Modified GIP peptide analogues
Inventors
Sparre-Ulrich, Alexander Hovard • SIVERTSEN, BJØRN BEHRENS • Riber, Ditte • Rosenkilde, Mette Marie
Assignees
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Publication Number
US-12187773-B2
Publication Date
2025-01-07
Expiration Date
Abstract
Disclosed are glucose-dependent insulinotropic peptide (GIP)-derived peptide analogues which are antagonists of the GIP receptor. These GIP peptide analogues are modified by comprising one or more individual amino acid substitutions and are fatty acid conjugated with/without a linker, so to have improved antagonistic activity and improved pharmacokinetic profile.
Core Innovation
The invention relates to glucose-dependent insulinotropic peptide (GIP) receptor antagonists. The GIP receptor antagonist is a GIP analogue selected from defined sequences based on SEQ ID NO: 1, 11, and 12, including functional variants with 1 to 4 individual amino acid substitutions at specified positions. The analogue is characterized by being an antagonist of the GIP receptor (GIPR).
The GIP analogue is modified by attaching a fatty acid molecule at the amino acid at position 18 of the referenced SEQ ID NO or a functional variant thereof. The attachment involves amino acid choices at position 18 and related side-chain constraints, including X1 being P, G, A, S, or pyroE, X2 being K or Orn, and X3 being R or E. The fatty-acid modification is further constrained to GIP analogues in which the peptide amino acid sequence is modified by fatty-acid attachment at position 18.
The invention further specifies that the fatty acid molecule and the peptide sequence variants can include defined structural constraints and optional linker/spacer elements for fatty-acid conjugation. Linkers/spacers include succinic-acid type spacers and peptide-based linkers such as γ-Glu-(AEEAc)n, with n in a defined range, as well as other specified linker moieties. The described embodiments include various acyl-group and diacyl/diacid structural depictions and allow selected amino-acid sequence variants that incorporate these lipid-conjugation architectures.
Claims Coverage
The independent claim basis covers 4 inventive features: GIPR-antagonist GIP analogue sequences, fatty-acid attachment at position 18, defined sequence variants with limited substitutions, and therapeutic treatment claims for specified conditions. Dependent material further refines the fatty-acid, linker, and sequence constraints.
GIP analogue antagonist of GIPR with defined SEQ ID NO:1-derived substitutions and fatty-acid attachment at position 18
A GIP analogue consisting of the amino acid sequence of SEQ ID NO: 1, including functional variants with 1 to 4 individual amino acid substitutions at positions 4 to 15, 17 and 19 to 29, wherein X1 is P, G, A, S, or pyroE, X2 is K or Orn, and X3 is R or E; wherein the amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18; and wherein the GIP analogue is an antagonist of the GIP receptor (GIPR).
GIP analogue antagonist of GIPR with defined SEQ ID NO:11 substitutions and fatty-acid attachment at position 18
A GIP analogue consisting of the amino acid sequence of SEQ ID NO: 11, including functional variants with 1 to 4 individual amino acid substitutions at positions 4 to 17 and 19 to 29, wherein X2 is K or Orn and X3 is R or E; wherein the peptide amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18; and wherein the GIP analogue is an antagonist of GIPR.
GIP analogue antagonist of GIPR with defined SEQ ID NO:12 substitutions and fatty-acid attachment at position 18
A GIP analogue consisting of the amino acid sequence of SEQ ID NO: 12, including functional variants with 1 to 4 individual amino acid substitutions at positions 3 to 30; wherein the amino acid sequence is modified by attaching a fatty acid molecule at the amino acid at position 18; wherein X2 is K or Orn and the remaining defined position is consistent with the SEQ ID NO:12 pattern; and wherein the GIP analogue is an antagonist of GIPR.
Acyl chain length constraint for attached fatty acid
The GIP analogue where the fatty acid molecule contains an acyl group of the formula CH3(CH2)nCO— where n is an integer from 4 to 24.
Lipid attachment to epsilon amino group of lysine at position 18
The GIP analogue where a fatty acid molecule is attached at the epsilon amino group of the lysine side chain at position 18, either directly or through a linker.
Defined linker moiety set and linker length range
The GIP analogue where the linker comprises one or more specified moieties including α/γ/ω-amino acids, specified amino-acid-containing groups including γ-aminobutanoyl, γ-Glu, β-Asp, β-Ala, an N-terminal Gly dipeptide, and an [8-amino-3,6-dioxaoctanoic acid]n moiety with n between 1 and 50.
Selected enumerated SEQ ID variants with specified lipid/linker patterns
A GIP analogue of claim 1 selected from multiple listed amino-acid sequence variants characterized by differing N-terminal modifications and side-chain options, with specified linker/acid moieties including C16-diacid or C18-diacid and γ-Glu conjugates, and allowing 1 or 2 individual amino acid substitutions at positions 4 to 15, 17 and 19 to 29.
Therapeutic treatment of metabolic and cardiovascular conditions
Treating a condition selected from metabolic syndrome, obesity, overweight, obesity-related disorder, pre-diabetes, diabetes mellitus (type 1 or type 2), diabetes-related disorder, insulin resistance, hyperglycemia, elevated VLDL triglyceride, low HDL, fatty acid metabolism disorder, cardiovascular disease, elevated blood pressure, and atherosclerosis by administering a therapeutically effective amount of a GIP analogue of claim 1 to an individual in need thereof.
Across the provided claims, the coverage centers on GIPR antagonist GIP analogues with defined SEQ ID NO: 1/11/12-derived sequences and functional variants, modified by attaching a fatty acid molecule at position 18. Additional constraints specify acyl chain length, lysine-position attachment and linker presence, permitted linker moieties and linker length, selected enumerated sequence variants with lipid/linker patterns, and therapeutic treatment of specified metabolic and cardiovascular conditions.
Stated Advantages
Unexpected selectivity of selected acylated variants as GIPR antagonists versus other receptors including GLP-1R, GLP-2R, glucagon receptor, and secretin receptor.
Retained or improved antagonistic potency as described by IC50/pIC50 outcomes for selected acylated variants.
Improved elimination half-life for selected acylated variants as described in vivo-like elimination half-life outcomes.
Provides GIPR antagonism of glucose-dependent insulinotropic peptide (GIP) analogues.
Exhibits antagonist activity as indicated by inhibition activity and described “silent antagonist”/low agonistic activity.
Documented Applications
Treating a condition selected from metabolic syndrome, obesity, overweight, obesity-related disorder, pre-diabetes, diabetes mellitus (type 1 or type 2), diabetes-related disorder, insulin resistance, hyperglycemia, elevated VLDL triglyceride, low HDL, fatty acid metabolism disorder, cardiovascular disease, elevated blood pressure, and atherosclerosis by administering a therapeutically effective amount of a GIP analogue as defined.
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