Modified gip peptide analogs

Abstract

Disclosed are glucose-dependent insulinotropic peptide (GIP) derived peptide analogs that are antagonists of the GIP receptor. These GIP peptide analogs are modified by the inclusion of one or more individual amino acid substitutions and are conjugated to a fatty acid with / without a linker, thereby having improved antagonistic activity and improved pharmacokinetic profiles.

Description

Technical Field

[0001] The present invention relates to glucose-dependent insulinotropic peptide (GIP)-derived peptide analogs that are GIP receptor antagonists. These GIP peptide analogs are modified by comprising one or more individual amino acid substitutions and are conjugated to fatty acids with or without linkers, thereby having improved antagonistic activity and improved pharmacokinetic profiles. Background Art

[0002] Glucose-dependent insulinotropic peptide (GIP) is a hormone secreted from intestinal K cells after a meal. 1 Like its sister hormone, glucagon-like peptide 1 (GLP-1), GIP is a potent insulin secretagogue. 2 Glucagon inhibition with GLP-1 3，4 In contrast, GIP has been shown to exhibit glucagon-releasing properties under certain conditions ( 3，5-13 The association between rodent GIPR (GIP receptor) and obesity has heightened interest in understanding the biology of GIP. 14-21 In humans, although less clear, there is also evidence for a role for GIP in fat metabolism, as demonstrated by the expression of GIPR in adipose tissue. 22 Association between high BMI and elevated GIP levels 22，23 GIP administration increases adipose tissue blood flow and TAG (triglyceride) deposition in high insulin and high glucose states 24 Decreased basal and postprandial GIP levels were observed in obese children on a diet 25 , and elevated fasting GIP levels were observed in healthy young men consuming a high-fat diet 26 .

[0003] Therefore, in addition to the general demand of researchers who have witnessed the progress in the understanding of GLP-1 after the discovery of the GLP-1 receptor antagonist exendin (9-39), 27，28 In addition to its potential as an anti-obesity agent, it has also attracted more attention to the development of effective GIPR antagonists. Many different strategies have been adopted to antagonize the function of GIP, such as small molecule receptor antagonists 29 , immunity against GIP 30-32 Various truncations and mutations of GIP molecules with antagonistic properties 33-39 and recently, potent antagonist antibodies targeting GIPR 40 .

[0004] Under physiological conditions, the 42-amino acid hormone GIP is degraded by dipeptidyl peptidase 4 (DPP-4), which cleaves the GIP molecule at the third position to yield GIP3-42. Synthetic porcine GIP3-42 did not exhibit antagonist properties in porcine or perfused rat pancreas at physiological concentrations, but it antagonized human GIPR in vitro. 41 Many peptide hormones undergo post-translational modifications to give rise to various biological forms with varying lengths and amino acid modifications. 42，43 Thus, GIP1-30 has been shown to be the result of post-translational processing 44 , and it is an agonist of GIPR 33，45 If GIP1-30 is secreted into the human circulation, DPP-4-catalyzed cleavage will produce GIP3-30.

[0005] US 7,875,587 discloses GIP receptor antagonists derived from GIP (1-42) with enhanced resistance to degradation of DPP-4, and its use in treating insulin resistance and obesity. In WO 2004 / 067548, DPP-4 metabolites are modified by covalent coupling of pharmacophores to achieve a longer half-life associated with peptide metabolites, and retain the biological activity of cleavage peptides similar to natural peptides (including GIP). WO 2012 / 055770 discloses GIP (3-42) as an endogenous metabolite, which is easy to clear and has a GIPR antagonist effect, while GIP (2-30) is an example of a truncated GIP analogue with GIPR agonist activity. WO 1998 / 24464 discloses antagonist GIP (7-30).

[0006] WO 2016 / 034186 and Hansen et al. 2016 disclose the antagonists GIP (3-30) and GIP (5-30). Pathak et al. 2015 disclose GIP (3-30), whose C-terminus is modified with a 9-amino acid Cex from exendin (1-39) and the lysine residue is modified with a palmitoyl group.

[0007] A range of different approaches have been used to modify the structure of GLP-1 compounds to provide a longer duration of action in vivo. These include the introduction of lipophilic substituents into amino acid residues (WO 96 / 29342 and WO 98 / 08871) and acylated GLP-1 analogs (WO 00 / 34331). WO 02 / 46227 discloses GLP-1 and exendin-4 analogs fused to human serum albumin to extend their half-life in vivo. Summary of the Invention

[0008] The inventors have identified GIP peptides that are antagonists of GIPRs, comprising one or more individual substitutions that result in GIP peptides with improved antagonistic properties. The GIP peptides of the present disclosure are acylated to increase half-life and in vivo stability. The GIP peptides of the present disclosure are also N-terminally truncated compared to native GIP(1-42) and do not contain at least the first two amino acids in positions 1 and 2 of GIP(1-42). The inventors have further surprisingly discovered that acylated longer GIP peptides (such as peptides comprising one or more of the GIP(31-42) residues or peptides comprising one or more residues of exendin-4 attached to the C-terminus of any of GIP3-30, GIP5-30, and GIP6-30) retain or even exhibit improved GIPR antagonistic properties and / or ultralong in vivo half-life and / or increased selectivity. This makes them potentially useful in a range of therapeutic applications.

[0009] In one aspect, the present disclosure relates to glucose-dependent insulinotropic peptide (GIP) analogs consisting of the amino acid sequence SEQ ID NO: XX:

[0010]

[0011] wherein X1 and X2 are independently any amino acid or are omitted;

[0012] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0013] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0014] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E).

[0015] In the case of GIP (3-30) / GIP (5-30) / GIP (6-30) and analogs thereof extended with amino acid residues from the C-terminal portion of exendin-4 or GIP (1-42), such as, for example, GPSSGAPPPS, PSSGAPPPS or GKKNDW, an important advantage of the above aspects is that the in vivo half-life is extended to a surprisingly high extent compared to the corresponding non-extended analogs. In particular, this may be the case when the extended GIP analogs are lipidated at specific positions, such as, for example, position 18 for extended GIP (3-30) analogs and position 11 for extended GIP (5-30) analogs.

[0016] Another important advantage of the above aspects is that the antagonistic properties may be increased and / or the selectivity with respect to GIP receptor agonism may be increased when GIP (3-30) / GIP (5-30) / GIP (6-30) and analogs thereof are extended with amino acid residues from the C-terminal portion of exendin-4 or GIP (1-42), such as, for example, GPSSGAPPPS, PSSGAPPPS or GKKNDW. Thus, when the extended GIP analogs are lipidated at specific positions, such as, for example, position 18 for extended GIP (3-30) analogs and position 11 for extended GIP (5-30) analogs, improved antagonism may be obtained, while also increasing the half-life to a surprising extent.

[0017] A further important point of the above aspects is the increased selectivity with respect to activation or inhibition of other receptor members of the family B GPCRs, such as, for example, GLP-1R and glucagon-R, in case GIP(3-30) / GIP(5-30) / GIP(6-30) and their analogs are extended with amino acid residues from the C-terminal part of exendin-4 or GIP(1-42), such as, for example, GPSSGAPPPS, PSSGAPPPS or GKKNDW. BRIEF DESCRIPTION OF THE DRAWINGS

[0018] Figure 1. GIP(3-30) antagonists with C-terminal extensions (such as AT631) exhibit an ultra-long T of over 30 hours compared to non-C-terminally extended GIP(3-30) antagonists (such as the analog AT158). 1 / 2Pigs were administered subcutaneously the lipidated GIP(3-30)NH2 analog AT158 and the lipidated GIP(3-30)Cex(31-39) analog AT631, and blood samples were collected from a central venous catheter at the indicated time points. The half-life of AT631 was determined based on RIA (see "Materials and Methods"), and the percentage of Cmax was plotted against time (in hours). AT631 showed a surprisingly longer half-life than AT158.

[0019] definition

[0020] The term "affinity" refers to the strength of binding between a receptor and its ligand(s). In this context, the affinity of a peptide antagonist for its binding site (Ki) will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using Schild regression in functional studies or by radioligand binding studies such as 1) competitive binding experiments using the Cheng-Prusoff equation, 2) saturation binding experiments using the Scatchard equation, or 3) determining association and dissociation rates (K, respectively). on and K off ) was determined by kinetic studies.

[0021] The term "IC50" stands for half-maximal inhibitory concentration (IC50), which is a measure of the effectiveness of a substance in inhibiting a specific biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (e.g., antagonist) is needed to inhibit a given biological process (or component of a process, i.e., an enzyme, cell, cell receptor, or microorganism) by half. In pharmacological studies, it is often used as a measure of the potency of antagonist drugs. IC50 represents the concentration of drug required for 50% inhibition in vitro. In this context, the IC50 value may also refer to the concentration of drug at which 50% of a radiolabeled ligand is displaced from the receptor, which is an indicator of drug affinity in competition binding experiments.

[0022] In this context, the term "agonist" refers to a peptide or analog thereof that is capable of binding to a receptor and activating downstream signaling cascades.

[0023] In this context, the term "antagonist" refers to a GIP peptide analogue that is capable of binding to and blocking or reducing an agonist-mediated receptor response as defined herein. After binding to the receptor, the antagonist itself generally does not cause a biological response. Antagonists have affinity for their cognate receptors but have no efficacy, and the binding of the antagonist to its receptor inhibits the function of an agonist or inverse agonist on the receptor. Antagonists mediate their effects by binding to the active (orthosteric) site or allosteric site on the receptor, or they can interact at a unique binding site that is not normally involved in the biological regulation of receptor activity. Antagonist activity can be reversible or irreversible, depending on the lifespan of the antagonist-receptor complex, which in turn depends on the nature of the antagonist-receptor binding. Most drug antagonists typically achieve their effectiveness by competing with endogenous ligands or substrates at a structurally determined binding site on the receptor. Antagonists can be competitive, non-competitive, uncompetitive, silent antagonists, partial agonists or inverse agonists.

[0024] Competitive antagonists (also known as overcoming antagonists) reversibly bind to the receptor at the same binding site (i.e., active site) as the endogenous ligand or agonist, but do not activate the receptor. Agonists and antagonists therefore "compete" for the same binding site on the receptor. Once bound, the antagonist blocks agonist binding. The activity level of the receptor is determined by the relative affinity of each molecule for the site and its relative concentration. High concentrations of competitive antagonists will increase the proportion of receptors occupied by the antagonist.

[0025] The term "noncompetitive antagonism" (also called non-surmountable or insurmountable antagonism) describes two different phenomena with functionally similar results: one in which the antagonist binds to the active site of the receptor, and the other in which the antagonist binds to the allosteric site of the receptor. Unlike competitive antagonists, which affect the amount of agonist required to achieve a maximal response but do not affect the magnitude of that maximal response, noncompetitive antagonists reduce the magnitude of the maximal response that can be achieved with any amount of agonist.

[0026] The term "silent antagonist" refers to a competitive receptor antagonist that has absolutely no intrinsic activity to activate the receptor.

[0027] The term "partial agonist" refers to an agonist that may vary in the magnitude of the functional response it elicits after maximal receptor occupancy at a given receptor. In the presence of a full agonist (or a more potent agonist), a partial agonist can act as a competitive antagonist because it competes with the full agonist for receptor occupancy, resulting in a net reduction in receptor activation compared to that observed with the full agonist alone.

[0028] The term "inverse agonist" refers to a ligand that binds to the same receptor binding site as an agonist and antagonizes its effects, such as a GIP peptide analog. In addition, an inverse agonist can also inhibit the basal activity of a constitutively active receptor.

[0029] As used herein, the term "glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist" refers to a compound, such as a peptide, that is capable of binding to and blocking or reducing agonist-mediated GIPR responses.

[0030] The term "individual" refers to a vertebrate, ie, a specific member of a mammalian species, preferably a primate, including humans. As used herein, "subject" and "individual" are used interchangeably.

[0031] An "isolated peptide" is a peptide that has been separated and / or recovered from a component of its natural environment (typically a cellular environment) and is substantially free from contamination by cellular components (such as carbohydrates, lipids, or other protein impurities associated with the polypeptide in nature). Typically, a preparation of isolated peptide contains the peptide in a highly purified form (i.e., at least about 80% pure, at least about 90% pure, at least about 95% pure, greater than 95% pure, or greater than 99% pure). The term "isolated" does not exclude the presence of the same peptide in alternative physical forms (such as dimers, tetramers, or alternatively glycosylated or derivatized forms).

[0032] "Amino acid residue" can be a natural or non-natural amino acid residue connected by a peptide bond or a bond different from a peptide bond. The amino acid residue can be in D- or L-configuration. The amino acid residue comprises an amino terminal portion (NH2) and a carboxyl terminal portion (COOH) separated by a central portion comprising a carbon atom or a chain of carbon atoms, at least one of which comprises at least one side chain or functional group. NH2 refers to the amino group present at the amino terminal of an amino acid or peptide, while COOH refers to the carboxyl group present at the carboxyl terminal of an amino acid or peptide. The general term amino acid includes natural amino acids and non-natural amino acids. Natural amino acids of the standard nomenclature as listed in J.Biol.Chem., 243:3552-59 (1969) and adopted in 37 CFR, Section 1.822 (b) (2) belong to the group of amino acids listed here: Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N and C. Non-natural amino acids are those not listed immediately above. Furthermore, non-natural amino acid residues include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues.

[0033] "Equivalent amino acid residues" refer to amino acid residues that can replace another amino acid residue in a polypeptide without substantially changing the structure and / or function of the polypeptide. Thus, equivalent amino acids have similar properties, such as side chain volume, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic), and carbon molecule side chain organization (aromatic / aliphatic). Thus, "equivalent amino acid residues" can be considered "conservative amino acid substitutions," and are substitutions of amino acids whose side chains have similar biochemical properties and therefore do not affect the function of the peptide.

[0034] Among common amino acids, for example, "conservative amino acid substitutions" can also be illustrated by substitutions between amino acids within the following groups: (1) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine, and tryptophan, (3) serine and threonine, (4) aspartic acid and glutamate, (5) glutamine and asparagine, and (6) lysine, arginine, and histidine.

[0035] In one embodiment, one amino acid in the amino acid groups indicated below may be substituted by another in the amino acid groups indicated herein below, within the meaning of the term "equivalent amino acid substitutions" as used herein:

[0036] i) amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Tyr, and Cys),

[0037] ii) amino acids with non-polar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Pro, and Met),

[0038] iii) Amino acids with aliphatic side chains (Gly, Ala, Val, Leu, Ile)

[0039] iv) Amino acids with cyclic side chains (Phe, Tyr, Trp, His, Pro)

[0040] v) Amino acids with aromatic side chains (Phe, Tyr, Trp)

[0041] vi) Amino acids with acidic side chains (Asp, Glu)

[0042] vii) Amino acids with basic side chains (Lys, Arg, His)

[0043] viii) Amino acids with amide side chains (Asn, Gln)

[0044] ix) Amino acids with hydroxyl side chains (Ser, Thr, Tyr)

[0045] x) Amino acids with sulfur-containing side chains (Cys, Met)

[0046] xi) Neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr)

[0047] xii) hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and

[0048] xiii) Hydrophobic amino acids (Leu, Ile, Val)

[0049] In addition, the serine residues of the peptides of the present disclosure may be substituted with an amino acid selected from Gln, Asn and Thr (all amino acids having polar uncharged side chains); and independently thereof, the glycine residue (Gly) may be substituted with an amino acid selected from Ala, Val, Leu and Ile; and independently thereof, the arginine residue (Arg) may be substituted with an amino acid selected from Lys and His (all having positively charged side chains); and independently thereof, the lysine residue (Lys) may be substituted with an amino acid selected from Arg and His; and independently thereof, the methionine residue (Met) may be substituted with an amino acid selected from Leu, Pro, Ile, Val, Phe, Tyr and Trp (all having hydrophobic side chains); and independently thereof, the glutamine residue (Gln) may be substituted independently with an amino acid selected from Asp, Glu and Asn; and independently thereof, the alanine residue (Ala) may be substituted independently with an amino acid selected from Gly, Val, Leu and Ile.

[0050] In the absence of designation of the L or D form (optical isomer), it is understood that the amino acid in question has a natural L form (see Pure & Appl. Chem. Vol. (56(5) pp. 595-624 (1984)) or D form, so that the peptide formed can be composed of amino acids in the L form, the D form, or a mixed L and D form sequence.

[0051] As used herein, a glutamate (Glu) mimetic is a moiety having two carboxyl functional groups separated by three carbon atoms. Examples are β-Glu, γ-Glu or glutaric acid.

[0052] A "functional variant" of a peptide is a peptide that is capable of performing substantially the same function as the peptide of which it is a functional variant. Specifically, a functional variant can substantially bind to the same molecule (such as a receptor) as the peptide of which it is a functional variant or perform the same receptor-mediated reaction as the peptide of which it is a functional variant. A functional variant of a "glucose-dependent insulinotropic peptide (GIP) analog" is a peptide that is capable of binding to the GIPR and activating or inhibiting GIPR downstream signaling (such as cAMP production). A functional variant of a glucose-dependent insulinotropic peptide receptor (GIPR) antagonist is a peptide that is capable of binding to the GIPR and inhibiting or reducing agonist-mediated GIPR signaling (such as cAMP production).

[0053] A "biologically active agent" (i.e., a biologically active substance / agent) is any agent, drug, compound, composition of matter, or mixture that provides some pharmacological (usually beneficial) effect that can be demonstrated in vivo or in vitro. It refers to GIP peptide analogs as defined herein, as well as compounds or compositions comprising these. As used herein, this term further includes any physiologically or pharmacologically active substance that produces a local or systemic effect in a subject.

[0054] As used herein, the term "drug" or "pharmaceutical agent" includes a biologically, physiologically or pharmacologically active substance that acts locally or systemically on the human or animal body.

[0055] As used herein, the terms "treatment" and "treating" refer to the management and care of a patient for the purpose of combating a condition, disease, or disorder. The term is intended to include the full range of treatments for a given condition suffered by a patient, and equally refers to curative therapy, prophylactic / preventative therapy, and palliative or palliative therapy, such as the administration of the peptide or composition for the following purposes: alleviating or relieving symptoms or complications; delaying the progression of a condition, partially preventing clinical manifestations, disease, or disorder; curing or eliminating a condition, disease, or disorder; alleviating or relieving, and regressing (whether partial or total), whether detectable or undetectable, a condition or symptom; and / or preventing or reducing the risk of acquiring a condition, disease, or disorder, wherein "preventing" or "prevention" is understood to refer to the management and care of a patient for the purpose of hindering the development of a condition, disease, or disorder, and includes the administration of active compounds to prevent or reduce the risk of onset of symptoms or complications. As used herein, the term "alleviate" and variations thereof means that the extent and / or undesirable manifestations of a physiological condition or symptom are reduced and / or the time course of progression is slowed or prolonged, compared to when the compositions of the present invention are not administered.

[0056] The individual to be treated is preferably a mammal, in particular a human. However, the treatment of animals such as mice, rats, dogs, cats, cows, horses, sheep and pigs is also encompassed herein.

[0057] "Individual in need" refers to an individual who can benefit from the present disclosure. In one embodiment, the individual in need is a diseased individual, wherein the disease can be a metabolic disease or disorder (such as obesity or diabetes), a bone density disorder, or cancer.

[0058] Treatment according to the invention may be prophylactic, palliative and / or curative.

[0059] A "pharmacologically effective amount," "pharmaceutically effective amount," or "physiologically effective amount" of a biologically active agent is the amount of the active agent present in the pharmaceutical composition described herein that is required to provide the desired level of the active agent in the bloodstream or at the site of action (e.g., lungs, gastric system, colorectal system, prostate, etc.) of the treated subject to produce the desired physiological response when the composition is administered. In this context, the biologically active agent refers to a GIP peptide analog as disclosed herein.

[0060] As used herein, "co-administering" or "co-administration" refers to the administration of one or more GIP peptide analogs of the present invention and a state-of-the-art pharmaceutical composition. The at least two components may be administered separately, sequentially or simultaneously. DETAILED DESCRIPTION

[0061] GIP refers to glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory peptide (or polypeptide). As used herein, the abbreviation GIP or hGIP is human GIP (Uniprot accession number P09681). GIP is derived from a 153 amino acid precursor protein and circulates as a biologically active 42 amino acid peptide. It is synthesized by the K cells of the duodenal mucosa and the jejunum of the gastrointestinal tract.

[0062] GIPR (or GIP receptor) refers to gastric inhibitory polypeptide receptor. These seven transmembrane proteins are found at least in the beta cells of the pancreas. As used herein, the abbreviation GIPR or hGIPR is human GIPR (Uniprot accession number P48546).

[0063] The inventors have identified GIP peptides that are antagonists of GIPRs, comprising one or more individual substitutions that result in GIP peptides with improved antagonistic properties. The GIP peptides of the present disclosure are acylated to increase half-life and in vivo stability. The inventors have further surprisingly found that acylated longer GIP peptides (such as peptides comprising one or more of the GIP (31-42) residues or peptides comprising one or more residues of exendin-4 attached to the C-terminus of any of GIP3-30, GIP5-30, and GIP6-30) retain GIPR antagonistic properties. This makes them potentially useful in a range of therapeutic applications.

[0064] In one embodiment, Exendin-4 is a peptide having the amino acid sequence HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS (SEQ ID NO: ).

[0065] GIP peptide

[0066] The present invention relates to GIP peptide analogs comprising a GIP peptide fragment containing one or more individual substitutions (having unprecedented GIPR antagonistic properties) and one or more fatty acids attached thereto to increase the half-life of the peptide while retaining GIPR antagonistic properties.

[0067] Extended GIP peptide analogs

[0068] In one aspect of the present disclosure there is provided a glucose-dependent insulinotropic peptide (GIP) analog consisting of the amino acid sequence SEQ ID NO: XX:

[0069]

[0070] wherein X1 and X2 are independently any amino acid or are omitted;

[0071] or a functional variant thereof, wherein the variant has 1 to 8 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0072] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0073] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E).

[0074] In one aspect of the present disclosure there is provided a glucose-dependent insulinotropic peptide (GIP) analog consisting of the amino acid sequence SEQ ID NO: XX:

[0075]

[0076] wherein X1 and X2 are independently any amino acid or are omitted;

[0077] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0078] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0079] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E).

[0080] In one embodiment, the present disclosure provides a glucose-dependent insulinotropic peptide (GIP) analog selected from the group consisting of:

[0081] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0082]

[0083] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0084]

[0085] and

[0086] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0087]

[0088] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of SEQ ID NO: and SEQ ID NO:, wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues at positions 4 to 29 of any one of SEQ ID NO: and SEQ ID NO: or a functional variant thereof comprising between 1 and 4 amino acid substitutions in any one of SEQ ID NO: and SEQ ID NO:,

[0089] where Z is:

[0090] Glycine or proline,

[0091] Excerpts from the following:

[0092] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0093] Excerpts from the following:

[0094] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, selected from the following fragments:

[0095] or

[0096] Excerpts from the following:

[0097] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0098] Excerpts from the following:

[0099] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, PSSGAPPPS, or a variant thereof comprising 1 or 2 single amino acid substitutions at any of the amino acid residues.

[0100] In the case of GIP antagonists GIP (3-30) / GIP (4-30) / GIP (5-30) / GIP (6-30) and analogs thereof extended with amino acid residues from the C-terminal portion of exendin-4 or GIP (1-42) (such as, for example, GPSSGAPPPS, PSSGAPPPS or GKKNDW), an important advantage of the above aspects is that the in vivo half-life is extended to a surprisingly high extent compared to the corresponding non-extended analogs. In particular, this may be the case when the extended GIP (3-30) analogs are lipidated at specific positions (such as, for example, at positions 11, 12, 17 and 18 for extended GIP (3-30), GIP (4-30) GIP (5-30) and GIP (6-30) analogs). Thus, a C-terminal extension of, for example, GPSSGAPPPS, PSSGAPPPS, GKKNDW or fragments thereof and lipidation at specific positions can lead to an improved antagonistic effect and at the same time to a surprisingly large extent an improved half-life of more than 5 or 10 hours or even more than 15 or 20 hours compared to the corresponding sequence without the C-terminal extension.

[0101] As used herein, "GIP (3-30)" refers to a GIP peptide analogue consisting of residues 3 to 30 of GIP or a functional variant thereof, such as SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30) and functional variants thereof. As used herein, "GIP (4-30)" refers to a GIP peptide analogue consisting of residues 4 to 30 of GIP or a functional variant thereof, such as SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30) and functional variants thereof. As used herein, "GIP (5-30)" refers to a GIP peptide analogue consisting of residues 5 to 30 of GIP (such as SEQ ID NO: GIP (5-30)) or a functional variant thereof. As used herein, "GIP (6-30)" refers to a GIP peptide analog consisting of residues 6 to 30 of GIP (such as SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0102] In one embodiment, the peptide is C-terminally carboxylated (-COOH).

[0103] Without being bound by any theory, the free C-terminal carboxylic acid may be able to help increase binding to albumin and thus unexpectedly further extend the in vivo half-life.

[0104] Another important advantage of the above aspect is that the antagonistic properties may be increased and / or the selectivity with respect to GIP receptor agonism may be increased in case the GIP antagonists of SEQ ID NO: GIP(3-30)X1-X2, SEQ ID NO: GIP(3-30)X2, SEQ ID NO: GIP(3-30)X1, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X2, SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30) and analogs thereof are extended with amino acid residues of the C-terminal part of exendin-4 or GIP(1-42), such as GPSSGAPPPS, PSSGAPPPS or GKKNDW. Since GIP(3-42) is a poorer antagonist than GIP(3-30) [Hansen et al. 2016 Br J Pharmacol], it was unexpected that the antagonism of AT631 with a C-terminal extension derived from exendin-4 (-PSSGAPPPS) was improved. Furthermore, exendin-4 is a GLP-1 agonist, and therefore the improvement in GIP antagonism by extension of analogs of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) with amino acid residues from the C-terminal portion of exendin-4 is highly unexpected.

[0105] A further important advantage of the above aspects is the increased selectivity with respect to activation or inhibition of other receptor members of GPCR family B, such as GLP-1R and glucagon-R, in case the GIP antagonists of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)X1-X2, SEQ ID NO: GIP(3-30)X2, SEQ ID NO: GIP(3-30)X1, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X2, SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30) and analogs thereof are extended with amino acid residues from the C-terminal part of exendin-4 or GIP(1-42), such as GPSSGAPPPS, PSSGAPPPS or GKKNDW.

[0106] In one embodiment, provided are GIP antagonists of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), and analogs thereof, which are extended with amino acid residues from the C-terminal portion of exendin-4 or GIP (1-42), such as GPSSGAPPPS, PSSGAPPPS, or GKKNDW, and are C-terminally carboxylated.

[0107] In one embodiment, a GIP peptide analog or functional variant thereof is provided as an isolated peptide.

[0108] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof as disclosed herein, wherein

[0109] The amino acid at position 5 is T or omitted;

[0110] The amino acid at position 9 is selected from the group consisting of D, E, and T;

[0111] The amino acid at position 11 is selected from the group consisting of S, K, and A;

[0112] the amino acid at position 12 is selected from I, K, and 2-aminoisobutyric acid (Aib);

[0113] The amino acid at position 13 is selected from A and Aib;

[0114] the amino acid at position 14 is selected from the group consisting of M, K, E, S, L, and Nle;

[0115] The amino acid at position 15 is selected from D and E;

[0116] The amino acid at position 16 is selected from K and R;

[0117] the amino acid at position 17 is selected from I and K;

[0118] The amino acid at position 18 is selected from H and K;

[0119] The amino acid at position 20 is selected from the group consisting of Q and K;

[0120] The amino acid at position 21 is selected from D and E;

[0121] The amino acid at position 24 is selected from the group consisting of N, K, Q, and E;

[0122] The amino acid at position 28 is selected from A and E;

[0123] The amino acid at position 29 is selected from Q and G; and / or

[0124] The amino acid at position 30 is selected from the group consisting of K, R, G and A.

[0125] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 single amino acid substitution, such as 2 single amino acid substitutions, such as 3 single amino acid substitutions, such as 4 single amino acid substitutions at any amino acid residue of SEQ ID NO: XX.

[0126] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 single amino acid substitution, such as 2 single amino acid substitutions, for example 3 single amino acid substitutions, such as 4 single amino acid substitutions at any amino acid residue of SEQ ID NO: XX, wherein the substitutions are conservative amino acid substitutions.

[0127] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 2 separate amino acid substitutions, such as 2 to 3 separate amino acid substitutions, such as 3 to 4 separate amino acid substitutions, such as 4 to 5 separate amino acid substitutions, such as 5 to 6 separate amino acid substitutions, such as 6 to 7 separate amino acid substitutions, such as 7 to 8 separate amino acid substitutions at any amino acid residue of SEQ ID NO: XX.

[0128] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the GIP peptide analogue consists of the amino acid sequence SEQ ID NO: XX, and wherein X1 and X2 are omitted.

[0129] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the GIP peptide analogue consists of the amino acid sequence SEQ ID NO: XX, and the amino acid residues at positions X1, X2 and 5 are omitted. In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 7 individual amino acid substitutions, such as 1 individual amino acid substitution, such as 2 individual amino acid substitutions, such as 3 individual amino acid substitutions, such as 4 individual amino acid substitutions, such as 5 individual amino acid substitutions, such as 6 individual amino acid substitutions, such as 7 individual amino acid substitutions, at any one of amino acid residues 3 to 30 of SEQ ID NO: XX.

[0130] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 2 individual amino acid substitutions, such as 2 to 3 individual amino acid substitutions, such as 3 to 4 individual amino acid substitutions, such as 4 to 5 individual amino acid substitutions, such as 5 to 6 individual amino acid substitutions, such as 6 to 7 individual amino acid substitutions, such as 7 to 8 individual amino acid substitutions at any one of amino acid residues 3 to 30 of SEQ ID NO: XX.

[0131] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 2 individual amino acid substitutions, such as 2 to 3 individual amino acid substitutions, such as 3 to 4 individual amino acid substitutions, such as 4 to 5 individual amino acid substitutions, such as 5 to 6 individual amino acid substitutions, such as 6 to 7 individual amino acid substitutions, such as 7 to 8 individual amino acid substitutions at any one of amino acid residues 3, 4, 7, 8, 9, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 24, 28, 29 and 30 of SEQ ID NO: XX.

[0132] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 2 separate amino acid substitutions at any one of amino acid residues 4 to 10 of SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30).

[0133] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the functional variant has 1 to 2, such as 1 to 3, such as 2 to 3, individual amino acid substitutions at any one of amino acid residues 19 to 27 of SEQ ID NO: XX (such as any one of SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)).

[0134] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein at least one amino acid residue of the GIP peptide analogue of SEQ ID NO: XX is substituted by E.

[0135] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein at least one amino acid residue at any one of positions 9, 14, 15, 21, 24 and 28 is substituted by E, preferably at least one amino acid residue at any one of positions 9, 15, 21 and 24 of SEQ ID NO: XX is substituted by E.

[0136] Substitution of one or more amino acid residues of the peptide of SEQ ID NO: XX by E as defined herein is particularly advantageous, as it may result in increased antagonism, increased solubility, and / or increased stability of the substituted peptide.

[0137] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein X1 is an amino acid residue selected from E, S, G, V, 2-aminoisobutyric acid (Aib), P, D, γ-glutamic acid (γGlu), D-γ-glutamic acid (D-γGlu), β-glutamic acid (βGlu), pyroE (pyroglutamic acid), glutaric acid.

[0138] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein X1 is E.

[0139] In one embodiment, there is provided a GIP peptide analogue as disclosed herein or a functional variant thereof, wherein X1 is pyroE (pyroglutamic acid).

[0140] In one embodiment, a GIP peptide analog or functional variant thereof as disclosed herein is provided, wherein the E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as SEQ ID NO: XX) is substituted with any amino acid, such as an amino acid residue selected from the group consisting of S, G, V, 2-aminoisobutyric acid (Aib), P, D, γ-glutamic acid (γGlu), D-γ-glutamic acid (D-γGlu), β-glutamic acid (βGlu), pyroE (pyroglutamic acid), and glutaric acid. Glutaric acid, also known as pentanedioic acid, is a deaminoglutamic acid, i.e., a glutamic acid lacking an amino group. Glutaric acid is also known as a glutamate mimetic.

[0141] In one embodiment, there is provided a GIP peptide analogue as disclosed herein or a functional variant thereof, wherein X1 is E or glutaric acid.

[0142] GIP peptide analogs according to the present disclosure having an E at position 3 can be very effective antagonists against GIPR. However, having an E at position 3 may result in unstable compounds. Without wishing to be bound by theory, E at position 3 may form pyroGlu via cyclization between the amino group at the N-terminus and the side chain carboxylic acid of E. Therefore, substitution of E at position 3 may be advantageous. The inventors have discovered that an amino group at the N-terminus may not be necessary to obtain an effective antagonist.

[0143] Replacing the E at position 3 (i.e., the first amino acid from the N-terminus) with glutaric acid may be advantageous because glutaric acid has no amino group and therefore cannot form an N-terminal pyroGlu. The formation of pyroGlu may be an unwanted side reaction with glutamate. Replacing position 3 with glutaric acid may also increase potency. Glutaric acid is naturally produced in the body during the metabolism of some amino acids, including lysine and tryptophan.

[0144] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30)) is substituted by S (Ser).

[0145] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein the E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30)) is substituted by pyroE (pyroglutamic acid).

[0146] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30)) is substituted by P (Pro).

[0147] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30)) is substituted by G (Gly).

[0148] In one embodiment, a GIP peptide analogue or a functional variant thereof as disclosed herein is provided, wherein E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30)) is substituted by A (Ala).

[0149] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein X2 is an amino acid residue selected from G and E.

[0150] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein D at position 9 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0151] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein D at position 9 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0152] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the D at position 9 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof is substituted with an amino acid residue selected from E and T. An advantage of having an E at position 9 is that it may increase potency and / or physical stability, such as solubility. An E at position 9 may also prevent agonist activity.

[0153] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the S at position 11 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by any amino acid.

[0154] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the S at position 11 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0155] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the S at position 11 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid residue selected from A, K and Orn.

[0156] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the S at position 11 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid selected from A, R, K and Orn.

[0157] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the S at position 11 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by K or Orn.

[0158] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the I at position 12 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by any amino acid.

[0159] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the I at position 12 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0160] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the I at position 12 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid residue selected from K, Orn and 2-aminoisobutyric acid (Aib).

[0161] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the A at position 13 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0162] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the A at position 13 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0163] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the A at position 13 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof is substituted with 2-aminoisobutyric acid (Aib). The advantage of having Aib at position 13 is that the potency may be significantly improved. In addition, Aib at position 13 may also increase the stability of the peptide, such as in vivo stability or physical stability.

[0164] It has been observed that substitution of any of the amino acid residues at positions 12 and 13 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or functional variants thereof can further increase the stability and half-life of the GIP peptide analogs.

[0165] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the M at position 14 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0166] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the M at position 14 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0167] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the M at position 14 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid residue selected from L, norleucine (Nle), E, ​​S, K and Orn.

[0168] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the M at position 14 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof is substituted with an amino acid residue selected from L, norleucine (Nle) and K. In some embodiments, the amino acid at position 14 is L or Nle. Since M is susceptible to oxidation, it may be advantageous to replace it with another amino acid such as L, Nle or K (e.g., L or Nle).

[0169] In some embodiments, the amino acid at position 14 is L.

[0170] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein D at position 15 of any one of SEQ ID NO: XX, SEQ ID NO: SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0171] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein D at position 15 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0172] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the D at position 15 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), SEQ ID NO: (GIP6-30), or a functional variant thereof is substituted with E. The advantage of having E at position 15 is that potency and / or physical stability, such as solubility, may be increased. E at position 15 may also prevent agonist activity.

[0173] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein D at position 9 and / or position 15 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by E.

[0174] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein K at position 16 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0175] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein K at position 16 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid substitution.

[0176] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the K at position 16 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid selected from R, A and E.

[0177] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein K at position 16 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by R.

[0178] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the I at position 17 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0179] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the I at position 17 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0180] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the I at position 17 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by K or Orn.

[0181] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the H at position 18 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0182] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the H at position 18 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0183] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the H at position 18 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by an amino acid selected from A, R, K and Orn.

[0184] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the H at position 18 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by K or Orn.

[0185] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the S at position 11 and / or the H at position 18 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by K.

[0186] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein Q at position 20 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by any amino acid.

[0187] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the Q at position 20 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0188] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the Q at position 20 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by K or Orn.

[0189] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein D at position 21 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0190] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein D at position 21 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0191] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein D at position 21 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof is substituted with E. An advantage of having E at position 21 is that potency and / or physical stability, such as solubility, may be increased.

[0192] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the N at position 24 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0193] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the N at position 24 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0194] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the N at position 24 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by an amino acid selected from Q, A and E.

[0195] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the N at position 24 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof is substituted with E. The advantage of having E at position 24 is that physical stability, such as solubility, may be increased. It may also reduce sensitivity to aggregation.

[0196] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the A at position 28 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by any amino acid.

[0197] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the A at position 28 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0198] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein A at position 28 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by E.

[0199] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein Q at position 29 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by any amino acid.

[0200] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the Q at position 29 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by a conservative amino acid.

[0201] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein Q at position 29 of any one of SEQ ID NO:XX, SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:GIP(3-30)X1, SEQ ID NO:GIP(3-30), SEQ ID NO:GIP(4-30)X2, SEQ ID NO:GIP(4-30), SEQ ID NO:GIP(5-30), SEQ ID NO:GIP(6-30) or a functional variant thereof is substituted by G.

[0202] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein K at position 30 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by any amino acid.

[0203] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein K at position 30 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof is substituted by a conservative amino acid substitution.

[0204] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the K at position 30 of any one of SEQ ID NO: XX, SEQ ID NO: (GIP3-30 X1-X2), SEQ ID NO: (GIP3-30 X2), SEQ ID NO: (GIP3-30 X1), SEQ ID NO: (GIP3-30), SEQ ID NO: (GIP4-30 X2), SEQ ID NO: (GIP4-30), SEQ ID NO: (GIP5-30), SEQ ID NO: (GIP6-30), or a functional variant thereof is substituted by an amino acid selected from the group consisting of R, A, E and G, preferably by an amino acid selected from the group consisting of R, A and G.

[0205] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the amino acid residues at positions 9, 15, 21, and 24 are each independently an alpha helix stabilizing amino acid residue selected from A, L, E, and K.

[0206] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the GIP peptide analogue comprises at least one substitution to K and one substitution to E or Aib at any one of amino acid residues 3 to 30 of SEQ ID NO: XX (such as any one of SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)).

[0207] In one embodiment, a GIP peptide analogue or a functional variant thereof is provided, wherein the GIP peptide analogue comprises at least one substitution to K and one substitution to E or Aib at any of amino acid residues 3 to 30 of SEQ ID NO: XX (such as any of SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)), wherein at least one amino acid residue at position 11, 14 and / or 18 is substituted to K, and wherein at least one amino acid residue at position 9, 15, 21 and / or 24 is substituted to E.

[0208] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein

[0209] The amino acid at position 5 is T;

[0210] The amino acid at position 6 is F;

[0211] The amino acid at position 10 is Y;

[0212] The amino acid at position 22 is F;

[0213] The amino acid at position 23 is V;

[0214] The amino acid at position 25 is W;

[0215] The amino acid at position 26 is L;

[0216] The amino acid at position 27 is L.

[0217] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 5 is T.

[0218] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 6 is F.

[0219] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 7 is 1.

[0220] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 10 is Y.

[0221] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 22 is F.

[0222] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 23 is V.

[0223] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 25 is W.

[0224] In one embodiment, a GIP peptide analogue (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 26 is L.

[0225] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 27 is L.

[0226] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid residues at positions 29 and 30 are not both G.

[0227] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein only one of the amino acid residues at positions 29 and 30 is G.

[0228] In one embodiment, a GIP peptide analogue (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the 29th and 30th amino acid residues are independently selected from Q, E and K.

[0229] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 29 is Q.

[0230] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) or a functional variant thereof is provided, wherein the amino acid at position 30 is K.

[0231] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) is provided, wherein

[0232] The amino acid residue at position 3 is E or glutaric acid or is absent.

[0233] The amino acid residue at position 4 is G or absent,

[0234] The amino acid residue at position 5 is T,

[0235] The amino acid residue at position 6 is F,

[0236] The amino acid residue at position 7 is 1,

[0237] The amino acid residue at position 8 is S,

[0238] The amino acid residue at position 9 is D or E,

[0239] The amino acid residue at position 10 is Y,

[0240] The amino acid residue at position 11 is K or S,

[0241] The amino acid residue at position 12 is I or K,

[0242] The amino acid residue at position 13 is A or Aib or K,

[0243] The amino acid residue at position 14 is M, L, Nle or K,

[0244] The amino acid residue at position 15 is D or E,

[0245] The amino acid residue at position 16 is K,

[0246] The amino acid residue at position 17 is I or K,

[0247] The amino acid residue at position 18 is H or K,

[0248] The amino acid residue at position 19 is Q,

[0249] The amino acid residue at position 20 is Q,

[0250] The amino acid residue at position 21 is D or E,

[0251] The amino acid residue at position 22 is F,

[0252] The amino acid residue at position 23 is V,

[0253] The amino acid residue at position 24 is N, A, Q or E,

[0254] The amino acid residue at position 25 is W,

[0255] The amino acid residue at position 26 is L,

[0256] The amino acid residue at position 27 is L,

[0257] The amino acid residue at position 28 is A, E, or K,

[0258] The amino acid residue at position 29 is Q, G, or K, and

[0259] The amino acid residue at position 30 is K or G,

[0260] or functional variants thereof.

[0261] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) is provided, wherein

[0262] The amino acid at position 3 is E or glutaric acid or absent;

[0263] The amino acid at position 4 is Gly or absent;

[0264] The amino acid at position 5 is T;

[0265] The amino acid at position 9 is selected from D and E;

[0266] The amino acid at position 11 is selected from the group consisting of S, K, and A;

[0267] The amino acid at position 12 is selected from I and K;

[0268] The amino acid at position 13 is selected from A and Aib;

[0269] The amino acid at position 14 is selected from the group consisting of M, L, and Nle;

[0270] The amino acid at position 15 is selected from D and E;

[0271] The amino acid at position 16 is selected from K and R;

[0272] the amino acid at position 17 is selected from I and K;

[0273] The amino acid at position 18 is selected from H and K;

[0274] The amino acid at position 20 is selected from the group consisting of Q and K;

[0275] The amino acid at position 21 is selected from D and E;

[0276] The amino acid at position 24 is selected from the group consisting of N, Q, and E;

[0277] The amino acid at position 28 is selected from A and E;

[0278] The amino acid at position 29 is selected from Q and G; and / or

[0279] The amino acid at position 30 is selected from the group consisting of K, R, G and A.

[0280] In one embodiment, a GIP peptide analog (SEQ ID NO: XX) is provided, wherein

[0281] The amino acid at position 3 is Glu or glutaric acid or is absent

[0282] The amino acid at position 4 is Gly or absent

[0283] The amino acid at position 5 is T;

[0284] The amino acid at position 6 is F;

[0285] The amino acid at position 7 is 1;

[0286] The amino acid at position 9 is selected from D and E;

[0287] The amino acid at position 10 is Y;

[0288] The amino acid at position 11 is selected from the group consisting of S, K, and A;

[0289] The amino acid at position 12 is selected from I and K;

[0290] The amino acid at position 13 is selected from A and Aib;

[0291] The amino acid at position 14 is selected from the group consisting of M, L, and Nle;

[0292] The amino acid at position 15 is selected from D and E;

[0293] The amino acid at position 16 is selected from K and R;

[0294] the amino acid at position 17 is selected from I and K;

[0295] The amino acid at position 18 is selected from H and K;

[0296] The amino acid at position 20 is selected from the group consisting of Q and K;

[0297] The amino acid at position 21 is selected from D and E;

[0298] The amino acid at position 22 is F;

[0299] The amino acid at position 23 is V;

[0300] The amino acid at position 24 is selected from the group consisting of N, Q, and E;

[0301] The amino acid at position 25 is W;

[0302] The amino acid at position 26 is L;

[0303] The amino acid at position 27 is L;

[0304] The amino acid at position 29 is Q; and / or

[0305] The amino acid at position 30 is K or R.

[0306] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X1-X2):

[0307]

[0308] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X2):

[0309]

[0310] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X1):

[0311]

[0312] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30):

[0313]

[0314] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP4-30 X2):

[0315]

[0316] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP4-30):

[0317]

[0318] In one embodiment, the present disclosure provides a GIP peptide analog, wherein when the amino acid residue at position 3 is absent, then the amino acid residue at position 4 is absent.

[0319] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP5-30):

[0320]

[0321] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP6-30):

[0322]

[0323] One feature of the GIP peptide analogs of the present disclosure is the presence of a moiety designated Z, Z peptide, or peptide Z. As provided herein, Z is a peptide comprising one or more amino acid residues of GIP (31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E). The presence of the Z peptide is advantageous because it improves both the half-life and antagonistic potency of the GIP peptide analogs.

[0324] In one embodiment of the present disclosure, Z consists of one or more consecutive amino acid residues of GIP (31-42) (SEQ ID NO: Z).

[0325] In one embodiment of the present disclosure, Z consists of one or more consecutive amino acid residues of Exendin-4 (SEQ ID NO: E).

[0326] In one embodiment of the present disclosure, Z consists of one or more amino consecutive acid residues at the C-terminus of Exendin-4(30-39) (PSSGAPPPS; SEQ ID NO: CE30-39).

[0327] In one embodiment of the present disclosure, Z consists of one or more amino consecutive acid residues at the C-terminus of Exendin-4(29-39) (GPSSGAPPPS; SEQ ID NO: CE29-39).

[0328] In one embodiment of the present disclosure, Z comprises at least one G or one P. Without wishing to be bound by theory, it is believed that when Z comprises G or P (such as, for example, position 31 and / or 32), then the half-life of the GIP peptide analog is increased, possibly due to reduced degradation from the C-terminus, which increases the in vivo stability of the GIP peptide analog.

[0329] In one embodiment of the present disclosure, Z comprises at least two Ps.

[0330] In one embodiment of the present disclosure, Z is a peptide selected from:

[0331] - glycine or proline,

[0332] -GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0333] -PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0334] -GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDW KHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0335] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GKKKDW, GKKNDKGRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0336] -PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or

[0337] Variants thereof containing 1 or 2 single amino acid substitutions at any one of the amino acid residues.

[0338] In one embodiment of the present disclosure, the fatty acid molecule is not attached to the amino acid residue at position 3 of SEQ ID NO: XX or a variant thereof.

[0339] In one embodiment, the fatty acid molecule is not attached to the N-terminal amino group of the amino acid residue at position 3 of SEQ ID NO: GIP(3-30)X1-X2, SEQ ID NO: GIP(3-30)X2, SEQ ID NO: GIP(3-30)X1 or SEQ ID NO: GIP(3-30).

[0340] In one embodiment, the fatty acid molecule is not attached to the N-terminal amino group of the amino acid residue at position 4 of SEQ ID NO: GIP(4-30)X2 or SEQ ID NO: GIP(4-30).

[0341] In one embodiment, the fatty acid molecule is not attached to the N-terminal amino group of the amino acid residue at position 5 of SEQ ID NO: GIP(5-30).

[0342] In one embodiment, the fatty acid molecule is not attached to the amino acid residue of Z.

[0343] In one embodiment, the GIP peptide analogs of the present disclosure have a free N-terminus. Thus, the N-terminus of the GIP peptide analogs comprises an unsubstituted (such as unacetylated, acylated, or alkylated) amino (-NH2) moiety. Thus, the N-terminus of the GIP peptide analogs may comprise a free amino (-NH2) moiety.

[0344] In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 7 to 29 of the GIP peptide analogue (such as SEQ ID NO: XX). In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 7 to 29 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a variant thereof.

[0345] In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 6 to 29 of the GIP peptide analogue (such as SEQ ID NO: XX). In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 6 to 29 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a variant thereof.

[0346] In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 4 to 29 of the GIP peptide analog (such as SEQ ID NO: XX). In one embodiment, the fatty acid molecule is attached to an amino acid residue at any one of positions 4 to 29 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a variant thereof.

[0347] In one embodiment, the fatty acid molecule is attached to the amino acid residue at position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of said GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant thereof.

[0348] In one embodiment, the fatty acid molecule is attached to the amino acid residue at position 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of SEQ ID NO: hGIP(6-30) or a functional variant thereof.

[0349] In one embodiment, the fatty acid molecule is attached to the amino acid residue at position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of SEQ ID NO: hGIP(5-30) or a functional variant thereof.

[0350] In one embodiment, the fatty acid molecule is attached to the amino acid residue at position 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28 or 29 of SEQ ID NO: hGIP(3-30) or a functional variant thereof.

[0351] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues in the middle region of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof.

[0352] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues at any one of positions 11 to 21 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof.

[0353] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues at any one of positions 11, 12, 17, 18 and 20 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30) or a functional variant thereof.

[0354] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues at any one of positions 11, 12, 17, and 18 of any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), or a functional variant thereof. Attachment of a fatty acid at any of these positions may result in a GIP peptide analog having a particularly long half-life and having a particularly high antagonistic potency.

[0355] In one embodiment, the fatty acid molecule is attached to the ε-amino group of the K residue or the Orn residue of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof comprising at least one K or Orn residue.

[0356] In one embodiment, the fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 16 of the GIP peptide analog (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0357] In one embodiment, the fatty acid molecule is attached to K at position 16 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0358] In one embodiment, the fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 18 of the GIP peptide analog (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a variant thereof, wherein in the GIP peptide analog, H at position 18 has been substituted by K or Orn. ​​Attachment of the fatty acid to the side chain amino group of the amino acid residue at position 18 may result in the GIP peptide analog having a particularly long half-life and having a particularly high antagonistic potency.

[0359] In one embodiment, the fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 11 of the GIP peptide analog (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a variant thereof, wherein the S at position 11 in the GIP peptide analog has been substituted by K or Orn.

[0360] In one embodiment, the fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 12 of the GIP peptide analog (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a variant thereof, wherein the I at position 12 in the GIP peptide analog has been substituted by K or Orn.

[0361] In one embodiment, at least one fatty acid molecule is attached to the amino acid residue at position 11 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0362] In one embodiment, the fatty acid molecule is attached to K at position 11 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0363] In one embodiment, at least one fatty acid molecule is attached to the amino acid residue at position 12 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0364] In one embodiment, the fatty acid molecule is attached to K at position 12 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0365] In one embodiment, at least one fatty acid molecule is attached to the amino acid residue at position 17 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0366] In one embodiment, the fatty acid molecule is attached to K at position 17 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0367] In one embodiment, at least one fatty acid molecule is attached to the amino acid residue at position 18 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0368] In one embodiment, the fatty acid molecule is attached to K at position 18 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)) or a functional variant thereof.

[0369] In one embodiment, at least one fatty acid molecule is attached to lysine at position 18 of the GIP peptide analogue (such as any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)), and SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30)). At least two of the amino acids at positions 9, 15, and 24 of any one of SEQ ID NO: GIP (5-30) and SEQ ID NO: GIP (6-30) are E.

[0370] In one embodiment, at least one fatty acid molecule is attached to an amino acid in the middle of the GIP peptide analog, such as at any one of positions 11 to 18, such as at position 11 or 18, of the GIP peptide analog.

[0371] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the peptide is an analog of any one of SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), and has a sequence selected from the group consisting of:

[0372] EGTFISDYSIAMDKIHQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(3-30),

[0373] EGTFISDYSIAMDKIKQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(3-30)[H18K],

[0374] SGTFISDYSIAMDKIKQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(3-30)[E3S;H18K],

[0375] SGTFISDYSIAMDRIKQQDFVNWLLAQR–Z;SEQ ID NO:;GIP(3-30)[E3S;K16R;H18K;K30R],

[0376] EGTFISDYKIAMDKIHQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[S11K],

[0377] EGTFISDYSKAMDKIHQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[I12K],

[0378] EGTFISDYSIAMDKIHQKDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[Q20K],

[0379] EGTFISDYSIAMDKIHQQDFVKWLLAQK–Z;SEQ ID NO:;GIP(3-30)[N24K],

[0380] EGTFISDYSIAMDKKHQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[I17K],

[0381] EGTFISDYSIAMDKIKQQDFVNWLLAQG–Z;SEQ ID NO:;GIP(3-30)[H18K;K30G],

[0382] EGTFISDYSIAMDKIKQQDFVNWLLAGG–Z;SEQ ID NO:;GIP(3-30)[H18K;Q29G;K30G],

[0383] EGTFISEYSIAMEKIKQQEFVQWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9E;D15E;H18K;D21E;N24Q],

[0384] EGTFISEYSIAMEKIKQQDFVQWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9E;D15E;H18K;N24Q],

[0385] EGTFISEYSAibANleEKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9E;I12Aib;M14Nle;D15E;H18K;N24E],

[0386] EGTFISEYSIAibMEKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9E;A13Aib;D15E;H18K;N24E],

[0387] EGTFISDYSIAMDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[H18K;N24E],

[0388] EGTFISDYSIALDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14L;H18K],

[0389] EGTFISDYSIANleDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K],

[0390] EGTFISDYSIAEDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14E;H18K],

[0391] EGTFISDYSIAKDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14K;H18K],

[0392] EGTFISDYSIASDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14S;H18K],

[0393] EGTFISDYSIAMDKIKQQDFVEWLLAQA–Z;SEQ ID NO:;GIP(3-30)[H18K;N24E;K30A],

[0394] EGTFISDYSIAMDKIKQQDFVNWLLEQK–Z;SEQ ID NO:;GIP(3-30)[H18K;A28E],

[0395] VGTFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3V;H18K],

[0396] AibGTFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3Aib;H18K],

[0397] PGTFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3P;H18K],

[0398] VETFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3V;G4E;H18K],

[0399] AibETFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3Aib;G4E;H18K],

[0400] GETFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3G;G4E;H18K],

[0401] PETFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3P;G4E;H18K],

[0402] DTTFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3D;G4T;H18K],

[0403] GETFISDYAIALDKIKQQDFVEWLLAQG–Z;SEQ ID NO:;GIP(3-30)[E3G;G4E;S11A;M14L;H18K;N24E;K30G],

[0404] GETFISTYSIALDKIKQQDFVEWLLAQG–Z;SEQ ID NO:;GIP(3-30)[E3G;G4E;D9T;M14L;H18K;N24E],

[0405] EGTFISTYKIALDKIHQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9T;S11K;M14L;N24E],

[0406] EGTFISDYSIAibMDKIKQQDFVEWLLAQK–Z;SEQ ID NO;GIP(3-30)[A13Aib;H18K;N24E],

[0407] EGTFISDYSIAibLDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[A13Aib;M14L;H18K;N24E],

[0408] EGTFISDYSIAibNleDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[A13Aib;M14Nle;H18K;N24E],

[0409] EGTFISDYSIALDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14L;H18K;N24E],

[0410] EGTFISDYSIANleDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;N24E],

[0411] EGTFISDYSIAKDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14K;H18K;N24E],

[0412] EGTFISDYSIANleDKIKQQDFVNWLLAGG–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;Q29G;K30G],

[0413] EGTFISDYSIANleDKIKQQDFVEWLLAGG–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;N24E;Q29G;K30G],

[0414] EGTFISEYSIAibLEKIKQQEFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[D9E;A13Aib;M14L;D15E;H18K;D21E;N24E],

[0415] EGTFISEYSIAibNleEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], yGluGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3yGlu; H18K], βGluGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3βGlu; H18K],

[0416] XGTFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3 Glutaric acid (X); H18K],

[0417] EGTFISDYSIALDKIKQQDFVEWLLAGG–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K; N24E; Q29G; K30G],

[0418] EGTFISEYSIALEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; M14L; D15E; H18K; D21E; N24E],

[0419] EGTFISEYSIANleEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; M14Nle; D15E; H18K; D21E; N24E],

[0420] yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3yGlu (L isomer); M14Nle; H18K; N24E],

[0421] yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3yGlu (D isomer); M14Nle; H18K; N24E],

[0422] βGluGTFISDYSIANleDKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3βGlu; M14Nle; H18K; N24E],

[0423] XGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP (3-30) [E3 glutaric acid (X); M14Nle; H18K; N24E],

[0424] βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQK–Z; SEQ ID NO:GIP(3-30)[E3βGlu;A13Aib;M14Nle;H18K],

[0425] EGTFISDYSIALDKIKQQDFVNWLLEQK–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K; A28E],

[0426] EGTFISDYSIANleDKIKQQDFVNWLLEQK-Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;A28E], and

[0427] EGTFISDYSIALDKIKQQDFVNWLLEGG–Z;SEQ ID NO:;GIP(3-30)[M14L;H18K;A28E;Q29G;K30G]

[0428] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 4 to 29 of any of the above sequences, and wherein the peptide may be C-terminally carboxylated.

[0429] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the peptide is

[0430] An analog of hGIP5-30 (SEQ ID NO: GIP (5-30)) and having a sequence selected from the group consisting of:

[0431] TFISDYSIAMDKIHQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(5-30)

[0432] TFISDYKIAMDKIHQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(5-30)[S11K],

[0433] TFISDYSIAMDKIKQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(5-30)[H18K],

[0434] TFISDYKIAMDRIHQQDFVNWLLAQR–Z;SEQ ID NO:;GIP(5-30)[S11K;K16R;K30R],

[0435] TFISDYSKAMDKIHQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(5-30)[I12K],

[0436] TFISDYSIAMDKIHQKDFVNWLLAQK-Z; SEQ ID NO:; GIP (5-30) [Q20K], and

[0437] TFISDYSIAMDKIHQQDFVKWLLAQK–Z; SEQ ID NO:; GIP(5-30)[N24K], wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues from positions 4 to 29 of any of the above sequences, and wherein the peptide may be C-terminally carboxylated.

[0438] In one embodiment, a GIP peptide analog or a functional variant thereof is provided, wherein the peptide is an analog of hGIP6-30 (SEQ ID NO: GIP (6-30)) and has a sequence selected from the group consisting of: FISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP (6-30) [H18K]. wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 4 to 29 of any of the above sequences. and wherein the peptide may be C-terminally carboxylated.

[0439] In one embodiment, the GIP peptide analogs of the present disclosure are C-terminally amidated (—NH 2 ).

[0440] In one embodiment, the GIP peptide analogs of the present disclosure are C-terminally carboxylated (—COOH), such as where the C-terminus is a free carboxylic acid.

[0441] Functional variants-mutants

[0442] In one embodiment, one or more or all of the amino acid substitutions are conservative amino acid substitutions (or synonymous substitutions). Conservative substitutions are substitutions of amino acids whose side chains have similar biochemical properties and therefore do not affect the function of the peptide.

[0443] Specific amino acid substitutions as disclosed herein are K to R, A, G; E to D, S, P, G, V, 2-aminoisobutyric acid (Aib), γ-glutamic acid (γGlu), D-γ-glutamic acid (D-γGlu), β-glutamic acid (βGlu), pyroE (pyroglutamic acid), glutaric acid; L to M; Q to E; I to V; I to L, K, Aib; A to S, Aib, E; Y to W; K to Q; S to T, K; N to S; M to L, Nle, E, S, K; H to K; N, I, S, G to A; N, I, S to T; D to E, T; N to Q, E; Q to R, K, G; G to E, T, K.

[0444] In another embodiment, functional variants as defined herein include sequences wherein an alkyl amino acid is substituted for an alkyl amino acid, wherein an aromatic amino acid is substituted for an aromatic amino acid, wherein a sulfur-containing amino acid is substituted for a sulfur-containing amino acid, wherein a hydroxy-containing amino acid is substituted for a hydroxy-containing amino acid, wherein an acidic amino acid is substituted for an acidic amino acid, wherein a basic amino acid is substituted for a basic amino acid, and / or wherein a dibasic monocarboxylic acid amino acid is substituted for a dibasic monocarboxylic acid amino acid.

[0445] Conservative substitutions may be introduced into one or more of the above-specified positions of a GIP peptide analogue selected from any one of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: GIP (6-30), as long as the resulting variant retains function. However, it may also be desirable to introduce non-conservative substitutions (non-synonymous substitutions) into one or more positions.

[0446] In one embodiment, it results in the formation of a protein selected from the group consisting of SEQ ID NO: XX, SEQ ID NO: GIP (3-30) X1-X2, SEQ ID NO: GIP (3-30) X2, SEQ ID NO: GIP (3-30) X1, SEQ ID NO: GIP (3-30), SEQ ID NO: GIP (4-30) X2, SEQ ID NO: GIP (4-30), SEQ ID NO: GIP (5-30), SEQ ID NO: Non-conservative substitutions of variants of the GIP peptide of any one of NO:GIP(6-30) comprise substitutions of amino acid residues that: i) differ substantially in polarity, e.g., substitution of a residue having a non-polar side chain (Ala, Leu, Pro, Trp, Val, Ile, Leu, Phe, or Met) for a residue having a polar side chain (such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gln or a charged amino acid (such as Asp, Glu, Arg, or Lys)), or substitution of a charged or polar residue for a non-polar residue; and / or ii) ) its effect on the orientation of the peptide backbone is substantially different, such as substitution of Pro or Gly by another amino acid or substitution of Pro or Gly by another amino acid; and / or iii) the charge is substantially different, for example substitution of a positively charged residue (such as Lys, His or Arg) by a negatively charged residue (such as Glu or Asp) (and vice versa); and / or iv) the steric bulk is substantially different, for example substitution of a residue with a smaller side chain (e.g., Ala, Gly or Ser) by a bulky residue (such as His, Trp, Phe or Tyr) (and vice versa).

[0447] In one embodiment, amino acid substitutions can be made based on the hydrophobicity and hydrophilicity values ​​of the amino acids and the relative similarity (including charge, size, etc.) of the amino acid side-chain substituents.

[0448] GIP peptide analogs as defined herein or functional variant counterparts thereof comprise proproteins or natural amino acids, i.e., 22 amino acids naturally incorporated into polypeptides. Of these, 20 are encoded by the universal genetic code, and the remaining two (selenocysteine ​​(Sec, U) and pyrrolysine (Pyl, O) are incorporated into proteins by a unique synthetic mechanism.

[0449] In one embodiment, a GIP peptide analog as defined herein comprises one or more non-naturally occurring amino acid residues (non-natural, non-proteinogenic or non-standard amino acids) or amino acid mimetics (such as glutaric acid). Non-naturally occurring amino acids include, for example but not limited to, β-2-naphthyl-alanine, trans-3-methylproline, 2,4-methylproline (methanoproline), cis-4-hydroxyproline, ornithine (Orn), trans-4-hydroxyproline, N-methylglycine, allothreonine, methylthreonine, hydroxyethylcysteine, hydroxyethylhomocysteine, nitroglutamine, homoglutamine, pipecolic acid, thiazolidinecarboxylic acid, dehydroproline, 3- and 4-methylproline, 3,3-dimethylproline, tert-leucine, norleucine (Nle), methoxinine (Mox), norvaline, 2-azaphenylalanine, 3-azaphenylalanine, 4-azaphenylalanine and 4-fluorophenylalanine.

[0450] In one embodiment, the amino acid Met is substituted with an antioxidant amino acid analog, such as norleucine (Nle) or Leu, which retain the length of the amino acid side chain important for hydrophobic interactions but not its hydrogen bonding properties; or methoxythiothreitol (Mox), an atypical amino acid with electronic properties more similar to Met than Nle or Lys.

[0451] Standard and / or non-standard amino acids may be linked by peptide bonds (to form a linear peptide chain), or by non-peptide bonds (e.g. via the variable side chains of the amino acids). Preferably, the amino acids of the peptides defined herein are linked by peptide bonds.

[0452] As is known in the art, the term peptide also encompasses post-translational modifications introduced by chemical or enzyme-catalyzed reactions. These include acetylation, phosphorylation, methylation, glycosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation, and sulfation of one or more amino acid residues, as well as proteolytic modifications by known proteases, including lysosomal cathepsins and calpains, secretases, and matrix-metalloproteinases.

[0453] Likewise, functional equivalents of the peptides may comprise chemical modifications such as ubiquitination, labeling (e.g., with radionuclides, various enzymes, etc.), pegylation (derivatization with polyethylene glycol), or by insertion (or substitution by chemical synthesis) of amino acids not normally present in human proteins (non-proteinogenic), such as ornithine.

[0454] Spatially similar compounds can be formulated to mimic key portions of a peptide structure. This can be accomplished through modeling and chemical design techniques known to those skilled in the art. For example, esterification and other alkylations can be employed to modify the amino terminus of, for example, a diarginine peptide backbone to mimic a tetrapeptide structure. It should be understood that all such spatially similar constructs fall within the scope of the present invention. Peptides with N-terminal and C-terminal alkylations and esterifications are also encompassed within the present invention. For example, glutaric acid is a spatially similar compound that mimics glutamic acid.

[0455] In one embodiment, the N-terminal amino acid of the GIP peptide analog of the present disclosure does not have any chemical modifications. It may be advantageous that the N-terminal amino group of the GIP peptide analog is free, ie, unsubstituted, since substitutions may result in agonistic effects on GIPR.

[0456] It appears that extending the length of the fatty acid or linker (if present) may reduce the antagonistic potency. However, simultaneous incorporation of an Aib residue at position 13 appears to compensate for some or all of the reduced potency, particularly in combination with E at one or more of positions 9, 15, 21, and 24, such as in combination with E at one or more of positions 9, 15, and 21.

[0457] Attachment of fatty acid molecules

[0458] In one embodiment, the fatty acid molecule is attached to a molecule having a side chain amino-alkyl (-C n H 2n NH2) on one or more amino acid residues.

[0459] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues having a side chain amino group (NH2).

[0460] In one embodiment, the fatty acid molecule is attached to the amino group (NH2) of the amino acid residue.

[0461] In one embodiment, the fatty acid molecule is attached to the side chain amino group of an amino acid residue.

[0462] In one embodiment, the fatty acid molecule is attached to the epsilon side chain amino group of a lysine residue (Lys, K).

[0463] In one embodiment, the fatty acid molecule is attached to the delta side chain amino group of an ornithine residue (Orn).

[0464] In one embodiment the amino acid residue with the attached fatty acid molecule is selected from Lys and Orn.

[0465] In one embodiment, the amino acid residue with the attached fatty acid molecule is Lys.

[0466] In one embodiment, the fatty acid molecule is attached to the delta-amino group of the Orn residue of said GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant comprising an Orn amino acid residue.

[0467] In one embodiment, the fatty acid molecule is attached to the epsilon-amino group of the K residue of said GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant thereof.

[0468] In one embodiment, the amino acid residue with the attached fatty acid molecule is the most N-terminal amino acid residue, such as the most N-terminal amino acid residue of said GIP peptide analog (such as SEQ ID NO: XX) or a functional variant thereof, wherein the fatty acid is attached to an amino group comprised in the side chain of the N-terminal amino acid.

[0469] In one embodiment, the fatty acid molecules according to the present disclosure are straight chain fatty acids.

[0470] In one embodiment, the fatty acid molecules according to the present disclosure are branched chain fatty acids.

[0471] In one embodiment, the fatty acid molecule according to the present disclosure is a monoacyl fatty acid molecule comprising one fatty acid. A monoacyl fatty acid molecule is a fatty acid molecule comprising only one carboxyl group. Preferably, the carboxyl group is located at one end of the fatty acid molecule.

[0472] For example, the GIP peptide can be conjugated to a monoacyl fatty acid (such as hexadecanoyl) via a linker as depicted in Formula I:

[0473] Formula I

[0474] In one embodiment, the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule. A diacyl fatty acid molecule is a fatty acid molecule comprising two carboxyl groups. Preferably, one or two carboxyl groups are located at one or each end of the fatty acid molecule.

[0475] For example, the GIP peptide can be conjugated to a diacyl fatty acid (also known as a "diacid") such as 15-carboxy-pentadecanoyl via a linker as depicted in Formula II:

[0476] Formula II

[0477] In one embodiment, the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule comprising two fatty acids.

[0478] In one embodiment, the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule containing two carboxyl functional groups.

[0479] In one embodiment, a fatty acid molecule according to the present disclosure comprises the formula CH3(CH2) n wherein n is an integer from 4 to 24.

[0480] In one embodiment, the fatty acid molecule comprises an acyl group selected from the group consisting of: CH3(CH2)6CO-, CH3(CH2)8CO-, CH3(CH2) 10 CO-, CH3(CH2) 12 CO-, CH3(CH2)14CO-, CH3(CH2) 16 CO-, CH3(CH2) 18 CO-, CH3(CH2) 20 CO- and CH3(CH2) 22 CO-.

[0481] In one embodiment, the fatty acid molecule is a (mono)acyl fatty acid selected from the group consisting of: CH3(CH2) 10 CO-(Lauryl, C12), CH3(CH2) 12 CO-(myristoyl, C14), CH3(CH2) 14 CO-(palmitoyl, C16), CH3(CH2) 16 CO-(stearyl, C18), CH3(CH2) 18 CO-(arachidyl, C20) and CH3(CH2) 20 CO-(behenyl, C22).

[0482] In one embodiment, the fatty acid molecule is a (di)acyl fatty acid selected from the group consisting of: HOOC-CH3(CH2) 10 CO-(dodecanoyl, C12), HOOC-CH3(CH2) 12 CO-(1-tetradecanoyl, C14), HOOC-CH3(CH2) 14 CO-(hexadecanoyl, C16), HOOC-CH3(CH2) 15 CO-(15-carboxy-pentadecanoyl, C17), HOOC-CH3(CH2) 16 CO-(octadecanoyl, C18), HOOC-CH3(CH2) 17 CO-(17-carboxy-heptadecanoyl, C19), HOOC-CH3(CH2) 18CO-(eicosanoyl, C20), HOOC-CH3(CH2) 19 CO-(19-carboxy-nonadecanoyl, C21) and HOOC-CH3(CH2) 20 CO-(behenyl, C22).

[0483] In one embodiment, the fatty acid molecule comprises two fatty acids each selected from the group consisting of: CH3(CH2) 10 CO-(Lauryl, C12), CH3(CH2) 12 CO-(myristoyl, C14), CH3(CH2) 14 CO-(palmitoyl, C16), CH3(CH2) 16 CO-(stearyl, C18), CH3(CH2) 18 CO-(arachidyl, C20) and CH3(CH2) 20 CO-(behenyl, C22).

[0484] In one embodiment, the fatty acid molecule comprises the formula COOH(CH2) n An acyl group of CO-(dicarboxylic acid), wherein n is an integer from 4 to 24.

[0485] In one embodiment, the fatty acid molecule comprises an acyl group selected from the group consisting of: COOH(CH2) 14 CO-(C16 diacid), COOH(CH2) 16 CO-(C18 diacid), COOH(CH2) 18 CO-(C20 diacid) and COOH(CH2) 20 CO-(C22 diacid).

[0486] In one embodiment, the fatty acid molecules are selected from the group consisting of C12, C14, C16, C18, C20 and C22.

[0487] In one embodiment, the fatty acid molecule is selected from the group consisting of a C14 diacid, a C16 diacid, a C18 diacid, a C20 diacid, and a C22 diacid.

[0488] In one embodiment, the fatty acid molecule is palmitoyl.

[0489] In one embodiment, the fatty acid molecule is 1,16-hexadecanedioic acid.

[0490] In one embodiment, the fatty acid molecule is 15-carboxy-pentadecanoyl.

[0491] In one embodiment, the fatty acid molecule is stearoyl.

[0492] In one embodiment, the fatty acid molecule is 1,18-octadecanedioic acid.

[0493] In one embodiment, the fatty acid molecule is 17-carboxy-heptadecanoyl.

[0494] In one embodiment, the fatty acid molecule is arachidyl.

[0495] In one embodiment, the fatty acid molecule is 1,20-eicosanoic acid / eicosanoic acid.

[0496] In one embodiment, the fatty acid molecule is 19-carboxy-nonadecanoyl.

[0497] In one embodiment, the fatty acid molecule is behenyl.

[0498] In one embodiment, the fatty acid molecule is 1,22-docosanoic acid / docosanoic acid.

[0499] In one embodiment, the fatty acid molecule comprises COOH(CH2) 14 In one embodiment, the fatty acid molecule comprises COOH(CH2) 16 In one embodiment, the fatty acid molecule comprises COOH(CH2) 18 CO- or consisting of.

[0500] The fatty acid molecule can be directly attached to the amino acid residue in such a way that the carboxyl group of the fatty acid molecule forms an amide bond with the amino group of the amino acid residue.

[0501] Attachment of fatty acid molecules via linkers

[0502] Attachment of the fatty acid molecule to the peptide herein may occur directly or indirectly (ie via a linker or spacer).

[0503] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the amino acid residue.

[0504] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the α-amino group of an amino acid residue, wherein the amino acid residue is the N-terminal amino acid residue.

[0505] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the ε-amino group of a Lys residue.

[0506] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the delta-amino group of the Orn residue.

[0507] In one embodiment, the fatty acid molecule according to the present disclosure is attached to the amino acid residue via a linker or spacer, as depicted in Formula III:

[0508] Formula III:

[0509] In one embodiment, the fatty acid molecule according to the present disclosure is attached to the ε-amino group of a Lys residue via a linker or a spacer.

[0510] In one embodiment, the fatty acid molecule according to the present disclosure is attached to the delta-amino group of the Orn residue via a linker or spacer.

[0511] In one embodiment, the fatty acid molecule may be attached to the amino acid residue via a spacer (or linker) in such a way that the amino group of the linker forms an amide bond with the carboxyl group of the fatty acid molecule.

[0512] In one embodiment, the linker is an α, ω-amino acid. Examples of suitable linkers are succinic acid, Lys, Glu or Asp, or dipeptides such as Gly-Lys. When the linker is succinic acid, one of its carboxyl groups can form an amide bond with the amino group of the amino acid residue, and its other carboxyl group can form an amide bond with the amino group of the fatty acid molecule. When the linker is Lys, Glu or Asp, its carboxyl group can form an amide bond with the amino group of the amino acid residue, and its amino group can form an amide bond with the carboxyl group of the fatty acid molecule. When Lys is used as a linker, in some cases, another linker can be inserted between the ε-amino group of Lys and the fatty acid molecule. In one embodiment, the other linker is succinic acid, which forms an amide bond with the ε-amino group of Lys and with the amino group present in the fatty acid molecule. Other linkers are Nε-(γ-L-glutamyl), Nε-(β-L-asparaginyl), Nε-glycyl and Nε-(α-(γ-aminobutyryl)).

[0513] In one embodiment, the linker comprises one or more moieties independently selected from:

[0514] a. α-amino acid, γ-amino acid or ω-amino acid,

[0515] b. one or more amino acids selected from succinic acid, Lys, Glu, Asp,

[0516] c. one or more of γ-aminobutyryl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparaginyl), β-Ala (β-alanyl) and Gly, and

[0517] d.[8-Amino-3,6-dioxaoctanoic acid] n (AEEAc n ), where n is an integer between 1 and 50, such as an integer between 1-4, 1-3, or 1-2.

[0518] In one embodiment, the linker is a hydrophilic linker. In one embodiment, the linker is a non-natural amino acid hydrophilic linker.

[0519] In one embodiment, the linker is selected from the group consisting of γ-aminobutyryl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparaginyl, β-alanyl, and glycyl. In one embodiment, the linker comprises one or more of γ-aminobutyryl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparaginyl, β-alanyl, and glycyl.

[0520] In one embodiment, the linker is a repeat of a single linker moiety. In one embodiment, the linker is a repeat of the same linker moiety. In one embodiment, the linker is a repeat of different linker moieties.

[0521] In one embodiment, the linker is γ-glutamic acid.

[0522] In one embodiment, the linker is γ-glutamic acid-8-amino-3,6-dioxaoctanoic acid (γ-Glu)-(AEEAc) or repeats thereof.

[0523] In one embodiment, the linker comprises γ-glutamic acid-8-amino-3,6-dioxaoctanoic acid (γ-Glu)-(AEEAc n )

[0524] Examples of linkers disclosed herein are such that they can be attached to an amino acid residue of a GIP peptide analog via either end of the linker. Thus, for example, if the linker comprises γ-glutamic acid-8-amino-3,6-dioxaoctanoic acid (γ-Glu)-(AEEAc n ), the linker may be via γ-Glu or via AEEAc n Attached to an amino acid residue of the GIP peptide analog.

[0525] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid] n (γ-Glu)-(AEEAc n ), where n is an integer between 1 and 50.

[0526] In one embodiment, the linker is [γ-glutamic acid-8-amino-3,6-dioxaoctanoic acid] n (γ-Glu)-(AEEAc n ), wherein n is an integer between 1 and 50, such as an integer between 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50.

[0527] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid] n (γ-Glu)-(AEEAc n ), wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0528] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer between 1 and 50, such as an integer between 1-2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-11, 11-12, 12-13, 13-14, 14-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50.

[0529] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer selected from the group consisting of 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, and 50.

[0530] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] nAEEAc n ), wherein n is an integer selected from 1, 2, 3.

[0531] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid] n (γ-Glu)-(AEEAc n ), wherein n is an integer selected from 1, 2, 3.

[0532] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid](γ-Glu)-AEEAc or [8-amino-3,6-dioxaoctanoic acid]-[γ-glutamic acid](AEEAc-γ-Glu). For example, the GIP peptide can be conjugated to a fatty acid (e.g., C16 or palmitic acid / palmitoyl in Formula IV, but any other fatty acid can be used) via [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid], as depicted in Formula IV:

[0533]

[0534] Formula IV: Unless otherwise indicated, the formula does not depict stereochemistry, and the natural L-form is generally used.

[0535] For example, the GIP peptide can be conjugated to a fatty acid (e.g., C16 or palmitic acid / palmitoyl in Formula IV, but any other fatty acid can be used) via [8-amino-3,6-dioxaoctanoic acid]-[γ-glutamic acid] as depicted in Formula V:

[0536]

[0537] Formula V: Unless otherwise indicated, the formula does not depict stereochemistry, and the natural L-form is generally used.

[0538] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid]2(γ-Glu)-(AEEAc)2. For example, the linker can comprise or consist of γGlu-AEEAc-AEEAc- or AEEAc-γGlu-AEEAc- or AEEAc-AEEAc-γGlu-.

[0539] In one embodiment, the linker is [γ-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid] 3(γ-Glu)-(AEEAc) 3. For example, the linker can comprise or consist of γGlu-AEEAc-AEEAc-AEEAc-AEEAc- or AEEAc-γGlu-AEEAc-AEEAc- or AEEAc-AEEAc-γGlu-AEEAc- or AEEAc-AEEAc-AEEAc-γGlu-.

[0540] As provided herein, a linker comprising or consisting of one γ-glutamic acid and one, two or three 8-amino-3,6-dioxaoctanoic acid moieties can be linked via γ-Glu or via AEEAc. n Attached to an amino acid residue of the GIP peptide analog.

[0541] In one embodiment, the linker is an amino acid residue other than Cys. In one embodiment, the linker is 4-Abu. In one embodiment, the linker is γ-aminobutyric acid.

[0542] In another embodiment, the linker is a dipeptide, such as the following dipeptide, wherein the C-terminal amino acid residue is Lys, His or Trp, preferably Lys, and wherein the N-terminal amino acid residue is selected from the group comprising Ala, Arg, Asp, Asn, Gly, Glu, Gln, Ile, Leu, Val, Phe and Pro. In one embodiment, the dipeptide linker is Gly-Lys.

[0543] In one embodiment, the linker comprises one or more moieties selected from the group consisting of γ-aminobutyryl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparaginyl, β-alanyl, and glycyl. In one embodiment, the linker comprises γ-aminobutyryl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparaginyl, β-alanyl, glycyl, γ-glutamic acid-8-amino-3,6-dioxaoctanoic acid (γ-Glu-AEEAc n , wherein n is an integer between 1 and 50), one or more of an amino acid residue other than Cys, 4-Abu, γ-aminobutyric acid, and a dipeptide.

[0544] In another embodiment, the linker is an unbranched alkane α,ω-dicarboxylic acid group having 1 to 7 methylene groups (preferably two methylene groups), which forms a bridge between the amino group of the parent peptide and the amino group of the fatty acid molecule.

[0545] In one embodiment, the GIP peptide analogs disclosed herein comprise a fatty acid, and the fatty acid molecule is attached to the amino acid residue via a linker such that the combination of the linker and the fatty acid is selected from the group consisting of:

[0546] i. Hexadecanoyl-γ-Glu-

[0547] ii. Hexadecanoyl-γ-Glu-γ-Glu-

[0548] iii. Hexadecanoyl-γ-Glu-AEEAc-

[0549] iv. Hexadecanoyl-γ-Glu-AEEAc-AEEAc-

[0550] v. Hexadecanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[0551] vi.[15-Carboxy-pentadecanoyl]-Y-Glu-

[0552] vii.[15-Carboxy-pentadecanoyl]-γ-Glu-γ-Glu-

[0553] viii.[15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc-

[0554] ix.[15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc-

[0555] x.[15-Carboxy-pentadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-AEEAc-

[0556] xi. Octadecanoyl-γ-Glu-

[0557] xii. Octadecanoyl-γ-Glu-γ-Glu-

[0558] xiii. Octadecanoyl-γ-Glu-AEEAc-

[0559] xiv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-

[0560] xv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc-

[0561] xvi.[17-Carboxy-heptadecanoyl]-γ-Glu-

[0562] xvii.[17-Carboxy-heptadecanoyl]-γ-Glu-γ-Glu-

[0563] xviii.[17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc-

[0564] xix.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-

[0565] xx.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-

[0566] xxi. Eicosyl-γ-Glu-

[0567] xxii. Eicosyl-γ-Glu-γ-Glu-

[0568] xxiii. Eicosyl-γ-Glu-AEEAc-

[0569] xxiv. Eicosyl-γ-Glu-AEEAc-AEEAc-

[0570] xxv. Eicosyl-γ-Glu-AEEAc-AEEAc-AEEAc-

[0571] xxvi.[19-Carboxy-nonadecanoyl]-Y-Glu-

[0572] xxvii.[19-Carboxy-nonadecanoyl]-γ-Glu-γ-Glu-

[0573] xxviii.[19-Carboxy-nonadecanoyl]-Y-Glu-AEEAc-

[0574] xxix.[19-Carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-

[0575] xxx.[19-Carboxy-nonadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-.

[0576] In one embodiment, the GIP peptide analogs disclosed herein comprise a fatty acid, and the fatty acid molecule is attached to the amino acid residue via a linker such that the combination of the linker and the fatty acid is selected from the group consisting of:

[0577] i.[15-carboxypentadecanoyl-yGlu

[0578] ii. [17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-, and

[0579] iii. [17-Carboxy-heptadecanoyl]-yGlu-yGlu.

[0580] GIP peptide with fatty acids

[0581] In one embodiment, the GIP analogs as defined herein are selected from:

[0582] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C16-dioic acid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0583] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C16-dioic acid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0584] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C18-dioic acid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0585] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K],

[0586] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0587] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0588] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0589] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0590] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0591] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18 / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0592] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C16-diacid / K18; SEQID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0593] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-yGlu-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0594] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex[H18K],

[0595] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQID NO: GIP(3-30)+Cex[CexH18K],

[0596] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C16-diacid / K18: SEQID NO: GIP(3-30)+Cex[CexH18K],

[0597] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C18-diacid / K18: SEQID NO: GIP(3-30)+Cex[CexH18K],

[0598] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18:SEQ ID NO:GIP(3-30)+Cex[CexH18K],

[0599] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K]

[0600] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K]

[0601] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPP-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(9)[CexH18K],

[0602] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPP-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(Cex8)[H18K],

[0603] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAP-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(Cex7)[H18K],

[0604] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGA-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(Cex6)[H18K],

[0605] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSG-C16-diacid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex5)[H18K],

[0606] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSS-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(Cex4)[H18K],

[0607] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPS-C16-diacid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex3)[H18K],

[0608] EGTFISDYSIAMDKIKQQDFVNWLLAQKGP-C16-diacid / K18:SEQ ID NO:GIP(3-30)+Cex(Cex2)[H18K],

[0609] EGTFISDYSIAMDKIKQQDFVNWLLAQKG-C16-diacid / K18: SEQ ID NO: GIP(3-31)[H18K],

[0610] EGTFISDYSIAMDKIKQQDFVNWLLAQKGK-C16-diacid / K18: SEQ ID NO: GIP(3-32)[H18K],

[0611] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKK-C16-diacid / K18:SEQ ID NO:GIP(3-33)[H18K],

[0612] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKN-C16-diacid / K18: SEQ ID NO: GIP(3-34)[H18K],

[0613] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKND-C16-diacid / K18: SEQ ID NO: GIP(3-35)[H18K],

[0614] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-C16-diacid / K18: SEQ ID NO: GIP(3-36)[H18K],

[0615] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWK-C16-diacid / K18: SEQ ID NO: GIP(3-37)[H18K],

[0616] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKH-C16-dioic acid / K18: SEQ ID NO: GIP(3-38)[H18K],

[0617] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN-C16-dioic acid / K18: SEQ ID NO: GIP(3-39)[H18K],

[0618] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNI-C16-dioic acid / K18: SEQ ID NO: GIP(3-40)[H18K],

[0619] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNIT-C16-dioic acid / K18: SEQ ID NO: GIP(3-41)[H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ-C16-dioic acid / K18: SEQ ID NO: GIP(3-42)[H18K],

[0620] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C16-dioic acid / K18; SEQ IDNO: GIP(3-36)[E3S; H18K],

[0621] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C16-dioic acid / K18; SEQ IDNO: GIP(3-36)[E3S; H18K],

[0622] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C18-dioic acid / K18; SEQ IDNO: GIP(3-36)[E3S; H18K],

[0623] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C16-dioic acid / K18: SEQID NO: GIP(3-30)+Cex[E3S; H18K],

[0624] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc + y-glu-C16-dioic acid / K18:SEQ ID NO:GIP(3-30)+Cex[CexE3S;H18K],

[0625] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc + y-glu-C18-dioic acid / K18:SEQ ID NO:GIP(3-30)+Cex[CexE3S;H18K],

[0626] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc + y-glu-C18-dioic acid / K18:SEQ ID NO:GIP(3-30)+Cex[CexE3S;H18K],

[0627] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-2xAEEAc + y-glu-C16-dioic acid / K18;SEQ ID NO:GIP(3-36)[E3S;K16R;H18K;K30R],

[0628] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc + y-glu-C16-dioic acid / K18;SEQ ID NO:GIP(3-36)[E3S;K16R;H18K;K30R],

[0629] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc + y-glu-C18-dioic acid / K18;SEQ ID NO:GIP(3-36)[E3S;K16R;H18K;K30R],

[0630] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc + y-glu-C16-dioic acid / K18:SEQ ID NO:GIP(3-30)+Cex[E3S;K16R;H18K;K30R],

[0631] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc + y-glu-C18-dioic acid / K18:SEQ ID NO:GIP(3-30)+Cex[CexE3S;K16R;H18K;K30R],

[0632] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS - 2xAEEAc + y - glu - C16 - diacid / K18:SEQ ID NO:GIP(3 - 30)+Cex[CexE3S;K16R;H18K;K30R],

[0633] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS - 3xAEEAc + y - glu - C18 - diacid / K18:SEQ ID NO:GIP(3 - 30)+Cex[CexE3S;K16R;H18K;K30R],

[0634] EGTFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW - 2xAEEAc + yGlu - C18 - diacid / K11;SEQ IDNO:GIP(3 - 36)[S11K],

[0635] EGTFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW - 2xAEEAc + yGlu - C18 - diacid / K12;SEQ IDNO:GIP(3 - 36)[I12K],

[0636] EGTFISDYSIAMDKIHQKDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc + yGlu - C18 - diacid / K20;SEQ ID NO:GIP(3 - 30)+Cex(31 - 39)[CexQ20K],

[0637] EGTFISDYSIAMDKKHQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc + yGlu - C18 - diacid / K17;SEQ ID NO:GIP(3 - 30)+Cex(31 - 39)[CexI17K],

[0638] EGTFISDYSIAMDKIKQQDFVNWLLAQGPSSGAPPPS(NH2)-2xAEEAc + yGlu - C18 - diacid;SEQID NO:GIP(3 - 30)+Cex(31 - 39)[CexH18K;K30G],

[0639] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39) [CexH18K; Q29G; K30G],

[0640] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid; SEQ IDNO:GIP(3-30)+Cex(31-39)[CexH18K; Q29G; K30G],

[0641] EGTFISEYSIAMEKIKQQEFVQWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexD9E; D15E; H18K; D21E; N24Q],

[0642] EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; N24E],

[0643] EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[0644] EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; N24E],

[0645] EGTFISDYSIAMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K; N24E],

[0646] EGTFISDYSIALDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K],

[0647] EGTFISDYSIALDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K]

[0648] EGTFISDYSIANleDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K],

[0649] EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14E;H18K],

[0650] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K;H18K],

[0651] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K;H18K]

[0652] EGTFISDYSIASDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14S;H18K],

[0653] EGTFISDYSIAMDKIKQQDFVEWLLAQAPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:GIP(3-30)+Cex(31-39)[H18K; N24E; K30A],

[0654] EGTFISDYSIAMDKIKQQDFVNWLEAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K;L27E],

[0655] EGTFISDYSIAMDKIKQQDFVNWLLEQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K; A28E],

[0656] VGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3V;H18K],

[0657] AibGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3Aib; H18K]

[0658] PGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3P; H18K],

[0659] VETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3V; G4E; H18K],

[0660] AibETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3Aib; G4E; H18K]

[0661] GETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3G; G4E; H18K],

[0662] PETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-OFF / 18KSEQ ID NO:GIP(3-30)+Cex(31-39)[E3PG4EH18K],

[0663] DTTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-OFF / 18KSEQ ID NO:GIP(3-30)+Cex(31-39)[E3DG4TH18K],

[0664] GETFISDYAIALDKIKQQDFVEWLLAQGPSSGAPPPS-C16-OFF / 18KSEQ ID NO:(GIP(3-30)+Cex(31-39)[E3G1G4E4S11A4M14LH18KN24EK30G],

[0665] GETFISTYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-OFF / 18KCSEQ ID NO:GIP(3-30)+Cex(31-39)[E3GG4ED9TM14LH18KN24E],EGTFYSTYKIALDKIHQQDFVEWLLAQKPSSGAPPPS-yGlu-C16-free / 18KSEQ ID NO:GIP(3–30)+Cex(31–39)[D9T:S11K–M14L–N24E],

[0666] GETFISDYAIALDKIKQQDFVEWLLAQG(NH2)PSSGAPPPS-C16-OFF / 18KSEQ ID NO:GIP(3-30)+Cex(31-39)[E3GG4ES11AM14LH18KN24EK30G],

[0667] EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-OFF / 18KSEQ ID NO:GIP(3-30)+Cex(31-39)[A13Aib:H18K:N24E],

[0668] EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-C16-ONLY / 18KSEQ ID NO:GIP(3-30)+Cex(31-39)[A13Aib;M14LH18K:N24E],

[0669] EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K;SEQID NO:GIP(3-30)+Cex(31-39)[A13Aib;M14L;H18K;N24E],

[0670] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14Nle; H18K; N24E],

[0671] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14Nle; H18K; N24E],

[0672] EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K;N24E],

[0673] EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K;N24E],

[0674] EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K;N24E],

[0675] EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K;N24E],

[0676] EGTFISDYSIAKDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K; H18K; N24E],

[0677] EGTFISDYSIANleDKIKQQDFVNWLLAGGPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle; H18K; Q29G; K30G],

[0678] EGTFISDYSIANleDKIKQQDFVEWLLAGGPSSGAPPPS-C16-diacid / 18K;SEQ ID NO:GIP(3-30)+Cex(31-39)[M14Nle;H18K;N24E;Q29G;K30G],

[0679] EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E],

[0680] EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K;SEQID NO:GIP(3-30)+Cex(31-39)[D9E;A13Aib;M14L;D15E;H18K;D21E;N24E],

[0681] EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E],

[0682] EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E],

[0683] yGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3yGlu;H18K],

[0684] βGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3βGlu;H18K],

[0685] XGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39) [E3B diacid (X); H18K]

[0686] EGTFISDYSIALDKIKQQDFVEWLLAGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L; H18K; N24E; Q29G; K30G]

[0687] EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; M14L; D15E; H18K; D21E; N24E],

[0688] EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39) [D9E; M14Nle; D15E; H18K; D21EN24E],

[0689] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:GIP(3-30)+Cex(31-39)[E3yGlu(L-differential);M14Nle;H18K;N24E],

[0690] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:GIP(3-30)+Cex(31-39)[E3yGlu(D double structure); M14Nle; H18K; N24E],

[0691] βGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3βGlu; M14Nle; H18K; N24E],

[0692] βGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3βGlu; M14Nle; H18K; N24E],

[0693] XGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39) [E3E diacid (X); M14Nle; H18K; N24E]

[0694] XGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39) [E3B diacid (X); M14Nle; H18K; N24E]

[0695] βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3βGlu; A13Aib; M14Nle; H18K],

[0696] EGTFISDYSIAMDKIKQQDFVNWLLAQPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)+Cex(32-39)[H18K;Q29G;K30P]),

[0697] EGTFISDYSIALDKIKQQDFVNWLLEQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39)[M14L; H18K; A28E],

[0698] EGTFISDYSIANleDKIKQQDFVNWLLEQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39)[M14Nle; H18K; A28E],

[0699] EGTFISDYSIALDKIKQQDFVNWLLEGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39)[M14L; H18K; A28E; Q29G; K30G], AT691,

[0700] EGTFISDYSIAMDKIKQQDFVNWLLAQK(NH2)PSSGAPPPS C16-dioic acid / 18K; GIP(3-30+CEX31-39[H18K], AT650

[0701] EGTFISDYSIAMDKIKQQDFVNWLLEGGPSSGAPPPS-C16-dioic acid / K18; GIP(3-30)+Cex(31-39), AT626

[0702] or a functional variant thereof,

[0703] wherein the fatty acid is attached directly or via a linker / spacer as defined herein.

[0704] Therefore, C16 is a fatty acid CH3(CH2) 14 CO-(palmitoyl) and C18 is fatty acid CH3(CH2) 16 CO-(stearoyl). The suffix "-diacid" means that the fatty acid molecule is a diacyl fatty acid molecule. The absence of such a suffix refers to a monoacyl fatty acid molecule.

[0705] Therefore C20 is the fatty acid CH3(CH2) 18 CO-(arachidyl). The suffix "-diacid" means that the fatty acid molecule is a diacyl fatty acid molecule. The absence of such a suffix refers to a monoacyl fatty acid molecule.

[0706] Therefore, C22 is the fatty acid CH3(CH2)20 CO-(behenyl). The suffix "-diacid" means that the fatty acid molecule is a diacyl fatty acid molecule. The absence of such a suffix refers to a monoacyl fatty acid molecule.

[0707] In one embodiment, the GIP analogue as defined herein is selected from:

[0708] TFISDYKIAMDKIHQQDFVNWLLAQKGKK-y-glu-C16 diacid / K11 SEQ ID NO:GIP(5-33)[S11K],

[0709] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-y-glu-C16 diacid / K11 SEQ ID NO:GIP(5-36)[S11K],

[0710] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-diacid / K11, SEQ ID NO:GIP(5-36)[S11K],

[0711] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW(NH2)-2xAEEAc+yGlu-C18-diacid / K11, SEQID NO:GIP(5-36)[S11K],

[0712] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18 / K11,SEQ ID NO:GIP(5-36)[S11K],

[0713] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-yGlu-yGlu-C18 / K11,SEQ ID NO:GIP(5-36)[S11K],

[0714] TFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18 diacid / K12 SEQ ID NO:GIP(5-36)[I12K],

[0715] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHN-y-glu-C16 diacid / K11SEQ ID NO:GIP(5-39)[S11K],

[0716] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNIT - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-42)[S11K],

[0717] TFISDYKIAMDKIHQQDFVNWLLAQKG - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-31)[S11K],

[0718] TFISDYKIAMDKIHQQDFVNWLLAQKGK - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-32)[S11K],

[0719] TFISDYKIAMDKIHQQDFVNWLLAQKGKKN - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-34)[S11K],

[0720] TFISDYKIAMDKIHQQDFVNWLLAQKGKKND - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-35)[S11K],

[0721] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWK - γ-glu-C16 diacid / K11SEQ ID NO:GIP(5-37)[S11K],

[0722] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKH - γ-glu-Cid / K11SEQ ID NO:GIP(5-38)[S11K],

[0723] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNI - γ-glu-C16 diacid / K11SEQ ID NO:GIP(5-40)[S11K],

[0724] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNIT - γ-glu-C16 diacid / K11 SEQ ID NO:GIP(5-41)[S11K],

[0725] TFISDYKIAMDKIHQQDFVNWLLAQK PSSGAPPPS(NH2)-2xPEG+yGlu-C18-diacid / K11; SEQ ID NO: GIP(5-30)+Cex31-39[S11K],

[0726] TFISDYKIAMDRIHQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-36)[S11K; K16R; K30R; K32R; K33R],

[0727] TFISDYKIAMDRIHQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C18 diacid / K11; SEQ ID NO: GIP(5-36)[S11K; K16R; K30R; K32R; K33R],

[0728] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C16 diacid / K11; SEQ IDNO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0729] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ IDNO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0730] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C18 diacid / K11; SEQ IDNO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0731] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C18 diacid / K11; SEQ IDNO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0732] TFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C18 diacid / K18; SEQ ID NO: GIP(5-36)[H18K],

[0733] TFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xPEG+yGlu-C18-diacid / K18; SEQID NO:GIP(5-30)+Cex(31-39)[H18K],

[0734] TFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-yGlu-C16-diacid / K18; SEQ ID NO: GIP(5-30)+Cex(31-39)[H18K},

[0735] TFISDYSIAMDKIHQKDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C18 diacid / K20; SEQ ID NO:GIP(5-36)[Q20K],

[0736] TFISDYSIAMDKIHQKDFVNWLLAQKGKKNDW(NH2)-2xAEEAc+y-glu-C18 diacid / K20; SEQID NO:GIP(5-36)[Q20K],

[0737] TFISDYSIAMDKIHQQDFVKWLLAQKGKKNDW-2xAEEAc+y-glu-C18 diacid / K24; SEQ ID NO:GIP(5-36[N24K],

[0738] TFISDYKIAMDKIHQQDFVNWLLAGGPSSGAPPPS(NH2)-2xPEG+yGlu-C18-diacid / K11; SEQID NO:GIP(5-30)+Cex(31-39)[S11K; Q29G; K30G],

[0739] TFISDYKIAMDKIHQQDFVNWLLAQKPSSGAPPPS(NH2)

[0740] 2xPEG+yGlu-C18-diacid / K11 AT632, and

[0741] or functional variants thereof.

[0742] In one embodiment, the GIP analog is selected from the group consisting of:

[0743] FISDYSIAMDKIKQQDFVNWLLAQKGKK-C16 diacid / K18; SEQ ID NO: GIP(6-33)[H18K],

[0744] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-C16 diacid / K18; SEQ ID NO:GIP(6-36)[H18K],

[0745] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN-C16 diacid / K18; SEQ ID NO:GIP(6-39)[H18K],

[0746] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ-C16 diacid / K18; SEQ ID NO: GIP(6-42)[H18K], and

[0747] FISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-C16 diacid / K18; SEQ ID NO:GIP(6-30)+Cex[H18K],

[0748] or a functional variant thereof,

[0749] wherein the fatty acid is attached directly or via a linker / spacer as defined herein.

[0750] Compound

[0751] In another aspect there is provided a compound comprising or consisting of a peptide as defined herein. In one embodiment, the compound is formulated as a peptide monomer (i.e. comprising 1 copy of the peptide), and in another embodiment, the compound is formulated as a peptide multimer.

[0752] Polymeric compounds

[0753] In one embodiment, the peptides according to the present disclosure are formulated as multimers. A multimer is a protein comprising or consisting of multiple peptide monomers. A multimer is an aggregate of multiple molecules typically held together by non-covalent bonds. This definition distinguishes a multimer from a polymer, which is a series of monomers held together by covalent bonds.

[0754] In one embodiment, the peptide sequence of the present disclosure is linked to another (same or different) peptide sequence of the present disclosure by a chemical bond or by a linker group. In some embodiments, the peptide of the present disclosure is formulated as an oligomer or multimer of monomers, wherein each monomer is a peptide sequence defined according to the present disclosure.

[0755] Thus, in one embodiment, according to the present disclosure, the multimeric compound is a polymer comprising two or more peptide sequences according to the present disclosure, said peptide sequences being identical or different, wherein at least one of said two or more peptide sequences is a peptide according to the present disclosure. Preferably, both peptide sequences are peptides according to the present disclosure.

[0756] In one embodiment, the multimeric compound is a dimer comprising two peptides according to the present disclosure, said two peptides being identical or different with respect to each other.

[0757] In another embodiment, the multimeric compound is a trimer comprising three peptides according to the present disclosure, said peptides being identical or different with respect to each other.

[0758] In another embodiment, the multimeric compound is a tetramer comprising four peptides according to the present disclosure, which peptides are identical or different with respect to each other.

[0759] In one embodiment, the multimeric compound is a dendrimer, such as a tetrameric or octameric dendrimer.Dendrimers are repeatedly branched, roughly spherical macromolecules, typically symmetric around a core, usually adopting a spherical three-dimensional morphology.

[0760] The dendrimer according to the present disclosure may comprise 4 peptides, 8 peptides, 16 peptides or 32 peptides. In a particular embodiment, the dendrimer comprises four peptides (ie a tetrameric dendrimer) or eight peptides (an octameric dendrimer).

[0761] In some specific embodiments, the multimeric compound comprises two identical amino acid sequences of the present disclosure (dimer) or the compound comprises four identical copies of an amino acid sequence of the present disclosure (tetrameric dendrimer).

[0762] In one embodiment, the polymer according to the present disclosure is prepared by connecting two or more peptide monomers by peptide bonds or linker groups. In one embodiment, they are connected to a lysine backbone, such as a lysine residue (each peptide chain is connected to a single lysine residue), or are coupled to a polymer carrier, for example, a protein carrier. In one embodiment, the linker group comprises a plurality of lysine residues, such as a core part with a plurality of lysine residues, such as seen in a lysine-based dendritic structure containing three, seven, fifteen and more lysine residues, however, any other connection of peptide monomers well known to those skilled in the art is conceivable.

[0763] In one embodiment, the linkage occurs at the N-terminus and / or C-terminus of the peptide monomer.

[0764] In one embodiment, a multimeric compound is provided, consisting of:

[0765] A) one or more glucose-dependent insulinotropic peptide (GIP) analogs selected from the group consisting of:

[0766] -Glucose-dependent insulinotropic peptide (GIP) analogs

[0767] It consists of the amino acid sequence SEQ ID NO: XX:

[0768]

[0769] wherein X1 and X2 are independently any amino acid or are omitted;

[0770] or a functional variant thereof, wherein the variant has 1 to 7 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0771] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant, wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E); and

[0772] - a glucose-dependent insulinotropic peptide (GIP) analogue selected from the group consisting of:

[0773] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0774]

[0775] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0776]

[0777] and

[0778] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0779]

[0780] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30),

[0781] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues 4 to 29 of any one of SEQ ID NO: and SEQ ID NO: or a functional variant thereof comprising between 1 and 4 amino acid substitutions in any one of SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30),

[0782] where Z is:

[0783] a. Glycine or proline,

[0784] b. A fragment selected from the following:

[0785] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0786] b1. A fragment selected from the following:

[0787] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0788] c. A fragment selected from the following:

[0789] or

[0790] d. A fragment selected from the following:

[0791] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0792] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0793] e. A fragment selected from the following:

[0794] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0795] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues;

[0796] B) Optionally, one or more linker groups.

[0797] Determine antagonist properties and affinity

[0798] To determine whether a peptide is an antagonist of a GIPR, methods known in the art can be used, such as by determining the IC50 of the peptide. This can be accomplished by constructing a dose-response curve and examining the effect of varying concentrations of the peptide on the inverse agonist activity. The agonist can be GIP1-42, such as hGIP-1-42 or hGIP1-30. The GIPR can be an hGIPR, rGIPR, mGIPR, canine GIPR, porcine GIPR, or rhesus monkey (Macaca mulatta) GIPR. The IC50 value of a given antagonist can be calculated by determining the concentration required to inhibit half of the maximal biological response of the agonist. Example 4 describes a method for determining whether a peptide is an antagonist, but other methods known in the art can also be used. For example, Schild plot analysis can be performed on the hGIP1-42 cAMP dose-response curve as the concentration of the GIP-derived peptide increases. In this way, the type of antagonist activity can also be determined.

[0799] The GIP peptide analogs of the present disclosure are characterized by having antagonistic activity against GIPR. In particular, the GIP peptide analogs of the present disclosure are potent antagonists of GIPR, due in large part to the presence of fatty acids in the core of the GIP peptide (residues 3 to 29 of GIP) and an extension at the C-terminus of the GIP peptide.

[0800] In one embodiment, the GIP peptide analogs of the present disclosure are antagonists of GIPR.

[0801] In one embodiment, the GIP peptide analogs of the present disclosure inhibit, such as are capable of inhibiting, GIPR activity by at least 70%, such as at least 75%, such as at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100%, as measured via an assay that determines a reduction in intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which are described in "Materials and Methods").

[0802] In one embodiment, the GIP peptide analogs of the present disclosure inhibit GIPR activity by at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100%, wherein inhibition of GIPR activity is determined as a reduction in intracellular cAMP, for example, via an assay that determines a reduction in intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which is described in "Materials and Methods"). The % inhibition is the % inhibition of Emax, which means that if the peptide inhibits 85% of Emax, the GIPR remains 15% active.

[0803] In one embodiment, the GIP peptide analogs of the present disclosure have a GIPR antagonist activity corresponding to an IC50 of 50 nM or less, such as 45 nM or less, such as 40 nM or less, such as 35 nM or less, such as 30 nM or less, such as 25 nM or less, such as 20 nM or less, such as 15 nM or less, such as 10 nM or less, such as 5 nM or less, such as between 1 and 5 nM, wherein the antagonist activity (also referred to as "potency") is measured via an assay that determines the reduction of intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which is described in "Materials and Methods").

[0804] Methods for determining the antagonist activity of compounds (such as GIP peptide analogs) are known to those skilled in the art. Exemplary methods for determining the antagonist activity of compounds (such as GIP peptide analogs) can be found in the "Examples" herein, for example, these methods include measuring intracellular cAMP and determining the reduction of intracellular cAMP caused by treating cells with GIP peptide analogs.

[0805] The GIP peptide analogs of the present disclosure are also characterized by having low or no agonistic activity on GIPR. GIP peptide analogs having low or no agonistic activity on GIPR, such as 20% or less, preferably 10% or less, even more preferably 5% or less agonistic activity, are also referred to as "silent antagonists."

[0806] In one embodiment, the GIP peptide analog of the present disclosure is capable of stimulating GIPR activity by up to 30%, such as up to 25%, such as up to 20%, such as up to 15%, such as up to 10%, such as up to 5%. In one embodiment, the GIP peptide analog of the present disclosure has no agonistic activity on GIPR, i.e., it stimulates about 0% of GIPR activity.

[0807] Agonistic activity of GIP peptide analogs towards GIPR can be determined in the same manner as antagonistic activity, but measuring the increase in intracellular cAMP rather than the decrease, as described in "Materials and Methods".

[0808] Treatment

[0809] In one aspect there is provided a peptide as defined herein or a composition comprising said peptide for use as a medicament.

[0810] In one embodiment, a glucose-dependent insulinotropic peptide (GIP) analog is provided, which consists of the amino acid sequence SEQ ID NO: XX:

[0811]

[0812] wherein X1 and X2 are independently any amino acid or are omitted;

[0813] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0814] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0815] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use as a pharmaceutical agent.

[0816] In one embodiment, a GIP analog is provided that is selected from the group consisting of:

[0817] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0818]

[0819] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0820]

[0821] and

[0822] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0823]

[0824]

[0825] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP (3-30), SEQ ID NO: hGIP (5-30) and SEQ ID NO: hGIP (6-30),

[0826] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from positions 6 to 29 in any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30) or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0827] Glycine or proline,

[0828] Excerpts from the following:

[0829] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0830] Excerpts from the following:

[0831] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, selected from the following fragments:

[0832] or

[0833] Excerpts from the following:

[0834] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0835] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0836] Excerpts from the following:

[0837] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0838] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, for use as a medicament.

[0839] In one embodiment, a glucose-dependent insulinotropic peptide (GIP) analog is provided, which consists of the amino acid sequence SEQ ID NO: XX:

[0840]

[0841] wherein X1 and X2 are independently any amino acid or are omitted;

[0842] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0843] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0844] wherein Z is a peptide comprising one or more amino acid residues of GIP (31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use in a method of inhibiting or reducing one or more of the following: i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and / or fatty acid incorporation, vi) high or increased GIPR expression or activity, vii) postprandial GIP release, viiii) serum levels of free fatty acids and / or triglycerides, ix) GIP-induced increase in appetite, x) GIP-induced decrease in energy expenditure, xi) GIP-induced increase in intestinal nutrient absorption, xii) GIP-induced reduction in the appetite suppressant effect of GLP-1, xiii) GIP-induced leptin resistance.

[0845] In one embodiment, a GIP analog is provided that is selected from the group consisting of:

[0846] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0847]

[0848] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0849]

[0850]

[0851] and

[0852] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0853]

[0854] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP (3-30), SEQ ID NO: hGIP (5-30) and SEQ ID NO: hGIP (6-30),

[0855] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from positions 6 to 29 in any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30) or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0856] Glycine or proline,

[0857] Excerpts from the following:

[0858] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0859] Excerpts from the following:

[0860] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0861] Excerpts from the following:

[0862] or

[0863] Excerpts from the following:

[0864] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0865] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues,

[0866] or

[0867] Excerpts from the following:

[0868] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, for use in a method of inhibiting or reducing one or more of the following: i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and / or fatty acid incorporation, vi) high or increased GIPR expression or activity, vii) postprandial GIP release, viiii) serum levels of free fatty acids and / or triglycerides, ix) reduced GIP-induced bone resorption.

[0869] In one embodiment, a glucose-dependent insulinotropic peptide (GIP) analog is provided, which consists of the amino acid sequence SEQ ID NO: XX:

[0870]

[0871] wherein X1 and X2 are independently any amino acid or are omitted;

[0872] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0873] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0874] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E),

[0875] It is used in a method of treating a condition selected from the group consisting of metabolic syndrome, obesity, prediabetes, type 1 diabetes, type 2 diabetes, insulin resistance, elevated fasting blood glucose, hyperglycemia, elevated fasting serum triglyceride levels, low very low density lipoprotein (VLDL) levels, low high density lipoprotein (HDL) levels, dyslipidemia, elevated / decreased low density lipoprotein (LDL), high cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure, and atherosclerosis.

[0876] In one embodiment, a GIP analog is provided that is selected from the group consisting of:

[0877] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0878]

[0879] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0880]

[0881] and

[0882] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0883]

[0884] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP (3-30), SEQ ID NO: hGIP (5-30) and SEQ ID NO: hGIP (6-30),

[0885] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from positions 6 to 29 in any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30) or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0886] Glycine or proline,

[0887] Excerpts from the following:

[0888] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0889] Excerpts from the following:

[0890] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0891] a fragment selected from the group consisting of GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or

[0892] Excerpts from the following:

[0893] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues,

[0894] or

[0895] Excerpts from the following:

[0896] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0897] or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, for use in a method for treating a condition selected from the group consisting of metabolic syndrome, obesity, overweight, obesity-related disorders, prediabetes, type 1 diabetes, type 2 diabetes, diabetes-related disorders, insulin resistance, elevated fasting blood glucose, hyperglycemia, elevated fasting serum triglyceride levels, low very low density lipoprotein (VLDL) levels, low high density lipoprotein (HDL) levels, dyslipidemia, elevated / decreased low density lipoprotein (LDL), high cholesterol levels, abnormal deposition of lipids, cardiovascular disease, elevated blood pressure, and atherosclerosis.

[0898] In one embodiment, a glucose-dependent insulinotropic peptide (GIP) analog is provided, which consists of the amino acid sequence SEQ ID NO: XX:

[0899]

[0900] wherein X1 and X2 are independently any amino acid or are omitted;

[0901] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0902] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0903] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use in a method of inducing weight loss.

[0904] In one embodiment, a GIP analog is provided that is selected from the group consisting of:

[0905] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0906]

[0907] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0908]

[0909] and

[0910] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0911]

[0912] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP (3-30), SEQ ID NO: hGIP (5-30) and SEQ ID NO: hGIP (6-30),

[0913] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from positions 6 to 29 in any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30) or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0914] Glycine or proline,

[0915] Excerpts from the following:

[0916] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0917] Excerpts from the following:

[0918] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0919] Excerpts from the following:

[0920] or

[0921] Excerpts from the following:

[0922] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0923] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0924] Excerpts from the following:

[0925] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0926] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, for use in a method of inducing weight loss.

[0927] In one embodiment, a glucose-dependent insulinotropic peptide (GIP) analog is provided, which consists of the amino acid sequence SEQ ID NO: XX:

[0928]

[0929] wherein X1 and X2 are independently any amino acid or are omitted;

[0930] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any amino acid of SEQ ID NO: XX,

[0931] wherein the peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues 3 to 29 of SEQ ID NO XX or said functional variant,

[0932] wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E),

[0933] It is used to manufacture a medicament for:

[0934] - treating a condition selected from the group consisting of metabolic syndrome, obesity, overweight, obesity-related disorders, prediabetes, type 1 diabetes, type 2 diabetes, diabetes-related disorders, insulin resistance, elevated fasting plasma glucose, hyperglycemia, elevated fasting serum triglyceride levels, low very low density lipoprotein (VLDL) levels, low high density lipoprotein (HDL) levels, dyslipidemia, elevated / low low density lipoprotein (LDL), elevated cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure, and atherosclerosis, or

[0935] -Induce weight loss, or

[0936] Treatment of cancers including but not limited to colon cancer, neuroendocrine cancer, and adrenal adenomas.

[0937] In one embodiment, a GIP analog is provided that is selected from the group consisting of:

[0938] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (3-30):

[0939]

[0940] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (5-30):

[0941]

[0942] and

[0943] A peptide having an amino acid sequence consisting of SEQ ID NO: hGIP (6-30):

[0944]

[0945] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP (3-30), SEQ ID NO: hGIP (5-30) and SEQ ID NO: hGIP (6-30),

[0946] wherein the peptide is modified by attaching at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from positions 6 to 29 in any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30) or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30),

[0947] where Z is:

[0948] Glycine or proline,

[0949] Excerpts from the following:

[0950] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0951] Excerpts from the following:

[0952] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[0953] Excerpts from the following:

[0954] or

[0955] Excerpts from the following:

[0956] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0957] Excerpts from the following:

[0958] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or variants thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, for use in the manufacture of a medicament for:

[0959] - treating a condition selected from the group consisting of metabolic syndrome, obesity, overweight, obesity-related disorders, prediabetes, type 1 diabetes, type 2 diabetes, diabetes-related disorders, insulin resistance, elevated fasting plasma glucose, hyperglycemia, elevated fasting serum triglyceride levels, low very low density lipoprotein (VLDL) levels, low high density lipoprotein (HDL) levels, dyslipidemia, elevated / low low density lipoprotein (LDL), elevated cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure, and atherosclerosis, or

[0960] -Induce weight loss, or

[0961] -Treatment of cancer including but not limited to colon cancer, neuroendocrine cancer and adrenal adenoma.

[0962] In a specific embodiment, there is provided a GIP peptide analogue as defined herein for use in a method of treating obesity.

[0963] In a specific embodiment, there is provided a GIP peptide analogue as defined herein for use in a method of treating diabetes, including type I and type II diabetes.

[0964] In a specific embodiment, there is provided a GIP peptide analogue as defined herein for use in a method of treating insulin resistance.

[0965] In a further aspect there is provided a GIP peptide analogue as defined herein for use in a method of treating cancer.

[0966] Obesity-related disorders can be any of the following: increased food intake, increased appetite, overeating, bulimia nervosa, obesity caused by administration of antipsychotics or steroids, decreased / increased gastric motility, delayed / increased gastric emptying, decreased physical activity, osteoarthritis, dyslipidemia, increased / decreased low-density lipoprotein (LDL), high cholesterol levels, and abnormal lipid deposition.

[0967] In some embodiments, dyslipidemia, elevated / decreased low-density lipoprotein (LDL), cholesterol, and abnormal lipid deposition are referred to as fatty acid metabolism disorders.

[0968] Diabetes-related disorders can be any of the following: impaired glucose tolerance (IGT), progression from IGT to type 2 diabetes, progression from non-insulin-requiring type 2 diabetes to insulin-requiring type 2 diabetes, decreased β-cell function, decreased β-cell mass, increased β-cell apoptosis, or decreased β-cell sensitivity to glucose.

[0969] The cardiovascular disease can be any of the following: coronary heart disease, myocardial infarction, reperfusion injury, stroke, cerebral ischemia, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive emergency, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and / or chronic heart failure, arrhythmia, cardiac arrhythmia, syncope, angina pectoris, cardiac bypass and / or stent reocclusion, intermittent claudication (also known as atherosclerotic occlusion), diastolic dysfunction and systolic dysfunction and combinations thereof.

[0970] In one embodiment, the cancer is selected from colon cancer, neuroendocrine cancer, and adrenal adenoma.

[0971] In another aspect there is provided a GIP peptide analogue as defined herein for use in a method of treating a bone density disorder (or bone volume disorder).

[0972] In one embodiment, a GIP peptide analogue as defined herein is provided for use in a method of inhibiting osteocyte activity. In one embodiment, a peptide as defined herein is provided for use in a method of inhibiting (or antagonizing) GIP-induced reduction in postprandial bone resorption. In one embodiment, a peptide as defined herein is provided for use in a method of treating bone cancer.

[0973] In one embodiment, the bone density (or volume) disorder is selected from osteoporosis, a disorder characterized by low bone density and / or decreased bone volume, a disorder characterized by high bone density and / or increased bone volume, and osteoporosis.

[0974] In another aspect, a GIP peptide analogue as defined herein is provided for use in a method of characterizing or examining various aspects of a disorder and / or characterizing or examining various aspects of human physiology associated with the disorder, wherein in one embodiment, the disorder is selected from metabolic syndrome, obesity, diabetes, insulin resistance, an obesity-related disorder as defined herein, or a diabetes-related disorder as defined herein. In other aspects, the present invention relates to methods of treating cancer (such as colon cancer or adrenal adenoma). In other aspects, the present invention relates to methods of treating bone density disorders or osteoporosis characterized by high bone density and / or increased bone volume. In other aspects, the present invention relates to methods of treating atherosclerosis.

[0975] Also provided is a method for treating metabolic syndrome, obesity, overweight, diabetes, insulin resistance, an obesity-related disorder as defined herein, or a diabetes-related disorder as defined herein; cancer (such as colon cancer or adrenal adenoma); a bone density disorder (such as a bone density disorder characterized by high bone density and / or increased bone volume); or atherosclerosis; the method comprising the step of administering to an individual in need thereof an effective amount of a peptide as defined herein.

[0976] Individuality in need mentioned herein is the individuality that can benefit from the administration according to the peptide of the present disclosure or pharmaceutical composition.Such individuality may suffer from metabolic syndrome, and / or suffer from metabolic disorder (such as obesity, overweight, diabetes, insulin resistance, obesity related disorder as defined herein or diabetes related disorder as defined herein), cancer (such as colon cancer or adrenal adenoma), bone density disorder, or have the risk of suffering from these disorders.Described individuality can be anyone, male or female, baby, middle-aged or elderly.Individual obstacle to be treated or prevented may be with individual age, individual overall health status, be used to treat individual medicine and individual whether suffer from and may induce or have induced metabolic syndrome and / or metabolic disorder (such as obesity, overweight, diabetes, insulin resistance, obesity related disorder as defined herein or diabetes related disorder as defined herein), cancer (such as colon cancer or adrenal adenoma), atherosclerosis, the disease of bone density disorder or obstacle are relevant. In some embodiments, the disorder to be treated is associated with GIP-induced glucagon secretion, GIP-induced insulin secretion, GIP-induced somatostatin secretion, GIP-induced glucose uptake, GIP-induced fatty acid synthesis and / or fatty acid incorporation, higher GIPR expression or activity, postprandial GIP release; wherein the term "high" is to be construed as referring to levels above the corresponding levels observed in individuals not requiring treatment.

[0977] Preparation method (peptide)

[0978] The peptides according to the present disclosure may be prepared by any method known in the art.Thus, GIP-derived peptides may be prepared by standard peptide preparation techniques such as solution synthesis or Merrifield-type solid phase synthesis.

[0979] In one embodiment, the peptide defined herein is a non-naturally occurring peptide; derived from the naturally occurring protein native GIP, such as GIP(1-42).

[0980] In one embodiment, peptides according to the present disclosure are purified from their naturally occurring sources, such as serum. Protein purification is a series of processes intended to separate a single type of protein from a complex mixture. The starting material is typically biological tissue. The various steps in the purification process can free the protein from the matrix that defines it, separate the protein and non-protein fractions in the mixture, and finally separate the desired protein from all other proteins. The separation step can utilize, for example, differences in protein size, physicochemical properties, binding affinity, and biological activity.

[0981] In one embodiment, the peptides according to the present disclosure are manufactured or produced synthetically.

[0982] Methods for synthesizing peptides are well known in the art. Detailed instructions and practical advice for producing synthetic peptides can be found in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), edited by Grant GA, Oxford University Press, 2002, or in Pharmaceutical Formulation: Development of Peptides and Proteins, edited by Frokjaer and Hovgaard, Taylor and Francis, 1999.

[0983] In one embodiment, the peptides or peptide sequences of the invention are produced synthetically, in particular by a sequence-assisted peptide synthesis (SAPS) method, by solution synthesis, by solid phase peptide synthesis (SPPS) (such as Merrifield-type solid phase synthesis), by recombinant technology (produced by a host cell comprising a first nucleic acid sequence encoding a peptide, the first nucleic acid sequence being operably associated with a second nucleic acid capable of directing expression in the host cell) or enzymatic synthesis. These are well known to those skilled in the art.

[0984] Peptides can be synthesized batchwise on a fully automated peptide synthesizer using 9-fluorenylmethoxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc) as the Na-amino protecting group and appropriate common side chain functional group protecting groups.

[0985] After purification, such as by reverse phase HPLC, the peptide can be further processed to obtain, for example, cyclic or C-terminally or N-terminally modified isoforms. Methods for cyclization and terminal modifications are well known in the art.

[0986] The peptides according to the present invention may be synthesized as monomers or multimers (such as dimers or tetramers).

[0987] Pharmaceutical compositions and formulations

[0988] Although the bioactive agents of the present disclosure can be administered as chemical raw materials (peptides), it is sometimes preferred to be in the form of a pharmaceutical formulation. Such pharmaceutical formulations can be referred to as pharmaceutical compositions, pharmaceutically acceptable compositions, or pharmaceutically safe compositions.

[0989] Therefore, a pharmaceutical formulation is further provided, comprising a bioactive agent of the present invention or a pharmaceutically acceptable salt or ester thereof, and a pharmaceutically acceptable carrier, excipient and / or diluent. The pharmaceutical formulation can be prepared by conventional techniques, for example, as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0990] The present invention is also intended to cover pharmaceutically acceptable salts of the peptide compounds of the present invention (where they can be prepared). These salts will be salts that are acceptable in their use as pharmaceuticals. This means that the salts will retain the biological activity of the parent compound and will not have adverse or deleterious effects in their use and application for treating disease.

[0991] Pharmaceutically acceptable salts are prepared in a standard manner. If the parent compound is a base, it is treated with an excess of an organic or inorganic acid in a suitable solvent. If the parent compound is an acid, it is treated with an inorganic or organic base in a suitable solvent.

[0992] The peptide compounds disclosed herein can be administered in an effective amount in the form of their alkali metal salts or alkaline earth metal salts in conjunction with, simultaneously with or together with a pharmaceutically acceptable carrier or diluent, especially and preferably in the form of their pharmaceutical compositions, whether by oral, rectal or parenteral (including subcutaneous) routes.

[0993] For example, examples of pharmaceutically acceptable acid addition salts for use in the pharmaceutical compositions of the present invention include those derived from inorganic acids such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid and sulfuric acid, and organic acids such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, p-toluenesulfonic acid and arylsulfonic acids.

[0994] In specific embodiments, the peptides according to the present disclosure are formulated as acetate salts, HCl (hydrochloric acid) salts, or TFA (trifluoroacetic acid) salts.

[0995] Administration and dosage

[0996] According to the present disclosure, the peptides defined herein or compositions comprising the peptides defined herein are administered to an individual in need of treatment in a pharmaceutically effective dose or a therapeutically effective amount. Dosage requirements will vary with the specific pharmaceutical composition used, the route of administration, and the specific subject being treated, depending on the severity and type of the disorder and the weight and general condition of the subject. Those skilled in the art will also recognize that the optimal number and interval of individual doses of the peptide compound will depend on the nature and extent of the condition being treated, the form, route, and site of administration, and the specific patient being treated, and such optimal values ​​can be determined by conventional techniques. Those skilled in the art will also appreciate that conventional course determination tests can be used to determine the optimal course of treatment, i.e., the dose of the compound administered daily over a defined number of days.

[0997] In one embodiment, the bioactive agent is administered at least once a day, such as once a day, such as twice a day, such as three times a day, such as four times a day, such as five times a day.

[0998] The dose may also be administered at intermittent intervals or intervals, so that instead of administering a dose every day, one or more doses may be administered every second day, every third day, every fourth day, every fifth day, every sixth day, every week, every second week, every third week, every fourth week, every fifth week, every sixth week, or intervals within these ranges, such as every 2 to 4 weeks or 4 to 6 weeks.

[0999] In one embodiment, the dose is administered once a week, such as once a week, such as one dose per week.

[1000] Route of administration

[1001] It will be appreciated that the preferred route of administration will depend on the general condition and age of the subject to be treated, the nature of the condition to be treated, the location in the body of the tissue to be treated and the active ingredient chosen.

[1002] Systemic treatment

[1003] For systemic treatment according to the present disclosure, the route of administration is capable of introducing the biologically active agent into the bloodstream to ultimately target the desired site of action.

[1004] These administration routes are any suitable routes, such as enteral routes (including oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intracisternal and intraperitoneal administration), and / or parenteral routes (including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous and intradermal administration).

[1005] Parenteral administration

[1006] Parenteral administration refers to any route of administration other than the oral / enteral route, whereby the agent avoids first-pass degradation in the liver. Thus, parenteral administration includes any injection and infusion, e.g., bolus injection or continuous infusion, such as intravenous administration, intramuscular administration, or subcutaneous administration. In addition, parenteral administration includes inhalation and topical administration.

[1007] Thus, the bioactive agent can be administered topically to cross any mucous membrane of the animal to which the bioactive agent is to be administered, for example, in the nose, vagina, eyes, mouth, reproductive tract, lungs, gastrointestinal tract, or rectum, preferably the mucous membrane of the nose or mouth, and thus, parenteral administration can also include buccal, sublingual, nasal, rectal, vaginal, and intraperitoneal administration, as well as pulmonary and bronchial administration by inhalation or installation. In addition, the agent can also be administered topically to cross the skin.

[1008] According to an advantageous embodiment of the invention, the GIP analogue is administered subcutaneously.

[1009] Topical treatment

[1010] In one embodiment, the bioactive agents according to the present invention can be used as a topical treatment, i.e., directly introduced into one or more sites of action. Thus, the bioactive agent can be applied directly to the skin or mucous membranes, or the bioactive agent can be injected into the site of action, for example, into the diseased tissue or directly into a terminal artery that leads directly to the diseased tissue. These modes of administration preferably avoid the blood-brain barrier.

[1011] Multicomponent kits

[1012] The present disclosure also relates to a kit of parts comprising one or more biologically active agents as described above and at least one additional or other component, such as one or more second active ingredients.

[1013] References

[1014] 1.Baggio LL,Drucker DJ.Biology of Incretins:GLP-1andGIP.Gastroenterology 2007;132(6):2131-2157.

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[1016] 3.Heer J,Rasmussen C,Coy DH,Holst JJ.Glucagon-like peptide-1,but notglucose-dependent insulinotropic peptide,inhibits glucagon secretion viasomatostatin(receptor subtype 2)in the perfused rat pancreas.Diabetologia2008;51(12):2263-2270.

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[1019] 6.Pederson R,Brown J.Interaction of Gastric Inhibitory Polypeptide,Glucose,and Arginine on Insulin and Glucagon Secretion from the Perfused RatPancreas.Endocrinology 1978;103(2):610-615.

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[1022] 9.Dupre J,Caussignac Y,McDonald TJ,Van Vliet S.Stimulation ofGlucagon Secretion by Gastric Inhibitory Polypeptide in Patients with HepaticCirrhosis and Hyperglucagonemia.The Journal of Clinical Endocrinology&Metabolism 1991;72(1):125-129.

[1023] 10.Ding WG,Renstrom E,Rorsman P,Buschard K,Gromada J.Glucagon-likepeptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediatedmechanism.Diabetes 1997;46(5):792-800.

[1024] 11.Meier JJ,Gallwitz B,Siepmann N et al.Gastric inhibitorypolypeptide(GIP)dose-dependently stimulates glucagon secretion in healthyhuman subjects at euglycaemia.Diabetologia 2003;46(6):798-801.

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[1031] 18.Hauner H,Glatting G,Kaminska D,Pfeiffer EF.Effects of gastricinhibitory polypeptide on glucose and lipid metabolism of isolated ratadipocytes.Ann Nutr Metab 1988;32(5-6):282-288.

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[1033] 20.Nasteska D,Harada N,Suzuki K et al.Chronic Reduction of GIPSecretion Alleviates Obesity and Insulin Resistance Under High-

[1034] Fat Diet Conditions.Diabetes 2014;63(7):2332-2343.

[1035] 21.Miyawaki K,Yamada Y,Yano H et al.Glucose intolerance caused by adefect in the entero-insular axis:A study in gastric inhibitory polypeptidereceptor knockout mice.Proceedings of the National Academy of Sciences 1999;96(26):14843-14847.

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[1038] 24.Asmar M,Simonsen L,Madsbad S,Stallknecht B,Holst JJ,BülowJ.Glucose-Dependent Insulinotropic Polypeptide May Enhance Fatty Acid Re-esterification in Subcutaneous Abdominal Adipose Tissue in LeanHumans.Diabetes 2010;59(9):2160-2163.

[1039] 25.Deschamps I,Heptner W,Desjeux JF,Baltakse V,Machinot S,LestradetH.Effects of diet on insulin and gastric inhibitory polypeptide levels inobese children.Pediatr Res 1980;14(4 Pt 1):300-303.

[1040] 26. C,Jensen CB,Storgaard H et al.Impact of short-term high-fatfeeding on glucose and insulin metabolism in young healthymen.The Journal ofPhysiology 2009;587(10):2387-2397.

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[1043] 29.Nakamura T,Tanimoto H,Mizuno Y,Tsubamoto Y,Noda H.Biological andfunctional characteristics of a novel weight antagonist ofglucose-dependent insulinotropic polypeptidereceptor,SKL-14959,in vitro andin vivo.Diabetes,Obesity and Metabolism 2012;14(6):511-517.

[1044] 30.Ebert R,Illmer K,Creutzfeldt W.Release of gastric inhibitorypolypeptide(GIP)by intraduodenal acidification in rats and humans andabolishment of the incretin effect of acid by GIP-antiserum inrats.Gastroenterology 1979;76(3):515-523.

[1045] 31.Fulurija A,Lutz TA,Sladko K et al.Vaccination against GIP for theTreatment of Obesity.PLoS ONE 2008;3(9):e3163.

[1046] 32.Irwin N,McClean PL,Patterson S,Hunter K,Flatt PR.Activeimmunisation against gastric inhibitory polypeptide(GIP)improves bloodglucose control in an animal model of obesity-diabetes.BiologicalChemistry.bchm 390,75.2009.16-7-2014.

[1047] 33.Hinke SA,Manhart S,Pamir N et al.Identification of a bioactivedomain in the amino-terminus of glucose-dependent insulinotropic polypeptide(GIP).Biochimica et Biophysica Acta(BBA)-Prote in Structure and MolecularEnzymology 2001;1547(1):143-155.

[1048] 34.Tseng CC,Kieffer TJ,Jarboe LA,Usdin TB,Wolfe MM.Postprandialstimulation of insulin release by glucose-dependent insulinotropicpolypeptide(GIP).Effect of a specific glucose-dependent insulinotropicpolypeptide receptor antagonist in the rat.J Clin Invest 1996;98(11):2440-2445.

[1049] 35.Irwin N,Green BD,Parker JC,Gault VA,O'Harte FPM,FlattPR.Biological activity and antidiabetic potential of synthetic fragmentpeptides of glucose-dependent insulinotropic polypeptide,GIP(1-16)and(Pro3)GIP(1-16).Regulatory Peptides 2006;135 45-53.

[1050] 36.Kerr BD,Flatt AJS,Flatt PR,Gault VA.Characterization andbiological actions of N-terminal truncated forms of glucose-dependentinsulinotropic polypeptide.Biochemical and Biophysical ResearchCommunications 2011;404(3):870-876.

[1051] 37.Gelling RW,Coy DH,Pederson RAet al.GIP(6-30amide)contains the highaffinity binding region of GIP and is a potent inhibitor of GIP1-42 action invitro.Regulatory Peptides 1997;69(3):151-154.

[1052] 38.Deacon CFP.GIP-(3-42)does not antagonize insulinotropic effects ofGIP at physiological concentrations.American Journal of Physiology-Endocrinology and Metabolism 2006;291(3):E468-E475.

[1053] 39.Gault VA,O'Harte FPM,Harriott P,Flatt PR.Characterization of theCellular and Metabolic Effects of a Novel Enzyme-Resistant Antagonist ofGlucose-Dependent Insulinotropic Polypeptide.Biochemical and BiophysicalResearch Communications 2002;290(5):1420-1426.

[1054] 40.Ravn P,Madhurantakam C,Kunze S et al.Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal AntibodyAntagonists of Glucose-dependent Insulinotropic Polypeptide Receptor.Journalof Biological Chemistry 2013;288(27):19760-19772.

[1055] 41.Deacon CF,Plamboeck A,Rosenkilde MM,de Heer J,Holst JJ.GIP-(3-42)does not antagonize insulinotropic effects of GIP at physiologicalconcentrations.American Journal of Physiology-Endocrinology and Metabolism2006;291(3):E468-E475.

[1056] 42.Goetze JP,Hunter I,Lippert SK,Bardram L,Rehfeld JF.Processing-independent analysis of peptide hormones and prohormones in plasma.FrontBiosci 2012;17:1804-1815.

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[1058] 44.Fujita Y,Asadi A,Yang GK,Kwok YN,Kieffer TJ.Differentialprocessing of pro-glucose-dependent insulinotropic polypeptide ingut.AmericanJournal of Physiology-Gastrointestinal and Liver Physiology 2010;298(5):G608-G614.

[1059] 45.Widenmaier SB,Kim SJ,Yang GK et al.A GIP Receptor Agonist Exhibitsbeta-Cell Anti-Apoptotic Actions in Rat Models of Diabetes Resulting inImproved beta-Cell Function and Glycemic Control.PLoS ONE 2010;5(3):e9590.

[1060] 46.Graham FL,van der Eb AJ.A new technique for the assay of infectivity of human adenovirus 5DNA.Virology 1973;52(2):456-467.

[1061] 47.Kissow H,Hartmann B,Holst JJ et al.Glucagon-like peptide-1(GLP-1)receptor agonism or DPP-4 inhibition does not accelerate neoplasia incarcinogen treated mice.Regulatory Peptides 2012;179(1-3):91-100.

[1062] 48.Hoejberg PV,Vilsboell T,Raboel R et al.Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-likepeptide-1and glucose-dependent insulinotropic polypeptide in patients withtype 2diabetes.Diabetologia 2009;52(2):199-207.

[1063] 49. Hansen LS, Sparre-Ulrich AH, et al..N-terminally and C-terminallytruncated forms of glucosedependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. British Journal ofPharmacology 2016; 173 826–838.

[1064] Example

[1065] This example supports the following conclusions:

[1066] 1) Individual amino acid substitutions at certain positions lead to improved antagonistic profiles

[1067] 2) Several acylation sites showed great potential in both GIP (3-30) + extension and GIP (5-30) + extension

[1068] 3) Extension with C-terminal amino acid residues from GIP (1-42) or exendin-4 results in improved effects, such as antagonism and / or prolonged in vivo half-life and / or selectivity

[1069] 4) GIP peptide analogs according to embodiments of the present invention have increased physical stability, such as increased solubility.

[1070] 5) GIP peptide analogs according to embodiments of the present invention have reduced or no agonistic activity on GIPR.

[1071] Materials and Methods

[1072] WO 2016 / 034186 discloses the production and effects of the GIP(3-30) and GIP(5-30) peptides themselves.

[1073] Material

[1074] Human GIP (1-42) was purchased from Bachem (Bubendorf, Switzerland (H5645)), while the remaining ligands were purchased from Caslo TM(Lyngby, Denmark) and Almac Group (Craigavon, UK), Peptides & Elephants GmbH (Hennigsdorf, Germany), and WuXi AppTec (China). The cDNA of the human GIP receptor was purchased from Origene (Rockville, MD, USA (SC110906)) and cloned into the pCMV-Script vector. Iodinated human GIP (1-42) was purchased from PerkinElmer LifeSciences (Skolund, Denmark (NEX402025UC)).

[1075] animal

[1076] Göttingen miniature pigs or male Wistar rats were housed in the animal facility of the Faculty of Health and Medical Sciences.

[1077] Transfection and tissue culture

[1078] COS-7 cells were cultured in Dulbecco's modified Eagle's medium 1885 (supplemented with 10% fetal bovine serum, 2 mM glutamine, 180 units / ml penicillin, and 45 μg / ml streptomycin) at 10% CO2 and 37°C. Transient transfection of COS-7 cells for cAMP accumulation and competitive binding was performed using calcium phosphate precipitation and the addition of chloroquine. 46-47 .

[1079] cAMP assay

[1080] Alternative 1 (also known as the DiscoveRx assay):

[1081] Transiently transfected COS-7 cells expressing human GIP receptor were seeded in white 96-well plates at a density of 3.5*10 4 / well. The next day, cells were washed twice with Hepes-buffered saline (HBS) buffer and incubated with HBS and 1 mM 3-isobutyl-1-methylxanthine (IBMX) at 37°C for 30 min. To test agonistic properties, ligand was added and incubated at 37°C for 30 min. To test antagonistic properties, cells were pre-incubated with antagonist for 10 min, then agonist was added and incubated for an additional 20 min. The HitHunter™ cAMP XS assay (DiscoveRx) was performed according to the manufacturer's instructions.

[1082] Alternative 2 (also known as the CisBio assay):

[1083] The in vitro functional activity of the compounds against the human GIP receptor can also be determined in HEK-293 cells transiently expressing the receptor. On the day of the assay, cells were resuspended in HBSS buffer (Gibco, 14025-50) supplemented with 20 mM HEPES (Gibco, 15630-106), 0.1% Pluronic F-68 (Gibco, 24040-032), and 0.1% casein (Sigma, C4765) and plated in 384-well plates at a density of 5000 cells / well. The GIP peptide analogs of the present disclosure were diluted in HBSS buffer supplemented with 20 mM HEPES, 0.1% pluronic, 0.1% casein, and 500 uM IBMX. To test for antagonistic properties, each GIP peptide analog to be tested was added to the cells independently and incubated at 37°C for 20 min, followed by addition of the agonist (GIP1-42) at an EC50 concentration and subsequent incubation at 37°C for 30 min. The resulting reduction in intracellular cAMP was quantitatively determined using the CisBio cAMPDynamic 2HTRF assay kit. The assay is based on competition between natural cAMP produced by the cells and cAMP labeled with the dye d2 for binding to a cryptate-labeled antibody. The specific signal (i.e., energy transfer signal) is inversely proportional to the concentration of cAMP in the sample.

[1084] According to the manufacturer's protocol, cAMP-d2 conjugate and antibody anti-cAMP-cryptate (both diluted in lysis buffer provided in the kit) were added to the cells. The resulting competitive assay was incubated at room temperature for 60 minutes and the lysate was detected by using a PerkinElmer The instrument detects signals with excitation at 320 nm and emission at 665 nm and 620 nm. The HTRF ratio (emission at 665 nm / 620 nm*10,000) is inversely proportional to the amount of cAMP present and is converted to nM cAMP / well using a cAMP standard curve. Dose-response curves were fitted using nonlinear regression analysis (four logistic parameter equations) in GraphPad Prism to estimate pIC50 values.

[1085] To test the agonistic properties of the GIP receptor, compounds were diluted as described above and added to the cells and incubated for 30 min at 37° C. The resulting increase in intracellular cAMP was determined using the CisBio cAMP Dynamic 2 HTRF assay kit as described above.

[1086] The estimated elimination half-life (T 1 / 2 )

[1087] Two to three Göttingen minipigs were administered a GIP analog of the invention (1-10 nmol / kg, total volume 2-6 mL) subcutaneously via a central venous catheter, and blood samples were collected before and up to 432 hours after subcutaneous administration. The catheter was flushed with saline and heparin between samples. Blood was collected into cold EDTA tubes, centrifuged, and plasma was kept at -20°C pending analysis.

[1088] The estimated elimination half-life (T 1 / 2 )

[1089] Three Wistar rats were intravenously administered a GIP analogue of the present invention (7 nmol / kg, total dose volume 1 ml / kg), and blood samples were collected from the tail tip before administration and up to 72 hours thereafter. Blood was collected into cold EDTA tubes, centrifuged, and plasma was kept at -20°C pending analysis.

[1090] Determination of plasma concentrations of modified GIP peptide analogs

[1091] The plasma concentrations of the GIP analogs according to the present invention were analyzed in Göttingen minipigs or male Wistar rats by radioimmunoassay (RIA) or by liquid chromatography-mass spectrometry (LC / MS). For RIA-based determinations, the immunoreactivity of the analogs was determined using antisera Ab95234, Ab95235, or Ab95236 (polyclonal in-house antibodies generated in rabbits specific for the mid-region of GIP(1-30)NH2 or the amidated C-terminus of GIP(3-30)NH2). For LC / MS-based determinations, plasma samples were precipitated by adding 3 parts of ethanol and then mixing thoroughly. After centrifugation and dilution of the supernatant, the samples were analyzed by LC-MS / MS and compared to a 9-point calibration curve. The calibration curve was prepared in a naive plasma matrix of Göttingen minipigs. LC / MS was performed by Red Glead Discovery AB (Lund, Sweden).

[1092] Data Analysis

[1093] Determination of IC by nonlinear regression 50 、EC 50 These were calculated using GraphPad Prism 6.0 software (GraphPad, San Diego, CA, USA) and Microsoft Excel TM Pharmacokinetic parameters, including elimination T1 / 2, were calculated using PKsolutions 2.0 software (Summit Research Services, USA).

[1094] Example 1 - The antagonistic properties of human GIP(3-30) and GIP(5-30) extended with 1 to 12 C-terminal amino acid residues from GIP(1-42) or Exendin-4 are retained or improved after the addition of additional C-terminal amino acid residues

[1095] As described below, the addition of between 1 and 12 additional C-terminal amino acid residues to GIP (3-30) and GIP (5-30) was tested for their antagonistic activity and T. The GIP analogs were also acylated with or without a linker at, for example, position 11, 12, 17, 18, or 20, where serine-11, isoleucine-12, isoleucine-17, histidine-18, or glutamine-20 had previously been substituted with lysine.

[1096] result:

[1097] GIP(3-36) analogs (e.g., AT361, which is esterified with C16 diacid at position 18) exhibited an IC of 2 nM compared to, for example, AT158. 50 AT361 also has a very high T of 31h 1 / 2 The half-life is surprisingly long compared to analogs GIP(3-30) esterified with a C16 diacid at position 18 (such as AT158, which has a half-life of only 14 hours). The long half-life is achieved without N-capping or other types of stabilization at the N-terminus, such as AT361, which has a free amine group at the N-terminus.

[1098] GIP (3-30) + amino acids from the C-terminal part of exendin-4 (such as AT631) are generally highly effective antagonists. Compared to, for example, AT158, AT631 exhibits an improved IC of 1.9 nM 50 The half-life of AT631 in vivo also exceeds 30 hours, as a very long T1 / 2 of 56 hours was determined, which is surprisingly long compared to, for example, AT158 (see Figure 1) or liraglutide (which also has a C16 fatty acid). The long half-life is achieved without N-capping or other types of stabilization at the N-terminus, as is the case with, for example, AT631, which has a free amine group at the N-terminus.

[1099] Together with GIP(3-30) antagonists with C-terminal extensions, such as AT361 and AT631, which are better antagonists than those reported in PCT / EP2018 / 064355. 1 / 2The antagonists tested in the pigs studied were much better than the antagonists reported in PCT / EP2018 / 064355. Both AT361 and AT631 also showed an ultra-long T of over 30 hours compared to, for example, the GIP(3-30) analog AT158 (see Table 1B and Figure 1) and other C16 lipidated peptides known in the art, such as liraglutide (a once-daily GLP-1 analog). 1 / 2 AT437, AT632, AT587, AT589, AT614, AT616, AT618, AT619 also have very long half-lives. The combination of C-terminal extension of GIP (3-30) (as in, for example, AT361 and AT631) and acylation (i.e., attachment of fatty acids at specific positions, such as, for example, lysine at position 18) can result in surprisingly long half-lives.

[1100] Without being bound by any theory, the presence of a carboxylic acid at the C-terminus (as in AT361 and AT631) may also contribute to the improved half-life.

[1101] When evaluating and comparing the pharmacokinetic properties of multiple compounds, it may be beneficial to use more than one species. So far, the half-life in question has only been determined in miniature pigs. Although it is generally accepted that the elimination half-life in rats is shorter than that in miniature pigs, our pharmacokinetic findings in rats will be discussed below. From Tables 3A and 3B, the average and time-dependent plasma concentrations in Wistar rats, it can be seen that the exposure and half-life of the analogs in which the fatty acid is attached to the middle region of the peptide are much higher than, for example, the GIP analogs with a fatty acid attached at position 40 of the C-terminus (such as in AT651). For all tested peptides according to embodiments of the present invention, the exposure at each time point is also much higher than, for example, the GIP analogs with a fatty acid attached at position 40 of the C-terminus (such as in AT651). Therefore, attaching fatty acids to the middle region (e.g., positions 11 and 18) of GIP (3-30) with a C-terminal extension simultaneously produces an analog that is pharmacokinetically better than attaching fatty acids to position 40 of the C-terminus. It is also important to note that although many of the analogs tested had C16 fatty acids attached (AT361, AT631, AT366, AT632, AT447), the analogs tested had surprisingly long T1 / 2s (11 h, 7 h, 7 h, 8 h, 5.8 h, respectively) when compared to similar peptides with the same fatty acid length attached (e.g., liraglutide, which has a T1 / 2 of 4 h in rats). Without being bound by any theory, C-terminally extended GIP peptides may constitute molecules that are advantageous for extending half-life through lipidation.

[1102] It can also be seen from Table 2B that specific substitutions may be advantageous. Introducing alpha helix stabilizing amino acids, such as E, L, K, A and Aib, at specific positions (such as independently any one of positions 9, 13, 14, 15, 18, 21 and 24) may be particularly beneficial for increasing antagonistic potency.

[1103] For example, substitution of position 24 with E retains or increases potency.

[1104] As seen, for example, in AT618, AT619, and AT621, the 14th position is substituted with L, Nle, or K, retaining or even increasing effectiveness. As seen, for example, in AT613, AT614, AT616, and AT617, and for example, in AT693, AT695, AT696, and AT700, replacing the 9th and / or 15th and / or 21st D with E appears to increase effectiveness. It can also be seen that the free C-terminal carboxylic acid increases effectiveness. When the length of the fatty acid increases (such as increasing from a C16 diacid to a C18 diacid), effectiveness generally decreases. However, some substitutions may compensate for this. For example, Aib at the 13th position may be substituted with E at, for example, the 9th and / or 15th and / or 21st positions. The 24th position is substituted with E, resulting in retained or improved antagonistic effectiveness and improved solubility, for example, at a physiological pH of about 7.5. As can also be seen in Table 2B, various Zs retain or increase potency, as in, for example, AT467, AT468, AT469, AT470, AT471, AT472, AT473 and AT474. As can be seen, for example, in AT633 and AT635, N-terminal acetylation leads to (partial) agonism of GIPR.

[1105] Table 1A: Names and structures of GIP antagonists with extensions. When a linker consists of more than one unit, it is intended that the first named unit is linked to the peptide and the last named unit is linked to the fatty acid. However, the units of the linker can be placed in a different order with little or no effect on the function of the linker.

[1106]

[1107]

[1108]

[1109]

[1110]

[1111]

[1112]

[1113]

[1114] Table 1B: Antagonistic properties, agonistic properties and for some half-lives, T1 / 2, of GIP antagonists with extended activity. Data were obtained using a cAMP assay (DiscoveRx assay).

[1115]

[1116]

[1117] Table 1C: Antagonistic properties, agonistic properties and for some half-lives, elimination T1 / 2 of GIP antagonists with extension. The CisBio assay (Alternative 2 above) was used to determine the antagonistic and agonistic activities of the GIP peptide analogs listed in Table 1B.

[1118]

[1119]

[1120] Table 1C. Continued

[1121]

[1122]

[1123]

[1124] The half-life of AT631 was determined based on RIA and the half-life of AT361 was determined based on LC / MS (see Materials and Methods).

[1125] Table 2A: For a selected number of compounds, mean and time-dependent plasma concentrations in Wistar rats are shown. Plasma concentrations were determined by LC / MS (see "Materials and Methods").

[1126]

[1127]

[1128] na: Indicates that this time point / plasma sample was not collected and is therefore not available

[1129] Table 2B: Elimination T1 / 2 in Wistar rats is shown for a selected number of compounds, for which the data set enabled calculation (see "Materials and Methods").

[1130] ID T1 / 2 (hour) AT361 11 AT631 7 AT366 7 AT632 8 AT433 8 AT447 5.8 AT449 4.1 AT452 4

[1131] Example 2 - Selectivity

[1132] cAMP Assay - Selective

[1133] Transiently transfected COS-7 cells expressing any of the GLP1 receptor (GLP1R), GLP2 receptor (GLP2R), glucagon receptor (GcgR), or secretin receptor (SCTR) were cultured at 3.5*10 4 The cells were inoculated with a density of 100 μg / mL of 50 μg / mL of 40 μg / mL of 5 μg / mL of 40 μg / mL of 5 μg / mL of 5 μg / mL of 40 μg / mL of 5 μg / mL of 5 μg / mL of 6 μg / mL of 40 μg / mL of 5 μg / mL of 6 μg / mL of 5 μg / mL of 6 μg / mL of 40 μg / mL of 5 μg / mL of 6 μg / mL of 5 μg / mL of 6 μg / mL of 5 μg / mL of 6 μg / mL of 4 μg / mL of 6 μg / mL of 5 ...6 μg / mL of 5 μg / mL of 6 μg / mL of 5 μ

[1134] result:

[1135] We compared the selectivity data of the best antagonists from PCT / EP2018 / 064355 with those of the best antagonists from this application. This was done by determining the antagonistic properties of the peptides at the GIPR, glucagon receptor, and GLP-1 receptor. As shown in the data in Table 3, the antagonists from this application are more selective than the antagonists from PCT / EP2018 / 064355. The combination of C-terminal extension of GIP(3-30) (as in, for example, AT361 and AT631) and acylation at, for example, lysine 18 appears to produce surprisingly selective antagonists.

[1136] Table 3A. Antagonistic properties of GIP antagonists of the present disclosure and previously described in PCT / EP 2018 / 064355 with respect to GIPR, glucagon receptor and GLP-1 receptor.

[1137]

[1138] NA = Not Available

[1139] Italics indicate previously described antagonists

[1140] In addition, the antagonistic properties of the peptides against the GIPR, GLP-2 receptor, and secretin receptor were determined. As shown by the data in Table 3B, the GIP analogs of the present invention, such as AT361 and AT631, do not antagonize the GLP-2 or secretin receptor and are thus highly selective for the GIP receptor.

[1141] Table 3B. Antagonistic properties of the GIP antagonists of the present disclosure against the GIPR, GLP-2 receptor, and secretin receptor.

[1142] ​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​​<SEQ ID NO:11; PRT1; Artificial Sequence> GPSSGAPPP

[1155] <SEQ ID NO:12; PRT1; Artificial Sequence> PSSG

[1156] <SEQ ID NO:13; PRT1; Artificial Sequence> PSSGA

[1157] <SEQ ID NO:14; PRT1; Artificial Sequence> PSSGAP

[1158] <SEQ ID NO:15; PRT1; Artificial Sequence> PSSGAPP

[1159] <SEQ ID NO:16; PRT1; Artificial Sequence> PSSGAPPP

[1160] <SEQ ID NO:17; PRT1; Artificial Sequence>GKKN

[1161] <SEQ ID NO:18; PRT1; Artificial Sequence>GKKND

[1162] <SEQ ID NO:19; PRT1; Artificial Sequence>GKKNDW

[1163] <SEQ ID NO:20; PRT1; Artificial Sequence>GRKNDW

[1164] <SEQ ID NO:21; PRT1; Artificial Sequence>GKRNDW

[1165] <SEQ ID NO:22; PRT1; Artificial Sequence>GRRNDW

[1166] <SEQ ID NO:23; PRT1; Artificial Sequence>GKKNDWK

[1167] <SEQ ID NO:24; PRT1; Artificial Sequence>GKKNDWKH

[1168] <SEQ ID NO:25; PRT1; Artificial Sequence>GKKNDWKHN

[1169] <SEQ ID NO:26; PRT1; Artificial Sequence>GKKNDWKHNI

[1170] <SEQ ID NO:27; PRT1; Artificial Sequence>GKKNDWKHNIT

[1171] <SEQ ID NO:28; PRT1; Artificial Sequence>GKKKDW

[1172] <SEQ ID NO:29; PRT1; Artificial Sequence> GKKNDK

[1173] <SEQ ID NO:30; PRT1; Artificial Sequence> EXTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP3-30 X2),

[1174] <SEQ ID NO:31; PRT1; Artificial Sequence> XGTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP3-30 X1),

[1175] <SEQ ID NO:32; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP3-30),

[1176] <SEQ ID NO:33; PRT1; Artificial Sequence> XTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP4-30 X2),

[1177] <SEQ ID NO:34; PRT1; Artificial Sequence> GTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP4-30),

[1178] <SEQ ID NO:35; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP5-30),

[1179] <SEQ ID NO:36; PRT1; Artificial Sequence> FISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO: (GIP6-30),

[1180] <SEQ ID NO:37; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVNWLLAQK SEQ ID NO:; GIP(3-30),

[1181] <SEQ ID NO:38; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQK SEQ ID NO:; GIP(3-30)[H18K],

[1182] <SEQ ID NO:39; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWLLAQK SEQ ID NO:; GIP(3-30)[E3S; H18K],

[1183] <SEQ ID NO:40; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLLEQK GIP(3-30)Cex(31-39)[M14L; H18K; A28E]

[1184] <SEQ ID NO:41; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-diacid / K18; (3-30+CEX32-39[H18K][Q29G][K30P]), AT593

[1185] <SEQ ID NO:42; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWLLAQR GIP(3-30)[E3S; K16R; H18K; K30R],

[1186] <SEQ ID NO:43; PRT1; Artificial Sequence> EGTFISDYKIAMDKIHQQDFVNWLLAQK GIP(3-30)[S11K],

[1187] <SEQ ID NO:44; PRT1; Artificial Sequence> EGTFISDYSKAMDKIHQQDFVNWLLAQK GIP(3-30)[I12K],

[1188] <SEQ ID NO:45; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQKDFVNWLLAQK GIP(3-30)[Q20K],

[1189] <SEQ ID NO:46; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVKWLLAQK GIP(3-30)[N24K],

[1190] <SEQ ID NO:47; PRT1; Artificial Sequence> EGTFISDYSIAMDKKHQQDFVNWLLAQK GIP(3-30)[I17K],

[1191] <SEQ ID NO:48; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQG GIP(3-30)[H18K; K30G],

[1192] <SEQ ID NO:49; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAGG GIP(3-30)[H18K; Q29G; K30G],

[1193] <SEQ ID NO:50; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQEFVQWLLAQK GIP(3-30)[D9E; D15E; H18K; D21E; N24Q],

[1194] <SEQ ID NO:51; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQDFVQWLLAQK GIP(3-30)[D9E; D15E; H18K; N24Q],

[1195] <SEQ ID NO:52; PRT1; Artificial Sequence> EGTFISEYSAibANleEKIKQQDFVEWLLAQK GIP(3-30)[D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[1196] <SEQ ID NO:53; PRT1; Artificial Sequence> EGTFISEYSIAibMEKIKQQDFVEWLLAQK GIP(3-30)[D9E; A13Aib; D15E; H18K; N24E],

[1197] <SEQ ID NO:54; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWLLAQK GIP(3-30)[H18K; N24E],

[1198] <SEQ ID NO:55; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLLAQK GIP(3-30)[M14L; H18K],

[1199] <SEQ ID NO:56; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLAQK GIP(3-30)[M14Nle;; H18K],

[1200] <SEQ ID NO:57; PRT1; Artificial Sequence> EGTFISDYSIAEDKIKQQDFVNWLLAQK GIP(3-30)[M14E; H18K],

[1201] <SEQ ID NO:58; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVNWLLAQK GIP(3-30)[M14K; H18K],

[1202] <SEQ ID NO:59; PRT1; Artificial Sequence> EGTFISDYSIASDKIKQQDFVNWLLAQK GIP(3-30)[M14S; H18K],

[1203] <SEQ ID NO:60; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWLLAQAGIP(3-30)[H18K; N24E; K30A],

[1204] <SEQ ID NO:61; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLEQK GIP(3-30)[H18K; A28E],

[1205] <SEQ ID NO:62; PRT1; Artificial Sequence> VGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3V; H18K],

[1206] <SEQ ID NO:63; PRT1; Artificial Sequence> AibGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3Aib; H18K],

[1207] <SEQ ID NO:64; PRT1; Artificial Sequence> PGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3P; H18K],

[1208] <SEQ ID NO:65; PRT1; Artificial Sequence> VETFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3V; G4E; H18K],

[1209] <SEQ ID NO:66; PRT1; Artificial Sequence> AibETFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3Aib; G4E; H18K],

[1210] <SEQ ID NO:67; PRT1; Artificial Sequence> GETFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3G; G4E; H18K],

[1211] <SEQ ID NO:68; PRT1; Artificial Sequence> PETFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3P; G4E; H18K],

[1212] <SEQ ID NO:69; PRT1; Artificial Sequence> DTTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3D; G4T; H18K],

[1213] <SEQ ID NO:70; PRT1; Artificial Sequence> GETFISDYAIALDKIKQQDFVEWLLAQG GIP(3-30)[E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[1214] <SEQ ID NO:71; PRT1; Artificial Sequence> GETFISTYSIALDKIKQQDFVEWLLAQG GIP(3-30)[E3G; G4E; D9T; M14L; H18K; N24E],

[1215] <SEQ ID NO:72; PRT1; Artificial Sequence> EGTFISTYKIALDKIHQQDFVEWLLAQK GIP(3-30)[D9T; S11K; M14L; N24E],

[1216] <SEQ ID NO:73; PRT1; Artificial Sequence> EGTFISDYSIAibMDKIKQQDFVEWLLAQK GIP(3-30)[A13Aib; H18K; N24E],

[1217] <SEQ ID NO:74; PRT1; Artificial Sequence> EGTFISDYSIAibLDKIKQQDFVEWLLAQK GIP(3-30)[A13Aib; M14L; H18K; N24E],

[1218] <SEQ ID NO:75; PRT1; Artificial Sequence> EGTFISDYSIAibNleDKIKQQDFVEWLLAQK GIP(3-30)[A13Aib; M14Nle; H18K; N24E],

[1219] <SEQ ID NO:76; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLLAQK GIP(3-30)[M14L; H18K; N24E],

[1220] <SEQ ID NO:77; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWLLAQK GIP(3-30)[M14Nle; H18K; N24E],

[1221] <SEQ ID NO:78; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVEWLLAQK GIP(3-30)[M14K; H18K; N24E],

[1222] [[ID= 10]]<SEQ ID NO:79; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLAGG GIP(3-30)[M14Nle; H18K; Q29G; K30G],

[1223] <SEQ ID NO:80; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWLLAGG GIP(3-30)[M14Nle; H18K; N24E; Q29G; K30G],

[1224] <SEQ ID NO:81; PRT1; Artificial Sequence> EGTFISEYSIAibLEKIKQQEFVEWLLAQK GIP(3-30)[D9E; A13Aib; M14L; D 15E; H18K; D21E; N24E],

[1225] <SEQ ID NO:82; PRT1; Artificial Sequence> EGTFISEYSIAibNleEKIKQQEFVEWLLAQK GIP(3-30)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E],

[1226] <SEQ ID NO:83; PRT1; Artificial Sequence> yGluGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3yGlu; H18K],

[1227] <SEQ ID NO:84; PRT1; Artificial Sequence> βGluGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3βGlu; H18K],

[1228] <SEQ ID NO:85; PRT1; Artificial Sequence> XGTFISDYSIAMDKIKQQDFVNWLLAQK GIP(3-30)[E3 Glutaric Acid (X); H18K],

[1229] <SEQ ID NO:86; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLLAGG GIP(3-30)[M14L; H18K; N24E; Q29G; K30G],

[1230] <SEQ ID NO:87; PRT1; Artificial Sequence> EGTFISEYSIALEKIKQQEFVEWLLAQK GIP(3-30)[D9E; M14L; D15E; H18K; D21E; N24E],

[1231] <SEQ ID NO:88; PRT1; Artificial Sequence> EGTFISEYSIANleEKIKQQEFVEWLLAQK GIP(3-30)[D9E; M14Nle; D15E; H18K; D21E; N24E],

[1232] <SEQ ID NO:89; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQK GIP(3-30)[E3yGlu (L-isomer); M14Nle; H18K; N24E],

[1233] <SEQ ID NO:90; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQK GIP(3-30)[E3yGlu (D-isomer); M14Nle; H18K; N24E], <00​​​<SEQ ID NO:92; PRT1; Artificial Sequence> XGTFISDYSIANleDKIKQQDFVEWLLAQK GIP(3-30) [E3 Glutaric Acid (X); M14Nle; H18K; N24E],

[1236] <SEQ ID NO:93; PRT1; Artificial Sequence> βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQK(3-30E3βGlu A13Aib M14Nle H18K)

[1237] <SEQ ID NO:94; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLLEGG GIP(3-30) [M14L; H18K; A28E; Q29G; K30G]

[1238] <SEQ ID NO:95; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLEQK GIP(3-30)Cex(31-39) [M14Nle; H18K; A28E]

[1239] <SEQ ID NO:96; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVNWLLAQK GIP(5-30)

[1240] <SEQ ID NO:97; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQK GIP(5-30) [S11K],

[1241] <SEQ ID NO:98; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSK(NH2)C16-Diacid / K40; GIP(3-30+CEX31-39+K), Phenyl Lactic Acid at the N-terminus, AT651

[1242] <SEQ ID NO:99; PRT1; Artificial Sequence> PGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSK(NH2)C16-Diacid / K40; GIP(3-30+CEX31-39+K), Phenyl Lactic Acid at the N-terminus, AT652

[1243] <SEQ ID NO:100; PRT1; Artificial Sequence> TFISDYSIAMDKIKQQDFVNWLLAQK GIP(5-30) [H18K],

[1244] <SEQ ID NO:101; PRT1; Artificial Sequence> TFISDYKIAMDRIHQQDFVNWLLAQR GIP(5-30)[S11K; K16R; K30R],

[1245] <SEQ ID NO:102; PRT1; Artificial Sequence> TFISDYSKAMDKIHQQDFVNWLLAQK GIP(5-30)[I12K],

[1246] <SEQ ID NO:103; PRT1; Artificial Sequence> TFISDYSIAMDKIHQKDFVNWLLAQK GIP(5-30)[Q20K], and

[1247] <SEQ ID NO:104; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVKWLLAQK GIP(5-30)[N24K],

[1248] <SEQ ID NO:105; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQK GIP(6-30)[H18K],

[1249] <SEQ ID NO:106; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW2xAEEAc+y-glu-C16-diacid / K18; GIP(3-36H18K), AT415

[1250] <SEQ ID NO:107; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / K18; GIP(3-30+CEX31-39 H18K), AT631,

[1251] <SEQ ID NO:108; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30+CEX31-39H18K), AT587

[1252] [[ID=CHINESE=26]]<SEQ ID NO:109; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS

[1253] 2xAEEAc + y-glu-C16-diacid / K18:GIP(3-30+CEX H18K), AT431

[1254] <SEQ ID NO:110;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS(NH2)

[1255] 2xAEEAc + yGlu-C18-diacid / K18;GIP(3-31+CEX31-39 H18K), AT588,

[1256] <SEQ ID NO:111;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPC16-diacid / K18;GIP(3-30+CEX 9H18K), AT467

[1257] <SEQ ID NO:112;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPC16-diacid / K18;GIP(3-30+CEX 8H18K), AT468

[1258] <SEQ ID NO:113;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAP C16-diacid / K18;GIP(3-30+CEX 7H18K), AT469

[1259] <SEQ ID NO:114;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAC16-diacid / K18;GIP(3-30+CEX 6H18K), AT470

[1260] <SEQ ID NO:115;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSG C16-diacid / K18;GIP(3-30+CEX 5H18K), AT471

[1261] <SEQ ID NO:116;PRT1;Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSS C16-diacid / K18;GIP(3-30+CEX 4H18K), AT472

[1262] <SEQ ID NO:117; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGPS C16-diacid / K18 GIP(3-30+CEX 3H18K), AT473

[1263] <SEQ ID NO:118; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGP C16-diacid / K18 GIP(3-30+CEX 2H18K), AT474

[1264] <SEQ ID NO:119; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKG-C16-diacid / K18 GIP(3-31H18K), AT447

[1265] <SEQ ID NO:120; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGK C16-diacid / K18 GIP(3-32H18K), AT\alpha448

[1266] <SEQ ID NO:121; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGKK C16-diacid / K18 GIP(3-33H18K), AT360

[1267] <SEQ ID NO:122; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKN C16-diacid / K18 GIP(3-34H18K), AT449

[1268] <SEQ ID NO:123; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKND C16-diacid / K18 GIP(3-35H18K), AT450

[1269] <SEQ ID NO:124; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWK C16-diacid / K18 GIP(3-37H18K), AT451

[1270] It should be noted that in the original text, there is a "AT\alpha448" in line 9 which seems to be an incorrect expression. I translated it as "AT448" according to the context as best as possible. If this is a specific and correct format that needs to be strictly adhered to, you may need to provide more information for a more accurate translation.<SEQ ID NO:125; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHC16-diacid / K18 GIP(3-38H18K), AT452

[1271] <SEQ ID NO:126; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNC16-diacid / K18 GIP(3-39H18K), AT462

[1272] <SEQ ID NO:127; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNIC16-diacid / K18 GIP(3-40H18K), AT453

[1273] <SEQ ID NO:128; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITC16-diacid / K18:SEQ ID NO:(3-41H18K), AT454 <SEQ ID NO:129; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ C16-diacid / K18 GIP(3-42H18K), AT363

[1274] <SEQ ID NO:130; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW2xAEEAc+y-glu-C16-diacid / K18; GIP(3-30E3S H18K), AT419

[1275] <SEQ ID NO:131; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS2xAEEAc+y-glu-C16-diacid / K18 GIP(3-30+CEX E3S H18K), AT435

[1276] <SEQ ID NO:132; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW2xAEEAc+y-glu-C16-diacid / K18; GIP(3-30E3S K16R H18K K30R), AT423

[1277] <SEQ ID NO:133; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS2xAEEAc+y-glu-C16-dioic acid / K18 GIP(3-30+CEX E3S K16R H18K K30R), AT439

[1278] <SEQ ID NO:134; PRT1; Artificial Sequence> EGTFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW2xAEEAc+yGlu-C18-dioic acid / K11; GIP(3-36S11K), AT543

[1279] <SEQ ID NO:135; PRT1; Artificial Sequence> EGTFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW2xAEEAc+yGlu-C18-dioic acid / K12; GIP(3-36I12K), AT544,

[1280] <SEQ ID NO:136; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQKDFVNWLLAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid / K20; GIP(3-30+CEX31-39Q20K), AT594,

[1281] <SEQ ID NO:137; PRT1; Artificial Sequence> EGTFISDYSIAMDKKHQQDFVNWLLAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid / K17; GIP(3-30+CEX31-39I17K), AT586,

[1282] <SEQ ID NO:138; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQGPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid; GIP(3-30+CEX31-39H18K K30G), AT590

[1283] <SEQ ID NO:139; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid; GIP(3-30+CEX31-39H18K Q29G K30G), AT591

[1284] <SEQ ID NO:140; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS2xAEEAc+yGlu-C18-diacid; GIP(3-30+CEX31-39 H18KQ29G K30G), AT592

[1285] <SEQ ID NO:141; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQEFVQWLLAQKPSSGAPPPSC16-diacid; GIP(3-30+CEX31-39 D9E; D15E; H18K; D21E; N24Q), AT613,

[1286] <SEQ ID NO:142; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid; GIP(3-30)Cex(31-39)[D9E; D15E; H18K; N24E], AT614

[1287] <SEQ ID NO:143; PRT1; Artificial Sequence> EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30+CEX31-39 D9E; I12Aib; M14Nle; D15E; H18K; N24E), AT615,

[1288] <SEQ ID NO:144; PRT1; Artificial Sequence> EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 D9E; A13Aib; D15E; H18K; N24E), AT616,

[1289] <SEQ ID NO:145; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K N24E), AT617,

[1290] <SEQ ID NO:146; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 M14L H18K), AT618,

[1291] <SEQ ID NO:147; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 M14Nle H18K), AT619,

[1292] <SEQ ID NO:148; PRT1; Artificial Sequence> EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 M14E H18K), AT620, ?

[1293] <SEQ ID NO:149; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 M14K H18K), AT621,

[1294] <SEQ ID NO:15; PRT1; Artificial Sequence> EGTFISDYSIASDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 M14S H18K), AT622

[1295] <SEQ ID NO:151; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWLLAQAPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K N24E K30A), AT623,

[1296] <SEQ ID NO:152; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLEAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K L27E), AT624, [[ID=,18]]

[1297] <SEQ ID NO:153; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLEQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K A28E), AT625,

[1298] It should be noted that there seems to be an unclear or incorrect "15" in the "SEQ ID NO:15" in line 10. Please check and correct it if necessary.<SEQ ID NO:154; PRT1; Artificial Sequence> VGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3V H18K), AT636,

[1299] <SEQ ID NO:155; PRT1; Artificial Sequence> AibGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3Aib H18K), AT637,

[1300] <SEQ ID NO:156; PRT1; Artificial Sequence> PGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3P H18K), AT638,

[1301] <SEQ ID NO:157; PRT1; Artificial Sequence> VETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3V G4E H18K), AT639,

[1302] <SEQ ID NO:158; PRT1; Artificial Sequence> AibETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3Aib G4E H18K), AT640,

[1303] <SEQ ID NO:159; PRT1; Artificial Sequence> GETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3G G4E H18K), AT641,

[1304] <SEQ ID NO:160; PRT1; Artificial Sequence> PETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30 + CEX31-39 E3P G4E H18K), AT642,

[1305] <SEQ ID NO:161; PRT1; Artificial Sequence> DTTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30 + CEX31-39 E3D G4T H18K), AT643,

[1306] <SEQ ID NO:162; PRT1; Artificial Sequence> GETFISDYAIALDKIKQQDFVEWLLAQGPSSGAPPPSC16-diacid / 18K; GIP(3-30 + CEX31-39 E3G; G4E; S11A; M14L; H18K; N24E; K30G), AT644,

[1307] <SEQ ID NO:163; PRT1; Artificial Sequence> GETFISTYSIALDKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30 + CEX31-39 E3G; G4E; D9T; M14L; H18K; N24E), AT646,

[1308] <SEQ ID NO:164; PRT1; Artificial Sequence> EGTFISTYKIALDKIHQQDFVEWLLAQKPSSGAPPPSyGlu-C16-diacid / 18K; GIP(3-30 + CEX31-39 D9T; S11K; M14L; N24E), AT647,

[1309] <SEQ ID NO:165; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQK(NH2)PSSGAPPPS C16-diacid / 18K; GIP(3-30 + CEX31-39[H18K], AT650,

[1310] <SEQ ID NO:166; PRT1; Artificial Sequence> EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30 + CEX31-39 A13Aib H18KN24E), AT665,

[1311] <SEQ ID NO:167; PRT1; Artificial Sequence> EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30 + CEX31-39 A13Aib M14L H18K N24E), AT666,

[1312] <SEQ ID NO:168; PRT1; Artificial Sequence> EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30 + CEX31-39 A13Aib M14Nle H18K N24E), AT667,

[1313] <SEQ ID NO:169; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30 + CEX31-39 M14L H18K N24E), AT668,

[1314] <SEQ ID NO:170; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30 + CEX31-39 M14Nle H18K N24E), AT669,

[1315] [[ID=!1]]<SEQ ID NO:171; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[M14K H18K N24E], AT670,

[1316] [[ID=1!]]<SEQ ID NO:172; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLAGGPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[M14Nle H18K Q29G K30G], AT671,

[1317] <SEQ ID NO:173; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWLLAGGPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[M14Nle H18K N24E Q29G K30G], AT672,

[1318] It should be noted that there seems to be an error in the "[[ID=!1]]" and "[[ID=1!]]" in the original text. They are likely misformatted. I've translated them as they are for the sake of following the rules, but you may want to double-check their accuracy in the original source.<SEQ ID NO:174; PRT1; Artificial Sequence> EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30)+Cex(31-39)[D9E A13AibM14L D15E H18K D21E N24E], AT673,

[1319] <SEQ ID NO:175; PRT1; Artificial Sequence> EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[D9E A13AibM14Nle D15E H18K D21E N24E], AT674,

[1320] <SEQ ID NO:176; PRT1; Artificial Sequence> yGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu H18K], AT675,

[1321] <SEQ ID NO:177; PRT1; Artificial Sequence> βGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3βGlu H18K], AT676,

[1322] <SEQ ID NO:178; PRT1; Artificial Sequence> XGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3glutaric acid(X)H18K], AT677,

[1323] <SEQ ID NO:179; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLLAGGPSSGAPPPS2xAEEAc+yGlu-C18-diacid / 18K; GIP(3-30)+Cex(31-39)[M14L H18K N24E Q29G K30G], AT687,

[1324] <SEQ ID NO:180; PRT1; Artificial Sequence> EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS2xAEEAc+yGlu-C18-dioic acid / 18K; GIP(3-30)+Cex(31-39)[D9E M14L D15E H18K D21E N24E], AT693,

[1325] <SEQ ID NO:181; PRT1; Artificial Sequence> EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS2xAEEAc+yGlu-C18-dioic acid / 18K; GIP(3-30)+Cex(31-39)[D9E M14Nle D15E H18K D21EN24E], AT694,

[1326] <SEQ ID NO:182; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu (L-isomer) M14Nle H18K N24E], AT697,

[1327] <SEQ ID NO:183; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu (D-isomer) M14Nle H18K N24E], AT698,

[1328] <SEQ ID NO:184; PRT1; Artificial Sequence> βGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3βGlu M14Nle H18K N24E], AT699,

[1329] <SEQ ID NO:185; PRT1; Artificial Sequence> XGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3glutaric acid (X) M14Nle H18K N24E], AT700,

[1330] <SEQ ID NO:186; PRT1; Artificial Sequence>βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3βGluA13Aib M14Nle H18K], AT703,

[1331] <SEQ ID NO:187; PRT1; Artificial Sequence>Ac-EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS

[1332] -C16-diacid / K18; GIP(3-30+CEX31-39 H18K), AT 633

[1333] <SEQ ID NO:188; PRT1; Artificial Sequence>Ac-EGTFISEYSIAMEKIKQQDFVNWLLAQKPSSGAPPPS [[ID=eleven]]

[1334] -C16-diacid / K18; GIP(3-30+CEX31-39 D9E; D15E; H18K), AT635

[1335] <SEQ ID NO:189; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLLAQKGKK y-glu-C16 diacid / K11 GIP(5-33S11K), AT365

[1336] <SEQ ID NO:190; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW y-glu-C16 diacid / K11 GIP(5-36S11K), AT366

[1337] <SEQ ID NO:191; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW(NH2)2xAEEAc+yGlu-C18-diacid / K11, GIP(5-36S11K), AT559

[1338] <SEQ ID NO:192; PRT1; Artificial Sequence>TFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW 2xAEEAc+yGlu-C18 diacid / K12 GIP(5-36I12K), AT562

[1339] <SEQ ID NO:193; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHN-y-glu-C16 diacid / K11 GIP(5-39S11K), AT367

[1340] <SEQ ID NO:194; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQy-glu-C16 diacid / K11 GIP(5-42S11K), AT368

[1341] <SEQ ID NO:195; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKG y-glu-C16 diacid / K11 GIP(5-31S11K), AT45P

[1342] <SEQ ID NO:196; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGK y-glu-C16 diacid / K11 GIP(5-32S11K), AT456

[1343] <SEQ ID NO:197; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKN y-glu-C16 diacid / K11 GIP(5-34S11K), AT457

[1344] <SEQ ID NO:198; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKND y-glu-C16 diacid / K11 GIP(5-35SIIK), AT458

[1345] <SEQ ID NO:199; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWK y-glu-C16 diacid / K11 GIP(5-37S11K), AT459

[1346] <SEQ ID NO:200; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKH y-glu-C16 diacid / K11 GIP(5-38S11K), AT460

[1347] <SEQ ID NO:201; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNI y-glu-C16 diacid / K11 GIP(5-40S11K), AT461

[1348] <SEQ ID NO:202; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNIT y-glu-C16 diacid / K11 GIP(5-41S11K), AT462

[1349] <SEQ ID NO:203; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQK PSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39S11K), AT597,

[1350] <SEQ ID NO:204; PRT1; Artificial Sequence> TFISDYKIAMDRIHQQDFVNWLLAQRGRRNDW 3xAEEAc+y-glu-C16 diacid / K11; GIP(5-36S11K K16R K30R K32R K33R), AT428

[1351] <SEQ ID NO:205; PRT1; Artificial Sequence> TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS2xAEEAc+y-glu-C16 diacid / K11; GIP(5-30+CEX S11KK16R K30R), AT443

[1352] <SEQ ID NO:206; PRT1; Artificial Sequence> TFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW 2xAEEAc+y-glu-C18 diacid / K18; GIP(5-36H18K), AT563

[1353] <SEQ ID NO:207; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKGPSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39S11K), AT605,

[1354] <SEQ ID NO:208; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAQKPSSGAPPPSyGlu-C16-dioic acid / K11; GIP(5-30+CEX31-39 S11K), AT632

[1355] <SEQ ID NO:209; PRT1; Artificial Sequence> TFISDYSIAMDKIHQKDFVNWLLAQKGKKNDW 2xAEEAc+y-glu-C18-dioic acid / K20; GIP(5-36Q20K), AT564

[1356] <SEQ ID NO:210; PRT'1; Artificial Sequence> TFISDYSIAMDKIHQQDFVKWLLAQKGKKNDW 2xAEEAc+y-glu-C18-dioic acid / K24; GIP(5-36N24K), AT566

[1357] <SEQ ID NO:211; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQKGKK C16-dioic acid / K18; GIP(6-33H18K), AT463

[1358] <SEQ ID NO:212; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQKGKKNDW C16-dioic acid / K18; GIP(6-36H18K), AT464

[1359] <SEQ ID NO:213; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN C16-dioic acid / K18; GIP(6-39H18K), AT465

[1360] <SEQ ID NO:214; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQC16-dioic acid / K18; GIP(6-342H18K), AT466

[1361] <SEQ ID NO:215; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS C16-dioic acid / K18; GIP(6-30+CEX H18K), AT475

[1362] <SEQ ID NO:216; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLAGGPSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39[S11K Q29G K30G], AT602,

[1363] <SEQ ID NO:218; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLLEQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30)Cex(31-39)[M14L; H18K; A28E], AT689

[1364] <SEQ ID NO:219; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWLLEQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30)Cex(31-39)[M14Nle; H18K; A28E], AT690<000​​​​​​​​​​​​​​​​​​​​​​​​​

Claims

1. A pharmaceutical composition comprising a glucose-dependent insulinotropic peptide (GIP) analogue: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS (SEQ ID NO: 174) wherein the fatty acid molecule is attached to the lysine amino acid residue at position 16 of SEQ ID NO:

174. The pharmaceutical composition according to claim 1 , wherein the GIP analog is amidated at the C-terminus. The pharmaceutical composition according to claim 1 , wherein the GIP analog is carboxylated at the C-terminus.

4. The pharmaceutical composition according to claim 1, wherein the fatty acid molecule is selected from the group consisting of straight-chain fatty acids and branched-chain fatty acids.

5. The pharmaceutical composition of claim 1, wherein the fatty acid molecule comprises the formula CH3(CH2) n wherein n is an integer from 4 to 24.

6. The pharmaceutical composition according to claim 5, wherein the fatty acid molecule comprises a member selected from the group consisting of CH3(CH2)6CO-, CH3(CH2)8CO-, CH3(CH2) 10 CO-, CH3(CH2) 12 CO-, CH3(CH2) 14 CO-, CH3(CH2) 16 CO-, CH3(CH2) 18 CO-, CH3(CH2) 20 CO- and CH3(CH2) 22 One or more acyl groups of CO-.

7. The pharmaceutical composition of claim 1, wherein the fatty acid molecule comprises the formula COOH(CH2) n wherein n is an integer from 4 to 24.

8. The pharmaceutical composition according to claim 7, wherein the fatty acid molecule comprises one or more selected from COOH(CH2) 14 CO-, COOH(CH2) 16 CO-, COOH(CH2) 18 CO- and COOH(CH2) 20 CO-acyl group.

9. The pharmaceutical composition of claim 1, wherein the fatty acid molecule comprises COOH(CH2) 14 CO- or consisting of.

10. The pharmaceutical composition of claim 1, wherein the fatty acid molecule comprises COOH(CH2) 16 CO- or consisting of.

11. The pharmaceutical composition of claim 1, wherein the fatty acid molecule comprises COOH(CH2) 18 CO- or consisting of. 12 . The pharmaceutical composition according to claim 1 , wherein the fatty acid molecule is directly attached to the epsilon amino group of the side chain of the lysine amino acid residue at position 16 of SEQ ID NO:

174.

13. The pharmaceutical composition according to claim 1, wherein the fatty acid molecule is attached to the epsilon amino group of the side chain of the lysine amino acid residue at position 16 of SEQ ID NO: 174 via a linker.

14. The pharmaceutical composition according to claim 13, wherein the fatty acid molecule is attached to the lysine amino acid residue at position 16 of SEQ ID NO: 174 via a linker such that the carboxyl group of the fatty acid molecule forms an amide bond with the amino group of the linker.

15. The pharmaceutical composition according to any one of claims 13 and 14, wherein the linker comprises one or more moieties individually selected from: a. one or more of α-amino acids, γ-amino acids and ω-amino acids, b. one or more amino acids selected from succinic acid, Lys, Glu, Asp, 4-Abu and γ-aminobutyric acid, c. a dipeptide wherein the C-terminal amino acid residue is Lys, His or Trp and wherein the N-terminal amino acid residue is Ala, Arg, Asp, Asn, Gly, Glu, Gln, Ile, Leu, Val, Phe or Pro, d. one or more of γ-aminobutyryl, γ-Glu, β-Asp, β-Ala and glycyl, e.[8-Amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer from 1 to 50, and f.γ-Glutamic acid-[8-amino-3,6-dioxaoctanoic acid] n (γGlu-AEEAc n ), where n is an integer from 1 to 50.

16. The pharmaceutical composition of claim 15, wherein the linker comprises or consists of one or more γ-Glu, one or more 8-amino-3,6-dioxaoctanoic acid (AEEAc), or a combination thereof.

17. The pharmaceutical composition according to claim 15, wherein the linker comprises or consists of one γ-Glu and one AEEAc, or comprises or consists of one γ-Glu and two AEEAc, or comprises or consists of one γ-Glu and three AEEAc.

18. The pharmaceutical composition according to claim 13, wherein the combination of the linker and the fatty acid molecule is selected from: i. Hexadecanoyl-γ-Glu- ii. Hexadecanoyl-γ-Glu-γ-Glu- iii. Hexadecanoyl-γ-Glu-AEEAc- iv. Hexadecanoyl-γ-Glu-AEEAc-AEEAc- v. Hexadecanoyl-Y-Glu-AEEAc-AEEAc-AEEAc- vi.[15-Carboxy-pentadecanoyl]-Y-Glu- vii.[15-Carboxy-pentadecanoyl]-γ-Glu-γ-Glu- viii.[15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc- ix.[15-Carboxy-pentadecanoyl]-γ-Glu-AEEAc-AEEAc- x.[15-Carboxy-pentadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-AEEAc- xi. Octadecanoyl-γ-Glu- xii. Octadecanoyl-γ-Glu-γ-Glu- xiii. Octadecanoyl-γ-Glu-AEEAc- xiv. Octadecanoyl-γ-Glu-AEEAc-AEEAc- xv. Octadecanoyl-γ-Glu-AEEAc-AEEAc-AEEAc- xvi.[17-Carboxy-heptadecanoyl]-γ-Glu- xvii.[17-Carboxy-heptadecanoyl]-γ-Glu-γ-Glu- xviii.[17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc- xix.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc- xx.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc- xxi. Eicosyl-γ-Glu- xxii. Eicosyl-γ-Glu-γ-Glu- xxiii. Eicosyl-γ-Glu-AEEAc- xxiv. Eicosyl-γ-Glu-AEEAc-AEEAc- xxv. Eicosyl-γ-Glu-AEEAc-AEEAc-AEEAc- xxvi.[19-Carboxy-nonadecanoyl]-Y-Glu- xxvii.[19-Carboxy-nonadecanoyl]-γ-Glu-γ-Glu- xxviii.[19-Carboxy-nonadecanoyl]-Y-Glu-AEEAc- xxix[19-carboxy-nonadecanoyl]-γ-Glu-AEEAc-AEEAc-, and xxx.[19-Carboxy-nonadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-.

19. The pharmaceutical composition according to any one of claims 13, wherein the combination of the linker and the fatty acid is selected from: i.[15-Carboxypentadecanoyl]-yGlu ii. [17-Carboxy-heptadecanoyl]-γ-Glu-AEEAc-AEEAc-, and iii. [17-Carboxy-heptadecanoyl]-yGlu-yGlu.

20. The pharmaceutical composition according to claim 1, wherein the GIP analog is selected from: EGTFISEYSIAiBLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-dioic acid / 16K (SEQ ID NO: 174), EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 16K (SEQ ID NO: 174), wherein the GIP analog is C-terminally carboxylated, and EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 16K (SEQ ID NO: 174), wherein the GIP analog is C-terminally amidated.

21. The pharmaceutical composition of claim 1, wherein the GIP analog is selected from the group consisting of: EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 16K; SEQ ID NO: 174 GIP (3-30)+Cex (31-39), EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 16K; SEQ ID NO: 174 GIP (3-30)+Cex (31-39), wherein the GIP analog is C-terminally carboxylated, and EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 16K; SEQ ID NO: 174 GIP (3-30) + Cex (31-39), wherein the GIP analog is C-terminally amidated.

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