US2021340211A1PendingUtilityA1
Gip peptide analogues
Est. expirySep 5, 2034(~8.1 yrs left)· nominal 20-yr term from priority
Inventors:Alexander Hovard Sparre-UlrichMette Marie RosenkildeJens Juul HolstFilip Krag KnopMikkel Bring ChristensenLaerke Smidt Gasbjerg
A61P 3/00C07K 14/605A61K 38/00A61K 38/26A61P 5/00
51
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Claims
Abstract
Provided herein are glucose-dependent insulinotropic polypeptide (GIP)-derived peptide analogues, for example GIP(3-30), and their use as antagonists of the GIP receptor and for treatment of disorders such as obesity, diabetes mellitus and insulin resistance.
Claims
exact text as granted — not AI-modified1 .- 28 . (canceled)
29 . A peptide selected from the group consisting of:
a peptide consisting of 28 contiguous amino acids of sequence
(GIP3-30; SEQ ID NO: 74)
EGTFISDYSIAM X 0a X 0b I X 1 QQDFVNWLLAQ X 2 ,
a peptide consisting of 27 contiguous amino acids of sequence
(GIP4-30; SEQ ID NO: 75)
GTFISDYSIAM X 0a X 0b I X 1 QQDFVNAVLLAQ X 2 ,
a peptide consisting of 26 contiguous amino acids of sequence
(GIP5-30; SEQ ID NO: 76)
TFISDYSIAM X 0a X 0b I X 1 QQDFVNAVLLAQ X 2 ,
wherein X 0a , X 0b , X 1 and X 2 are individually any amino acid, and
a variant of any of the above peptides having at least 80% sequence identity to said peptide,
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR),
with the proviso that said peptide or variant thereof does not have 100% sequence identity to native hGIP3-30 (SEQ ID NO: 1), to native hGIP4-30 (SEQ ID NO: 77) or to native hGIP5-30 (SEQ ID NO: 78).
30 . The peptide according to claim 29 , wherein
X 0a is selected from the group consisting of D and E; X 0b is selected from the group consisting of K, A, H, and R; X 1 is selected from the group consisting of H, R, A, K, F, and Y; and X 2 is selected from the group consisting of K, R, H, and A.
31 . The peptide according to claim 29 , wherein the amino acid sequence of said peptide or variant thereof differs from SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76, in that the amino acid sequence of the variant comprises one, two, three, four, or five amino acid substitutions.
32 . The peptide according to claim 29 , wherein the amino acid sequence of said peptide or variant thereof differs from SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76, in that the amino acid sequence of the variant comprises one, two, three, or four amino acid substitutions.
33 . The peptide according to claim 29 , wherein the amino acid sequence of said peptide or variant thereof differs from SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76, in that the amino acid sequence of the variant comprises one, two, or three amino acid substitutions.
34 . The peptide according to claim 29 , wherein the amino acid sequence of said peptide or variant thereof differs from SEQ ID NO: 74, SEQ ID NO: 75 or SEQ ID NO: 76, in that the amino acid sequence of the variant comprises one or two amino acid substitutions.
35 . The peptide according to claim 31 , wherein said amino acid substitutions are selected from the group consisting of:
i) substitution of an amino acid having a polar side chain for a different amino acid having a polar side chain wherein amino acids having a polar side chain are Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Tyr, and Cys; ii) substitution of an amino acid having a non-polar side chain for a different amino acid having a non-polar side chain wherein amino acids having a non-polar side chain are Gly, Ala, Val, Leu, Be, Phe, Trp, Pro, and Met; iii) substitution of an amino acid having an aliphatic side chain for a different amino acid having an aliphatic side chain wherein amino acids having a polar side chain are Gly, Ala Val, Leu, and Ile; iv) substitution of an amino acid having a cyclic side chain for a different amino acid having a cyclic side chain wherein amino acids having a cyclic side chain are Phe, Tyr, Trp, His, and Pro; v) substitution of an amino acid having an aromatic side chain for a different amino acid having an aromatic side chain wherein amino acids having an aromatic side chain are Phe, Tyr, and Trp; vi) substitution of an amino acid having an acidic side chain for a different amino acid having an acidic side chain wherein amino acids having an acidic side chain are Asp, and Glu; vii) substitution of an amino acid having a basic side chain for a different amino acid having a basic side chain wherein amino acids having a basic side chain are Lys, Arg, and His; viii) substitution of an amino acid having an amide side chain for a different amino acid having an amide side chain wherein amino acids having an amide side chain are Asn, and Gln; ix) substitution of an amino acid having a hydroxy side chain for a different amino acid having a hydroxy side chain wherein amino acids having a hydroxy side chain are Ser, and Thr; x) substitution of an amino acid having a sulphur-containing side chain for a different amino acid having a sulphur-containing side chain wherein amino acids having a sulphur-containing side chain are Cys and Met; xi) substitution of a neutral, weakly hydrophobic amino acid for a different neutral, weakly hydrophobic amino acid wherein neutral, weakly hydrophobic amino acids are Pro, Ala, Gly, Ser, and Thr; xii) substitution of a hydrophilic, acidic amino acid for a different hydrophilic, acidic amino acid wherein hydrophilic, acidic amino acids are Gln, Asn, Glu, and Asp; and xiii) substitution of a hydrophobic amino acid for a different hydrophobic amino acid wherein hydrophobic amino acids are Leu, Ile, and Val.
36 . The peptide according to claim 29 , wherein said peptide is selected from the group consisting of:
a peptide consisting of 28 contiguous amino acids of sequence
(GIP3-30; SEQ ID NO: 11)
EGTFISDYSIAMDKI X 1 QQDFVNAVLLAQ X 2 ,
a peptide consisting of 27 contiguous amino acids of sequence
(GIP4-30; SEQ ID NO: 28)
GTFISDYSIAMDKI X 1 QQDFVNAVLLAQ X 2 ,
a peptide consisting of 26 contiguous amino acids of sequence
(GIP5-30; SEQ ID NO: 45)
TFISDYSIAMDKI X 1 QQDFVNWLLAQ X 2 ,
wherein X 1 is selected from the group consisting of H, R, A, K, F, and Y; and X 2 is selected from the group consisting of K, R, H, and A; and
a variant of any of the above peptides having at least 80% sequence identity to said peptide,
with the proviso that said peptide or variant thereof does not have 100% sequence identity to native hGIP3-30 (SEQ ID NO: 1), to native hGIP4-30 (SEQ ID NO: 77) or to native hGIP5-30 (SEQ ID NO: 78);
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR).
37 . The peptide according to claim 36 , wherein the amino acid sequence of the variant differs from SEQ ID NO: 11, SEQ ID NO: 28 or SEQ ID NO: 45, in that the amino acid sequence of the variant comprises one or two amino acid substitutions.
38 . The peptide according to claim 29 , wherein said peptide is selected from the group consisting of:
a peptide consisting of 28 contiguous amino acids of sequence
(GIP3-30; SEQ ID NO: 74)
EGTFISDYSIAM X 0a X 0b I X 1 QQDFVNWLLAQ X 2 ,
or
(GIP3-30; SEQ ID NO: 11)
EGTFISDYSIAMDKI X 1 QQDFVNWLLAQ X 2 ,
or a variant of any one of the above peptides, wherein the amino acid sequence of the variant differs from SEQ ID NO: 74 and SEQ ID NO: 11 in that the amino acid sequence of the variant comprises one, two, three, four or five amino acid substitutions,
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR),
with the proviso that said peptide or variant thereof does not have 100% sequence identity to native hGIP3-30 (SEQ ID NO: 1).
39 . The peptide according to claim 38 , wherein the amino acid sequence of the variant differs from SEQ ID NO: 11, SEQ ID NO: 28 or SEQ ID NO: 45, in that the amino acid sequence of the variant comprises one or two amino acid substitutions.
40 . The peptide according to claim 29 , wherein said peptide is selected from the group consisting of:
(hGIP(3-30)H18A; SEQ ID NO: 79)
EGTFISDYSIAMDKIAQQDFVNWLLAQK,
(hGIP(3-30)H18K; SEQ ID NO: 80)
EGTFISDYSIAMDKIKQQDFVNWLLAQK,
(hGIP(3-30)D15EH18A; SEQ ID NO: 81)
EGTFISDYSIAMEKIAQQDFVNWLLAQK,
(hGIP(3-30)K16AH18A; SEQ ID NO: 82)
EGTFISDYSIAMDAIAQQDFVNWLLAQK,
(hGIP(3-30)D15E; SEQ ID NO: 83)
EGTFISDYSIAMEKIHQQDFVNWLLAQK,
(hGIP(3-30)D15N; SEQ ID NO: 84)
EGTFISDYSIAMNKIHQQDFVNWLLAQK,
(hGIP(3-30)K16A; SEQ ID NO: 85)
EGTFISDYSIAMDAIHQQDFVNWLLAQK,
(hGIP(3-30)K16H; SEQ ID NO: 86)
EGTFISDYSIAMDHIHQQDFVNWLLAQK,
(hGIP(3-30)K16R; SEQ ID NO: 87)
EGTFISDYSIAMDRIHQQDFVNWLLAQK,
(hGIP(3-30)H18F; SEQ ID NO: 88)
EGTFISDYSIAMDKIFQQDFVNWLLAQK,
(hGIP(3-30)H18W; SEQ ID NO: 89)
EGTFISDYSIAMDKIWQQDFVNWLLAQK,
(hGIP(3-30)K30R SEQ ID NO: 90)
EGTFISDYSIAMDKIHQQDFVNWLLAQR,
(hGIP(3-30)K30H; SEQ ID NO: 91)
EGTFISDYSIAMDKIHQQDFVNWLLAQH,
and
a variant of any one of the above peptides, wherein the amino acid sequence of the variant differs from SEQ ID NO: 79 to SEQ ID NO: 91 in that the amino acid sequence of the variant comprises one, two, three, four or five amino acid substitutions.
41 . The peptide according to claim 29 , wherein said peptide is C-terminally amidated (—NH 2 ) and/or N-terminally acetylated (COCH 3 ).
42 . A nucleic acid construct encoding a peptide selected from the group consisting of
a peptide consisting of 28 contiguous amino acids of amino acid sequence
(GIP3-30; SEQ ID NO: 74)
EGTFISDYSIAM X 0a X 0b I X 1 QQDFVNWLLAQ X 2 ,
a peptide consisting of 27 contiguous amino acids of amino acid sequence
(GIP4-30; SEQ ID NO: 75)
GTFISDYSIAM X 0a X 0b I X 1 QQDFVNWLLAQ X 2 ,
a peptide consisting of 26 contiguous amino acids of amino acid sequence
(GIP5-30; SEQ ID NO: 76)
TFISDYSIAM X 0a X 0b I X 1 QQDFVNWLLAQ X 2 ,
wherein X 0a , X 0b , X 1 and X 2 are individually any amino acid, and
a variant of any of the above peptides having at least 80% sequence identity to said peptide,
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR).
43 . The nucleic acid construct according to claim 42 , wherein
X 0a is selected from the group consisting of D and E; X 0b is selected from the group consisting of K, A, H, and R; X 1 is selected from the group consisting of H, R, A, K, F, and Y; and X 2 is selected from the group consisting of K, R, H, and A.
44 . The nucleic acid construct according to claim 42 , wherein said peptide is selected from the group consisting of:
a peptide consisting of 28 contiguous amino acids of sequence
(GIP3-30; SEQ ID NO: 11)
EGTFISDYSIAMDKI X 1 QQDFVNWLLAQ X 2 ,
a peptide consisting of 27 contiguous amino acids of sequence
(GIP4-30; SEQ ID NO: 28)
GTFISDYSIAMDKI X 1 QQDFVNWLLAQ X 2 ,
a peptide consisting of 26 contiguous amino acids of sequence
(GIP5-30; SEQ ID NO: 45)
TFISDYSIAMDKI X 1 QQDFVNWLLAQ X 2 ,
wherein X 1 is selected from the group consisting of H, R, A, K, F, and Y; and X 2 is selected from the group consisting of K, R, H, and A; and
a variant of any one of the above peptides, wherein the amino acid sequence of the variant differs from SEQ ID NO: 11, SEQ ID NO: 28 or SEQ ID NO: 45, in that the amino acid sequence of the variant comprises one, two, three, four or five amino acid substitutions,
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR).
45 . The nucleic acid construct according to claim 42 , wherein said peptide is selected from the group consisting of:
(hGIP3-30, SEQ ID NO: 1)
EGTFISDYSIAMDKIHQQDFVNWLLAQK,
(rGIP3-30, SEQ ID NO: 2)
EGTFISDYSIAMDKIRQQDFVNWLLAQK,
(mGIP3-30, SEQ ID NO: 3)
EGTFISDYSIAMDKIRQQDFVNWLLAQR,
(hGIP4-30, SEQ ID NO: 77)
GTFISDYSIAMDKIHQQDFVNWLLAQK,
(hGIP5-30, SEQ ID NO: 78)
TFISDYSIAMDKIHQQDFVNWLLAQK,
and
a variant of any one of the above peptides, wherein the amino acid sequence of the variant differs from SEQ ID NO: 1, SEQ ID NO: 2, SEQ ID NO: 3, SEQ ID NO: 77, or SEQ ID NO: 78, in that the amino acid sequence of the variant comprises one, two, three, four or five amino acid substitutions,
wherein said peptide or variant thereof is an antagonist of a GIP receptor (GIPR).
46 . The nucleic acid construct according to claim 42 , wherein said peptide is selected from the group consisting of
(hGIP(3-30)H18A; SEQ ID NO: 79)
EGTFISDYSIAMDKI A QQDFVNWLLAQK,
(hGIP(3-30)H18K; SEQ ID NO: 80)
EGTFISDYSIAMDKI K QQDFVNWLLAQK,
(hGIP(3-30)D15EH18A; SEQ ID NO: 81)
EGTFISDYSIAM E KI A QQDFVNWLLAQK,
(hGIP(3-30)K16AH18A; SEQ ID NO: 82)
EGTFISDYSIAMD A I A QQDFVNWLLAQK,
(hGIP(3-30)D15E; SEQ ID NO: 83)
EGTFISDYSIAM E KIHQQDFVNWLLAQK,
(hGIP(3-30)D15N; SEQ ID NO: 84)
EGTFISDYSIAM N KIHQQDFVNWLLAQK,
(hGIP(3-30)K16A; SEQ ID NO: 85)
EGTFISDYSIAMD A IHQQDFVNWLLAQK,
(hGIP(3-30)K16H; SEQ ID NO: 86)
EGTFISDYSIAMD H IHQQDFVNWLLAQK,
(hGIP(3-30)K16R; SEQ ID NO: 87)
EGTFISDYSIAMD R IHQQDFVNWLLAQK,
(hGIP(3-30)H18F; SEQ ID NO: 88)
EGTFISDYSIAMDKI F QQDFVNWLLAQK,
(hGIP(3-30)H18W; SEQ ID NO: 89)
EGTFISDYSIAMDKI W QQDFVNWLLAQK,
(hGIP(3-30)K30R SEQ ID NO: 90)
EGTFISDYSIAMDKIHQQDFVNWLLAQ R ,
and
(hGIP(3-30)K30H; SEQ ID NO: 91)
EGTFISDYSIAMDKIHQQDFVNWLLAQ H ,
and a variant of any one of the above peptides, wherein the amino acid sequence of the variant differs from SEQ ID NO: 79 to SEQ ID NO: 91 in that the amino acid sequence of the variant comprises one, two, three, four or five amino acid substitutions.
47 . The nucleic acid construct according to claim 42 , wherein said nucleic acid construct is comprised in a delivery vehicle.Join the waitlist — get patent alerts
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