSGSETPGTSESATPECGPGTSTEPSEG,
and
(SEQ ID NO: 237)
SEPATSGSETPGTSESATPESCPGTSTEPSEG.
27. The method according to claim 24 , wherein the combination of the MIC-1 polypeptide and the amino acid extension comprises an amino acid sequence selected from the group consisting of SEQ ID NO: 100, SEQ ID NO: 104, SEQ ID NO: 106, SEQ ID NO: 107, SEQ ID NO: 108, SEQ ID NO: 109, SEQ ID NO: 111, SEQ ID NO: 112, SEQ ID NO: 113, SEQ ID NO: 114, SEQ ID NO: 115, SEQ ID NO: 116, SEQ ID NO: 117, SEQ ID NO: 164, SEQ ID NO: 288, SEQ ID NO: 289, SEQ ID NO: 290, SEQ ID NO: 291, and SEQ ID NO: 292.
28. The method according to claim 24 , where the MIC-1 compound is selected from the group consisting of: