US2019248852A1PendingUtilityA1
MIC-1 Compounds and Use Thereof
Est. expiryMay 24, 2036(~9.9 yrs left)· nominal 20-yr term from priority
Inventors:Xujia ZhangXiang GaoHongtao GuanHenning ThoegersenKristian Sass-OerumLars Fogh IversenPer NoergaardSebastian Beck JoergensenKristian Tage HansenYi Wang
A61P 3/04C07K 14/475A61K 38/00A61K 38/19A61K 38/27C07K 2319/31C07K 7/08A61K 47/642C07K 5/1013C07K 14/495A61P 3/00C07K 7/06C07K 2319/00C07K 5/1008A61K 38/1841
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Claims
Abstract
The invention relates to MIC-1 compounds. More specifically it relates to compounds comprising a MIC-1 polypeptide and an N-terminal amino acid extension, wherein said extension consists of 3 to 36 amino acid residues and where the compound has a calculated pI lower than 6.5. The compounds of the invention have MIC-1 activity. 5 The invention also relates to pharmaceutical compositions comprising such compounds and pharmaceutically acceptable excipients, as well as the medical use of the compounds.
Claims
exact text as granted — not AI-modified1 . A MIC-1 compound comprising a MIC-1 polypeptide and an N-terminal amino acid extension, wherein said extension consists of 3 to 36 amino acid residues and where the compound has a calculated p1 lower than 6.5.
2 . The compound according to claim 1 , wherein the compound is a homodimer and consists of between 218-296, 224-296 or 230-296 amino acid residues.
3 . The compound according to claim 1 , wherein said extension is in the range of 3-36, 3-30, 3-24, 3-12, 4-36, 4-30, 4-24, 4-12, 5-36, 5-30, 5-24, 5-12, 6-36, 6-30, 6-24, 6-12, 7-36, 7-30, 7-24, 7-12, 8-36, 8-30, 8-24, 8-12, 30-36, 32-36, 30-34, or 30-32 amino acid residues in length.
4 . The compound according to claim 1 , wherein the extension has surplus of acidic amino acid residues (Aspartic acid and Glutamic acid) of at least 3, 4, 5 or 6 compared to the number of basic amino acid residues (Lysine, Arginine and Histidine)
5 . The compound according to claim 1 , wherein the extension is composed of amino acid residues selected among the group consisting of A, E, G, P, S, T, Q, and D and wherein said extension comprises at least three E and/or D amino acid residues.
6 . The compound according to claim 5 , wherein the extension comprises 6 Ser, 4 Pro, 4 Gly, 4 Thr, 4 Glu and 2 Ala.
7 . The compound according to claim 1 , wherein the extension comprises one or more of the following sequences
(SEQ ID NO: 4)
SPAGSP,
(SEQ ID NO: 5)
TSESAT,
(SEQ ID NO: 6)
TSTEPE,
(SEQ ID NO: 7)
SEPATS,
(SEQ ID NO: 8)
TSTEEG,
(SEQ ID NO: 9)
PESGPG,
(SEQ ID NO: 10)
SGSAPG,
(SEQ ID NO: 11)
GSETPG,
(SEQ ID NO: 12)
SEPATSGSETPGSPAGSPTSTEEG,
(SEQ ID NO: 13)
SEPATSGSETPGTSESATPESGPG,
(SEQ ID NO: 14)
SEPATSGSETPGTSTEPESGSAPG,
(SEQ ID NO: 15)
SEPATSGSETPGSPAGSPTSTEEGSPAGSP,
(SEQ ID NO: 16)
SEPATSGSETPGTSESATPESGPGSPAGSP,
(SEQ ID NO: 17)
SEPATSGSETPGTSTEPESGSAPGSPAGSP,
(SEQ ID NO: 18)
SEPATSGSETPGSPAGSPTSTEEGTSESAT,
(SEQ ID NO: 19)
SEPATSGSETPGTSESATPESGPGTSESAT,
(SEQ ID NO: 20)
SEPATSGSETPGTSTEPESGSAPGTSESAT,
(SEQ ID NO: 21)
SEPATSGSETPGSPAGSPTSTEEGTSTEPE,
(SEQ ID NO: 22)
SEPATSGSETPGTSESATPESGPGTSTEPE,
(SEQ ID NO: 23)
SEPATSGSETPGTSTEPESGSAPGTSTEPE,
(SEQ ID NO: 24)
SEPATSGSETPGSPAGSPTSTEEGSEPATS,
(SEQ ID NO: 25)
SEPATSGSETPGTSESATPESGPGSEPATS,
(SEQ ID NO: 26)
SEPATSGSETPGTSTEPESGSAPGSEPATS,
(SEQ ID NO: 27)
SEPATSGSETPGSPAGSPTSTEEGTSTEEG,
(SEQ ID NO: 28)
SEPATSGSETPGTSESATPESGPGTSTEEG,
(SEQ ID NO: 29)
SEPATSGSETPGTSTEPESGSAPGTSTEEG,
(SEQ ID NO: 30)
SEPATSGSETPGSPAGSPTSTEEGPESGPG,
(SEQ ID NO: 31)
SEPATSGSETPGTSESATPESGPGPESGPG,
(SEQ ID NO: 32)
SEPATSGSETPGTSTEPESGSAPGPESGPG,
(SEQ ID NO: 33)
SEPATSGSETPGSPAGSPTSTEEGSGSAPG,
(SEQ ID NO: 34)
SEPATSGSETPGTSESATPESGPGSGSAPG,
(SEQ ID NO: 35)
SEPATSGSETPGTSTEPESGSAPGSGSAPG,
(SEQ ID NO: 36)
SEPATSGSETPGSPAGSPTSTEEGGSETPG,
(SEQ ID NO: 37)
SEPATSGSETPGTSESATPESGPGGSETPG,
(SEQ ID NO: 38)
SEPATSGSETPGTSTEPESGSAPGGSETPG,
(SEQ ID NO: 70)
SEPATSGSETPGTSESATPESGPGTSTEPS,
(SEQ ID NO: 71)
SEPATSGSETPGTSESATPESGPGTSTEPSEG,
(SEQ ID NO: 39)
SEPATSGSETPGSPAGSPTSTEEGTSESATPESGPG,
(SEQ ID NO: 40)
SEPATSGSETPGSPAGSPTSTEEGSPAGSPTSTEEG,
(SEQ ID NO: 41)
SEPATSGSETPGSPAGSPTSTEEGTSTEPESGSAPG,
(SEQ ID NO: 42)
SEPATSGSETPGTSESATPESGPGSPAGSPTSTEEG,
(SEQ ID NO: 43)
SEPATSGSETPGTSESATPESGPGTSESATPESGPG,
(SEQ ID NO: 44)
SEPATSGSETPGTSESATPESGPGTSTEPESGSAPG,
(SEQ ID NO: 45)
SEPATSGSETPGTSESATPESGPGSEPATSGSETPG,
(SEQ ID NO: 46)
SEPATSGSETPGTSTEPESGSAPGSPAGSPTSTEEG,
(SEQ ID NO: 47)
SEPATSGSETPGTSTEPESGSAPGTSESATPESGPG,
(SEQ ID NO: 48)
SEPATSGSETPGTSTEPESGSAPGTSTEPESGSAPG,
(SEQ ID NO: 49)
SEPATSGSETPGTSTEPESGSAPGSEPATSGSETPG,
(SEQ ID NO: 50)
SEPATSGSETPGSEPATSGSETPGSPAGSPTSTEEG,
(SEQ ID NO: 51)
SEPATSGSETPGSEPATSGSETPGTSESATPESGPG,
(SEQ ID NO: 52)
SEPATSGSETPGSEPATSGSETPGTSTEPESGSAPG,
(SEQ ID NO: 53)
SEPATSGSETPGSEPATSGSETPGSEPATSGSETPG,
(SEQ ID NO: 136)
GGGS,
(SEQ ID NO: 137)
GSGS,
(SEQ ID NO: 138)
GGSS
and
(SEQ ID NO: 139)
SSSG.
8 . The compound according to claim 1 , wherein the extension comprises one or more of the following sequences
(SEQ ID NO: 118)
GEPS,
(SEQ ID NO: 119)
GPSE,
(SEQ ID NO: 120)
GPES,
(SEQ ID NO: 121)
GSPE,
(SEQ ID NO: 122)
GSEP,
(SEQ ID NO: 140)
GEPSGEPSGEPSGEPSGEPS,
(SEQ ID NO: 141)
GPSEGPSEGPSEGPSEGPSE,
(SEQ ID NO: 142)
GPESGPESGPESGPESGPES,
(SEQ ID NO: 143)
GSPEGSPEGSPEGSPEGSPE,
(SEQ ID NO: 144)
GSEPGSEPGSEPGSEPGSE,
(SEQ ID NO: 123)
GEPQ,
(SEQ ID NO: 124)
GEQP,
(SEQ ID NO: 125)
GPEQ,
(SEQ ID NO: 126)
GPQE,
(SEQ ID NO: 127)
GQEP,
(SEQ ID NO: 128)
GQPE,
(SEQ ID NO: 145)
GEPQGEPQGEPQGEPQGEPQ,
(SEQ ID NO: 146)
GEQPGEQPGEQPGEQPGEQP,
(SEQ ID NO: 147)
GPEQGPEQGPEQGPEQGPEQ,
(SEQ ID NO: 148)
GPQEGPQEGPQEGPQEGPQE,
(SEQ ID NO: 149)
GQEPGQEPGQEPGQEPGQEP,
(SEQ ID NO: 150)
GQPEGQPEGQPEGQPEGQPE,
(SEQ ID NO: 136)
GGGS,
(SEQ ID NO: 137)
GSGS,
(SEQ ID NO: 138)
GGSS
and
(SEQ ID NO: 139)
SSSG.
9 . The compound according to claim 1 , wherein the extension comprises one or more of the following sequences
(SEQ ID NO: 129)
PEDEETPEQE,
(SEQ ID NO: 130)
PDEGTEEETE,
(SEQ ID NO: 131)
PAAEEEDDPD,
(SEQ ID NO: 132)
AEPDEDPQSED,
(SEQ ID NO: 133)
AEPDEDPQSE,
(SEQ ID NO: 134)
AEPEEQEED,
(SEQ ID NO: 135)
AEPEEQEE,
(SEQ ID NO: 151)
AEEAEEAEEAEEAEE,
(SEQ ID NO: 136)
GGGS,
(SEQ ID NO: 137)
GSGS,
(SEQ ID NO: 138)
GGSS
and
(SEQ ID NO: 139)
SSSG.
10 . The compound according to claim 1 , wherein the MIC-1 polypeptide displays at least 85%, 90%, 95% or 98% sequence identity to MIC-1 of SEQ ID NO:1.
11 . The compound according to claim 1 , wherein the MIC-1 polypeptide comprise one or more of the following substitutions N3E, P11E, H18E, R21E, A30E, A47E, R53E, A54E, M57E, M57L, H66E, R67E, L68E, K69E, A75E, A81E, P85E, M86L, Q90E, T92E, L105E and K107E compared to MIC-1 of SEQ ID NO:1.
12 . The compound according to claim 1 , wherein the MIC-1 polypeptide comprise a deletion of the first three residues (MIC-1-Δ1-3) or a deletion of N3 (des-N3) compared to MIC-1 of SEQ ID NO:1.
13 . A MIC-1 compound comprising a MIC-1 polypeptide and an N-terminal amino acid extension, wherein the compound comprises an amino acid sequence according to SEQ ID NO: 100, 104, 106, 107, 108, 109, 111, 112, 113, 114, 115, 116, 117 or 164.
14 . The compound according to claim 13 , wherein the compound has a solubility of 0.5, 1.0, 5.0, 10, 30 or 50 mg/ml at pH 8.0 in a Tris buffer system.
15 . A method for treating a metabolic disorder, comprising administering to a subject in need thereof the compound according to claim 1 , wherein the metabolic disorder is selected from the group consisting of obesity, diabetes, cardiovascular like dyslipidaemia, arteriosclerosis, steatohepatitis, and diabetic nephropathy.Cited by (0)
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