Modified GIP peptide analogs

Abstract

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

Description

[0001] This application is a divisional application of Chinese Patent Application No. 201980090373.3 (Filing Date: December 3, 2019, Inventor Name: Modified GIP Peptide Analog). TECHNICAL FIELD

[0002] The present invention relates to 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 fatty acids with / without linkers, thereby having improved antagonistic activity and improved pharmacokinetic profiles. BACKGROUND

[0003] Glucose-dependent insulinotropic peptide (GIP) is a hormone secreted from intestinal K cells after meals 1 . Like its sister hormone, glucagon-like peptide 1 (GLP-1), GIP is a potent insulin secretagogue 2 . In contrast to the glucagon-inhibitory effect of GLP-1 3，4 , 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 increased interest in understanding the biology of GIP 14-21 . In humans, although less clear, there is also evidence for a role of GIP in fat metabolism, demonstrating expression of GIPR in adipose tissue 22 , an association between high BMI and elevated GIP levels 22，23 , increased adipose tissue blood flow and TAG (triglyceride) deposition after GIP administration in a high insulin and high glucose state 24 , a decrease in basal and postprandial GIP levels observed in obese children on a diet 25 , and an increase in fasting GIP levels observed in healthy young men on a high-fat diet 26 .

[0004] Thus, in addition to the general need of researchers who have witnessed progress in understanding of GLP-1 after the discovery of the GLP-1 receptor antagonist exendin (9-39) 27，28 , the potential as an anti-obesity agent has also raised more attention for developing potent GIPR antagonists. Many different strategies have been taken to antagonize the function of GIP, such as small molecule receptor antagonists 29 , immunization against GIP 30-32 , various truncations and mutations of GIP molecules with antagonistic properties 33-39 , and recently potent antagonist antibodies against GIPR 40.

[0005] Under physiological conditions, the 42 amino acid hormone GIP is degraded by dipeptidyl peptidase 4 (DPP-4), which cleaves GIP3-42 at the third position of the GIP molecule. Artificially synthesized porcine GIP3-42 does not exhibit antagonist properties in the porcine or perfused rat pancreas at physiological concentrations, but it antagonizes human GIPR 41 Many peptide hormones are subject to post-translational modifications, resulting in various biological forms of different 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 circulation of humans, cleavage by DPP-4 will result in GIP3-30.

[0006] US 7,875,587 discloses GIP receptor antagonists derived from GIP (1-42) with enhanced resistance to degradation by DPP-4, and their use in the treatment of 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 the peptide metabolite and to retain biological activity similar to the cleaved peptide of native peptides, including GIP. WO 2012 / 055770 discloses GIP (3-42) as an endogenous metabolite, which is readily cleared and has GIPR antagonist effects, while GIP (2-30) is an example of a truncated GIP analogue with GIPR agonist activity. WO 1998 / 24464 discloses the antagonist GIP (7-30).

[0007] 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) with the C-terminus modified by Cex from 9 amino acids of Exendin (1-39) and lysine residues modified by palmitoyl groups.

[0008] A range of different approaches have been used to modify the structure of GLP-1 compounds in order to provide longer duration of action in vivo. These approaches include the introduction of lipophilic substituents to amino acid residues (WO 96 / 29342 and WO 98 / 08871) and acylated GLP-1 analogues (WO 00 / 34331). WO 02 / 46227 discloses GLP-1 and Exendin-4 analogues fused to human serum albumin in order to prolong the half-life in vivo. SUMMARY

[0009] The inventors have identified GIP peptides that are antagonists of GIPR, which comprise one or more individual substitutions that result in GIP peptides with improved antagonistic properties. The GIP peptides of the present disclosure are acylated here 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 comprise at least the first two amino acids in positions 1 and 2 of GIP (1-42). The inventors further surprisingly found that acylated longer GIP peptides, such as peptides comprising one or more of the residues in GIP (31-42) 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 show improved GIPR antagonistic properties and / or super-long in vivo half-life and / or increased selectivity. This makes them potentially useful in a range of therapeutic applications.

[0010] In one aspect, the present disclosure relates to a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

[0011]

[0012] wherein X1and X2are independently any amino acid or are omitted;

[0013] 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,

[0014] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more amino acid residues in positions 3 to 29 of SEQ ID NO XX or the functional variant,

[0015] 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E).

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

[0017] In case of GIP(3-30) / GIP(5-30) / GIP(6-30) and analogs thereof extended with amino acid residues from the C-terminal part of Exendin-4 or GIP(1-42) such as e.g. GPSSGAPPPS, PSSGAPPPS or GKKNDW, another important advantage of the above aspects is that the antagonistic properties can increase and / or the selectivity with respect to GIP receptor agonism increases. Thus, when the extended GIP analogs are lipidated at specific positions such as e.g. at position 18 for the extended GIP(3-30) analogs and at position 11 for the extended GIP(5-30) analogs, an improved antagonism can be obtained while also the half-life can be increased to a surprising extent.

[0018] In case of GIP(3-30) / GIP(5-30) / GIP(6-30) and analogs thereof extended with amino acid residues from the C-terminal part of Exendin-4 or GIP(1-42) such as e.g. GPSSGAPPPS, PSSGAPPPS or GKKNDW, another important advantage of the above aspects is that the antagonistic properties can increase and / or the selectivity with respect to GIP receptor agonism increases. Thus, when the extended GIP analogs are lipidated at specific positions such as e.g. at position 18 for the extended GIP(3-30) analogs and at position 11 for the extended GIP(5-30) analogs, an improved antagonism can be obtained while also the half-life can be increased to a surprising extent. BRIEF DESCRIPTION OF DRAWINGS

[0019] Figure 1 GIP(3-30) antagonists with C-terminal extensions such as AT631 show ultra-long T 1 / 2Pigs were subcutaneously administered the lipidated GIP(3-30)NH2 analogue AT158 and the lipidated GIP(3-30)Cex(31-39) analogue 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 a plot of the percent of Cmax versus time in hours was plotted. AT631 showed a surprisingly longer half-life than AT158.

[0020] Definitions

[0021] The term "affinity" refers to the strength of binding between a receptor and one or more of its ligands. In the present context, the affinity (Ki) of a peptide antagonist for its binding site will determine the duration of inhibition of agonist activity. The affinity of an antagonist can be determined experimentally using a Schild regression of 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) kinetic studies to determine the association and dissociation rates (K on and K off ), respectively.

[0022] The term "IC50" denotes the half maximal inhibitory concentration (IC50), which is a measure of the effectiveness of a substance in inhibiting a particular biological or biochemical function. This quantitative measure indicates how much of a particular drug or other substance (e.g., an 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 research, it is commonly used as a measure of the potency of an antagonist drug. IC50 indicates the concentration of a drug needed to inhibit 50% in vitro. In the present context, the IC50 value can also refer to the concentration of a drug that causes 50% of the radiolabeled ligand to be displaced from the receptor, which is a characterization of the affinity of the drug in a competitive binding experiment.

[0023] In the present context, the term "agonist" refers to a peptide or analogue thereof that is capable of binding from the receptor and activating the downstream signaling cascade.

[0024] In the present context, the term "antagonist" refers to a GIP peptide analogue as defined herein that is capable of binding to and blocking or reducing an agonist-mediated response of the receptor. Upon binding to the receptor, antagonists do not normally elicit a biological response themselves. Antagonists have affinity for, but no efficacy at, their cognate receptors, and binding of an antagonist to its receptor inhibits the function of an agonist or inverse agonist at the receptor. Antagonists mediate their effects by binding to either the active (orthosteric) site or an allosteric site on the receptor, or they can interact at unique binding sites not normally involved in the biological regulation of receptor activity. Antagonist activity can be reversible or irreversible, depending on the lifetime of the antagonist-receptor complex, which in turn depends on the nature of antagonist-receptor binding. Most drug antagonists typically achieve their efficacy by competing with an endogenous ligand or substrate at a structurally defined binding site on the receptor. Antagonists can be competitive, non-competitive, uncompetitive, silent antagonists, partial agonists, or inverse agonists.

[0025] A competitive antagonist (also called an overridable antagonist) binds reversibly to the receptor at the same binding site (i.e., the active site) as the endogenous ligand or agonist, but does not activate the receptor. Agonists and antagonists thus "compete" for the same binding site on the receptor. Once bound, the antagonist blocks the binding of the agonist. The level of receptor activity is determined by the relative affinity of each molecule for the site and their relative concentrations. A high concentration of competitive antagonist increases the proportion of receptors occupied by the antagonist.

[0026] The term "non-competitive antagonism" (also called non-overridable or unoverridable antagonism) describes two different phenomena with functionally similar outcomes: one is that the antagonist binds to the active site of the receptor, and the other is that the antagonist binds to an allosteric site of the receptor. Unlike a competitive antagonist, which affects the amount of agonist necessary to reach a maximal response but does not affect the strength of the maximal response, a non-competitive antagonist reduces the strength of the maximal response that can be reached by any amount of agonist.

[0027] The term "silent antagonist" refers to a competitive receptor antagonist that absolutely lacks the intrinsic activity to activate the receptor.

[0028] The term "partial agonist" refers to an agonist that can elicit a functional response at a given receptor that can differ in strength after maximal receptor occupancy. In the presence of a full agonist (or more potent agonist), a partial agonist can act as a competitive antagonist, as it competes with the full agonist for receptor occupancy, resulting in a net decrease in receptor activation compared to the receptor activation observed with the full agonist alone.

[0029] The term "inverse agonist" refers to a ligand, such as a GIP peptide analog, that is capable of binding to the same receptor binding site as an agonist and antagonizing its effects. In addition, an inverse agonist can also inhibit the basal activity of a constitutively active receptor.

[0030] The term "glucose-dependent insulinotropic polypeptide receptor (GIPR) antagonist" as used herein refers to a compound, such as a peptide, that is capable of binding to and blocking or reducing an agonist-mediated GIPR response.

[0031] The term "individual" refers to a specific member of a vertebrate species, i.e., a mammalian species, preferably a primate, including a human. As used herein, "subject" and "individual" can be used interchangeably.

[0032] An "isolated peptide" is a peptide that is separated and / or recovered from a component of its natural environment, typically a cellular environment, that is essentially free of contamination from cellular components such as carbohydrate, lipid or other protein contaminants associated with the polypeptide in nature. Typically, preparations of an isolated peptide contain 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.

[0033] An "amino acid residue" can be a natural or non-natural amino acid residue linked by a peptide bond or a bond other than a peptide bond. The amino acid residue can be in the D-configuration or the L-configuration. An amino acid residue comprises an amino-terminal moiety (NH2) and a carboxyl-terminal moiety (COOH) separated by a central portion comprising a carbon atom or chain of carbon atoms, at least one of which comprises at least one side chain or functional group. NH2refers to an amino group present at the amino terminus of an amino acid or peptide, while COOH refers to a carboxyl group present at the carboxyl terminus of an amino acid or peptide. The general term amino acid includes natural and non-natural amino acids. The natural amino acids according to the standard nomenclature set forth in J. Biol. Chem., 243:3552-59 (1969) and adopted in 37 C.F.R., § 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 immediately listed above. Also, non-natural amino acid residues include, but are not limited to, stereoisomers of modified amino acid residues, L-amino acid residues, and D-amino acid residues.

[0034] "Equivalent amino acid residue" means an amino acid residue that can be substituted for another amino acid residue in a polypeptide without substantially altering the structure and / or function of the polypeptide. Thus, equivalent amino acids have similar properties such as the volume of the side chain, the polarity or nonpolarity of the side chain, the hydrophobicity or hydrophilicity of the side chain, the pH (acidic, neutral, or basic) of the side chain, and the side chain architecture of the carbon molecule (aromatic / aliphatic). Thus, an "equivalent amino acid residue" can be considered a "conservative amino acid substitution," and it is the substitution of an amino acid whose side chain has similar biochemical properties and therefore does not affect the function of the peptide.

[0035] Among common amino acids, for example, "conservative amino acid substitutions" can also be illustrated by substitutions within the following groups: (1) glycine, alanine, valine, leucine, and isoleucine, (2) phenylalanine, tyrosine, and tryptophan, (3) serine and threonine, (4) aspartic acid and glutamic acid, (5) glutamine and asparagine, and (6) lysine, arginine, and histidine.

[0036] In one embodiment, within the meaning of the term "equivalent amino acid substitution" as applied herein, one amino acid in the following indicated groups of amino acids can be substituted for another within the following indicated groups of amino acids:

[0037] i) amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gin, Ser, Thr, Tyr, and Cys),

[0038] ii) amino acids with nonpolar side chains (Gly, Ala, Val, Leu, He, Phe, Trp, Pro, and Met),

[0039] iii) amino acids with aliphatic side chains (Gly, Ala, Val, Leu, He)

[0040] iv) amino acids with cyclic side chains (Phe, Tyr, Trp, His, Pro)

[0041] v) amino acids with aromatic side chains (Phe, Tyr, Trp)

[0042] vi) amino acids with acidic side chains (Asp, Glu)

[0043] vii) amino acids with basic side chains (Lys, Arg, His)

[0044] viii) amino acids with amide side chains (Asn, Gin)

[0045] ix) amino acids with hydroxyl side chains (Ser, Thr, Tyr)

[0046] x) amino acids with sulfur-containing side chains (Cys, Met)

[0047] xi) neutral, weakly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr)

[0048] xii) hydrophilic, acidic amino acids (Gln, Asn, Glu, Asp), and xiii) hydrophobic amino acids (Leu, lie, Val)

[0049] In addition, a serine residue of a peptide of the present disclosure can be substituted with an amino acid selected from the group consisting of Gin, Asn, and Thr (all amino acids have polar uncharged side chains); and independently thereof, a glycine residue (Gly) is substituted with an amino acid selected from the group consisting of Ala, Val, Leu, and lie; and independently thereof, an arginine residue (Arg) is substituted with an amino acid selected from the group consisting of Lys and His (both have positively charged side chains); and independently thereof, a lysine residue (Lys) can be substituted with an amino acid selected from the group consisting of Arg and His; and independently thereof, a methionine residue (Met) can be substituted with an amino acid selected from the group consisting of Leu, Pro, lie, Val, Phe, Tyr, and Trp (all have hydrophobic side chains); and independently thereof, a glutamine residue (Gln) can independently be substituted with an amino acid selected from the group consisting of Asp, Glu, and Asn; and independently thereof, an alanine residue (Ala) can independently be substituted with an amino acid selected from the group consisting of Gly, Val, Leu, and lie.

[0050] In case no L or D form (optical isomer) is specified, it is to be understood that the amino acid in question has the natural L form (cf. Pure & Appl. Chem. Vol. (56(5)) pp. 595-624 (1984)) or the D form, such that the formed peptide can consist of amino acids of the sequence in the L form, the D form, or a mixture of the L form and the D form.

[0051] As used herein, a glutamic acid (Glu) mimetic is a moiety with 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 from which it is a functional variant. Specifically, a functional variant can substantially bind the same molecule (such as a receptor) or perform the same receptor-mediated response as the peptide from 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 GIPR and activating or inhibiting signaling downstream of GIPR, 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 GIPR and inhibiting or reducing agonist-mediated signaling of GIPR, such as cAMP production.

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

[0054] The term "drug" or "medicament" as used herein includes a biological, physiological or pharmacological agent that acts locally or systemically on the body of a human or animal.

[0055] The terms "treatment" and "treating" as used herein 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 spectrum of therapeutic interventions for a given condition from which the patient is suffering, equally referring to curative, prophylactic / preventative, and palliative / mitigative therapies, such as the administration of the peptide or composition for the purpose of reducing or alleviating symptoms or complications; delaying the progression of the condition, partially arresting the clinical manifestations, disease or disorder; curing or eliminating the condition, disease or disorder; reduction or alleviation, and remission (whether partial or total), whether detectable or undetectable, of a condition or symptom, and / or preventing or reducing the risk of acquiring a condition, disease or disorder, wherein "preventing" is understood to mean the management and care of a patient for the purpose of forestalling the development of a condition, disease or disorder, and includes the administration of an active compound to prevent or reduce the risk of onset of symptoms or complications. The term "palliate" and variants thereof as used herein means that the extent of a physiological condition or symptom and / or the time course of the progression of an undesired manifestation is lessened and / or lengthened as compared to not administering the composition of the present application.

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

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

[0058] The treatment according to the present application can 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 active agent present in a pharmaceutical composition described herein that is required to provide the desired level of active agent in the blood stream or at the site of action (e.g., lung, gastric system, colorectal system, prostate, etc.) of the individual being treated to produce the intended physiological response when the composition is administered. In the present context, the biologically active agent refers to a GIP peptide analogue as disclosed herein.

[0060] "Co-administering" or "co-administration" as used herein means the administration of one or more GIP peptide analogues of the present application and a state-of-the-art pharmaceutical composition. The at least two components can be administered separately, sequentially or simultaneously. DETAILED DESCRIPTION

[0061] GIP refers to a 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 pre-protein and circulates as a biologically active 42 amino acid peptide. It is synthesized by K cells of the mucosa of the duodenum and the jejunum of the gastrointestinal tract.

[0062] GIPR (or GIP receptor) refers to a 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 GIPR that comprise one or more individual substitutions that result in GIP peptides with improved antagonistic properties. The GIP peptides of the present disclosure are acylated here 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 peptides

[0066] The present invention relates to GIP peptide analogs comprising a GIP peptide fragment containing one or more individual substitutions with 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 X1and X2are independently any amino acid or are omitted;

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

[0072] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues from 3 to 29 of SEQ ID NO XX or the 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E).

[0074] In one embodiment, the present disclosure provides a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

[0075]

[0076] wherein Xi 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 attachment of at least one fatty acid molecule at one or more amino acid residues of positions 3 to 29 of SEQ ID NO XX or the 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E).

[0080] In one embodiment, the present disclosure provides a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

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

[0088] or a functional variant thereof, wherein the variant has between 1 and 4 individual amino acid substitutions in any of SEQ ID NO: and SEQ ID NO:

[0089] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of the amino acid residues from 4 to 29 of the peptide of any of SEQ ID NO: and SEQ ID NO: or a functional variant thereof comprising between 1 and 4 amino acid substitutions in any of SEQ ID NO: and SEQ ID NO:

[0090] wherein Z is:

[0091] glycine or proline,

[0092] a fragment selected from the group consisting of:

[0093] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, and GPSSGAPPPS,

[0094] a fragment selected from the group consisting of:

[0095] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, a fragment selected from the group consisting of:

[0096] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or

[0097] a fragment selected from the group consisting of:

[0098] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of said amino acid residues, or

[0099] a fragment selected from the group consisting of:

[0100] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues.

[0101] In 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 part of Exendin-4 or GIP(1-42) (such as e.g. GPSSGAPPPS, PSSGAPPPS or GKKNDW), an important advantage of the above aspects is that the in vivo half-life is prolonged to a surprisingly high degree compared to the corresponding non-extended analog. In particular, this can be the case when the extended GIP(3-30) analog is lipidated at specific positions (such as e.g. positions 11, 12, 17 and 18 for the extended GIP(3-30), GIP(4-30) GIP(5-30) and GIP(6-30) analogs). Thus, a C-terminal extension of e.g. GPSSGAPPPS, PSSGAPPPS, GKKNDW or fragments thereof and lipidation at specific positions can result in an improved antagonistic effect and at the same time an improved half-life of more than 5 or 10 hours or even more than 15 or 20 hours to a surprisingly large extent compared to the corresponding sequence without the C-terminal extension.

[0102] As used herein, "GIP(3-30)" refers to a GIP peptide analog 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 analog 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 analog 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.

[0103] In one embodiment, the peptide is C-terminally carboxylated (-COOH).

[0104] Without being bound by any theory, the free C-terminal carboxylic acid can be able to help increase the binding to albumin and thus unexpectedly further prolong the half-life in vivo.

[0105] Another important advantage of the above aspects is that the antagonistic properties can be increased and / or the selectivity for GIP receptor agonism is increased in case the GIP antagonist 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 from the C-terminal part of Exendin-4 or GIP(1-42) such as GPSSGAPPPS, PSSGAPPPS or GKKNDW. Since GIP(3-42) is a worse antagonist than GIP(3-30) [Hansen et al. 2016 Br J Pharmacol], it is unexpected that the antagonistic effect of AT631 with the C-terminal extension from Exendin-4 (-PSSGAPPPS) is improved. Furthermore, Exendin-4 is a GLP-1 agonist, so it is very unexpected that the GIP antagonistic effect is improved by extending the GIP antagonist 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) analogs with amino acid residues from the C-terminal part of Exendin-4.

[0106] In the case of 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 extended with amino acid residues from the C-terminal part of Exendin-4 or GIP(1-42) such as GPSSGAPPPS, PSSGAPPPS or GKKNDW, a further important advantage of the above aspects is an increased selectivity with respect to activation or inhibition of other receptor members of the GPCR family B such as GLP-1 R and Glucagon-R.

[0107] In one embodiment, 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) extended with amino acid residues from the C-terminal part of Exendin-4 or GIP(1-42) such as GPSSGAPPPS, PSSGAPPPS or GKKNDW and C-terminally carboxylated are provided.

[0108] In one embodiment, the GIP peptide analog or functional variant thereof is an isolated peptide.

[0109] In one embodiment, the GIP peptide analog or functional variant thereof as disclosed herein is provided, wherein

[0110] the amino acid at position 5 is T or is omitted;

[0111] the amino acid at position 9 is selected from the group consisting of D, E and T;

[0112] the amino acid at position 11 is selected from the group consisting of S, K and A;

[0113] the amino acid at position 12 is selected from the group consisting of I, K and 2- aminoisobutyric acid (Aib);

[0114] the amino acid at position 13 is selected from the group consisting of A and Aib;

[0115] the amino acid at position 14 is selected from M, K, E, S, L, and Nle;

[0116] the amino acid at position 15 is selected from D and E;

[0117] the amino acid at position 16 is selected from K and R;

[0118] the amino acid at position 17 is selected from I and K;

[0119] the amino acid at position 18 is selected from H and K;

[0120] the amino acid at position 20 is selected from Q and K;

[0121] the amino acid at position 21 is selected from D and E;

[0122] the amino acid at position 24 is selected from N, K, Q, and E;

[0123] the amino acid at position 28 is selected from A and E;

[0124] the amino acid at position 29 is selected from Q and G; and / or

[0125] the amino acid at position 30 is selected from K, R, G, and A.

[0126] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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.

[0127] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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, wherein the substitution is a conservative amino acid substitution.

[0128] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein the functional variant has 1 to 2 single amino acid substitutions, such as 2 to 3 single amino acid substitutions, such as 3 to 4 single amino acid substitutions, such as 4 to 5 single amino acid substitutions, such as 5 to 6 single amino acid substitutions, such as 6 to 7 single amino acid substitutions, such as 7 to 8 single amino acid substitutions at any amino acid residue of SEQ ID NO:XX.

[0129] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein the GIP peptide analogue consists of the amino acid sequence of SEQ ID NO:XX, and wherein X1and X2are omitted.

[0130] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein the GIP peptide analogue consists of the amino acid sequence of SEQ ID NO:XX, and X1, X2and the amino acid residue at position 5 are omitted. In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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.

[0131] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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.

[0132] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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.

[0133] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein the functional variant has 1 to 2 individual 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).

[0134] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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)).

[0135] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein at least one amino acid residue of the GIP peptide analogue of SEQ ID NO: XX is substituted with E.

[0136] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, wherein at least one amino acid residue at any one of positions 9, 14, 15, 21, 24 and 28 is substituted with 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 with E.

[0137] Substitution of one or more amino acid residues of the peptide of SEQ ID NO: XX with E as defined herein is particularly advantageous as it can result in an increased antagonistic effect, increased solubility, and / or increased stability of the substituted peptide.

[0138] In one embodiment, a GIP peptide analog 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), and glutaric acid.

[0139] In one embodiment, a GIP peptide analog or a functional variant thereof as disclosed herein is provided, wherein X1 is E.

[0140] In one embodiment, a GIP peptide analog or a functional variant thereof as disclosed herein is provided, wherein X1 is pyroE (pyroglutamic acid).

[0141] In one embodiment, a GIP peptide analog 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 SEQ ID NO:XX) is substituted with any amino acid, such as by substitution with an amino acid residue selected from: 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 deaminoglutamic acid, i.e., glutamic acid lacking the amino group. Glutaric acid can also be referred to as a glutamic acid mimic.

[0142] In one embodiment, a GIP peptide analog or a functional variant thereof as disclosed herein is provided, wherein X1 is E or glutaric acid.

[0143] GIP peptide analogs according to this disclosure having an E at the 3rd position can be highly effective antagonists against GIPR. However, having an E at the 3rd position may lead to instability of the compound. Without being bound by theory, the E at the 3rd position can form pyroGlu through cyclization between the N-terminal amino group and the carboxylic acid side chain of E. Therefore, substituting the E at the 3rd position may be advantageous. The inventors have discovered that the N-terminal amino group may not be necessary for obtaining an effective antagonist.

[0144] 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 lacks an amino group and therefore cannot form the N-terminal pyroGlu. The formation of pyroGlu would likely be an unwanted side effect for 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.

[0145] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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 S (Ser).

[0146] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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 (pyroglutamate).

[0147] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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 P (Pro).

[0148] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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 G (Gly).

[0149] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof as disclosed herein, 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 with A (Ala).

[0150] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein X2 is an amino acid residue selected from G and E.

[0151] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0152] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid.

[0153] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with an amino acid residue selected from E and T. The advantage of having E at position 9 is that it can increase potency and / or physical stability, such as solubility. E at position 9 can also prevent agonist activity.

[0154] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with any amino acid.

[0155] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with a conservative amino acid.

[0156] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid residue selected from the group consisting of A, K and Orn.

[0157] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid selected from the group consisting of A, R, K and Orn.

[0158] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with K or Orn.

[0159] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0160] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid.

[0161] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid residue selected from K, Orn and 2-aminoisobutyric acid (Aib).

[0162] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0163] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid.

[0164] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with 2-aminoisobutyric acid (Aib). The advantage of having Aib at position 13 is that potency can be significantly improved. In addition, Aib at position 13 can also increase the stability of the peptide, such as in vivo stability or physical stability.

[0165] It has been observed that substitution of any of the amino acid residues in positions 12 and 13 of any 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 can further increase the stability and half-life of the GIP peptide analogue.

[0166] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof, wherein the M in position 14 of any 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.

[0167] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof, wherein the M in position 14 of any 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.

[0168] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid residue selected from the group consisting of L, norleucine (Nle), E, S, K and Orn.

[0169] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid residue selected from the group consisting of L, norleucine (Nle) and K. In some embodiments, the amino acid at position 14 is L or Nle. Since M is prone to oxidation, it can be advantageous to substitute it with another amino acid such as L, Nle or K, for example L or Nle.

[0170] In some embodiments, the amino acid at position 14 is L.

[0171] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with any amino acid.

[0172] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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), or functional variant thereof, is substituted with a conserved amino acid.

[0173] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 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, can be increased. E at position 15 can also prevent agonist activity.

[0174] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with E.

[0175] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0176] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid substitution.

[0177] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid selected from R, A and E.

[0178] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof, 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 with R.

[0179] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof, 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 with any amino acid.

[0180] In one embodiment, there is provided a GIP peptide analogue or a functional variant thereof, 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 with a conservative amino acid.

[0181] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is replaced with K or Orn.

[0182] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is replaced with any amino acid.

[0183] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is replaced with a conservative amino acid.

[0184] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with an amino acid selected from the group consisting of A, R, K and Orn.

[0185] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with K or Orn.

[0186] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with K.

[0187] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0188] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid.

[0189] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with K or Orn.

[0190] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with any amino acid.

[0191] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with a conservative amino acid.

[0192] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with E. Having E at position 21 has the advantage that potency and / or physical stability, such as solubility, can be increased.

[0193] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with any amino acid.

[0194] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with a conservative amino acid.

[0195] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with an amino acid selected from Q, A and E.

[0196] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with E. The advantage of having E at position 24 is that physical stability, such as solubility, can be increased. It can also reduce sensitivity to aggregates.

[0197] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with any amino acid.

[0198] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof is substituted with a conservative amino acid.

[0199] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with E.

[0200] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with any amino acid.

[0201] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with a conservative amino acid.

[0202] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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 functional variant thereof, is substituted with G.

[0203] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with any amino acid.

[0204] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, wherein the 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 functional variant thereof, is substituted with a conservative amino acid substitution.

[0205] In one embodiment, a GIP peptide analog or 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 with an amino acid selected from the group consisting of R, A, E, and G, preferably an amino acid selected from the group consisting of R, A, and G.

[0206] In one embodiment, a GIP peptide analog or 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 the group consisting of A, L, E, and K.

[0207] In one embodiment, a GIP peptide analog or functional variant thereof is provided, wherein the GIP peptide analog 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)).

[0208] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, 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)), 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.

[0209] In one embodiment, there is provided a GIP peptide analogue (SEQ ID NO:XX) or functional variant thereof, wherein

[0210] the amino acid at position 5 is T;

[0211] the amino acid at position 6 is F;

[0212] the amino acid at position 10 is Y;

[0213] the amino acid at position 22 is F;

[0214] the amino acid at position 23 is V;

[0215] the amino acid at position 25 is W;

[0216] the amino acid at position 26 is L;

[0217] the amino acid at position 27 is L.

[0218] In one embodiment, there is provided a GIP peptide analogue (SEQ ID NO:XX) or functional variant thereof, wherein the amino acid at position 5 is T.

[0219] In one embodiment, there is provided a GIP peptide analogue (SEQ ID NO:XX) or functional variant thereof, wherein the amino acid at position 6 is F.

[0220] In one embodiment, there is provided a GIP peptide analogue (SEQ ID NO:XX) or functional variant thereof, wherein the amino acid at position 7 is I.

[0221] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 10 is Y.

[0222] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 22 is F.

[0223] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 23 is V.

[0224] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 25 is W.

[0225] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 26 is L.

[0226] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 27 is L.

[0227] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid residues at positions 29 and 30 are not both G.

[0228] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein only one of the amino acid residues at positions 29 and 30 is G.

[0229] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid residues at positions 29 and 30 are independently selected from Q, E, and K.

[0230] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 29 is Q.

[0231] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) or functional variant thereof is provided, wherein the amino acid at position 30 is K.

[0232] In one embodiment, a GIP peptide analog (SEQ ID NO:XX) is provided, wherein 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 is 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 I,

[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 and the amino acid residue at position 11 is K or S,

[0240] the amino acid residue at position 12 is I or K,

[0241] the amino acid residue at position 13 is A or Aib or K,

[0242] the amino acid residue at position 14 is M, L, Nle or K,

[0243] the amino acid residue at position 15 is D or E,

[0244] the amino acid residue at position 16 is K and the amino acid residue at position 17 is I or K,

[0245] the amino acid residue at position 18 is H or K,

[0246] the amino acid residue at position 19 is Q, the amino acid residue at position 20 is Q, and the amino acid residue at position 21 is D or E,

[0247] the amino acid residue at position 22 is F, the amino acid residue at position 23 is V, and the amino acid residue at position 24 is N, A, Q or E,

[0248] the amino acid residue at position 25 is W,

[0249] the amino acid residue at position 26 is L, the amino acid residue at position 27 is L, and the amino acid residue at position 28 is A, E or K,

[0250] the amino acid residue at position 29 is Q, G or K, and

[0251] the amino acid residue at position 30 is K or G,

[0252] or a functional variant thereof.

[0253] In one embodiment, there is provided a GIP peptide analogue (SEQ ID NO:XX) wherein the amino acid at position 3 is E or glutaric acid or is absent;

[0254] the amino acid at position 4 is Gly or is absent;

[0255] the amino acid at position 5 is T;

[0256] the amino acid at position 9 is selected from D, E;

[0257] the amino acid at position 11 is selected from S, K and A;

[0258] the amino acid at position 12 is selected from I and K;

[0259] the amino acid at position 13 is selected from A and Aib;

[0260] the amino acid at position 14 is selected from M, L and Nle;

[0261] the amino acid at position 15 is selected from D and E;

[0262] the amino acid at position 16 is selected from K and R;

[0263] the amino acid at position 17 is selected from I and K;

[0264] the amino acid at position 18 is selected from H and K;

[0265] the amino acid at position 20 is selected from Q and K;

[0266] the amino acid at position 21 is selected from D and E;

[0267] the amino acid at position 24 is selected from N, Q and E;

[0268] the amino acid at position 28 is selected from A and E;

[0269] the amino acid at position 29 is selected from Q and G; and / or

[0270] the amino acid at position 30 is selected from K, R, G and A.

[0271] In one embodiment there is provided a GIP peptide analogue (SEQ ID NO:XX) wherein the amino acid at position 3 is Glu or glutaric acid or is absent

[0272] the amino acid at position 4 is Gly or is absent

[0273] the amino acid at position 5 is T;

[0274] the amino acid at position 6 is F;

[0275] the amino acid at position 7 is I;

[0276] the amino acid at position 9 is selected from D and E;

[0277] the amino acid at position 10 is Y;

[0278] the amino acid at position 11 is selected from S, K, and A;

[0279] the amino acid at position 12 is selected from I and K;

[0280] the amino acid at position 13 is selected from A and Aib;

[0281] the amino acid at position 14 is selected from M, L, and Nle;

[0282] the amino acid at position 15 is selected from D and E;

[0283] the amino acid at position 16 is selected from K and R;

[0284] the amino acid at position 17 is selected from I and K;

[0285] the amino acid at position 18 is selected from H and K;

[0286] the amino acid at position 20 is selected from Q and K;

[0287] the amino acid at position 21 is selected from D and E;

[0288] the amino acid at position 22 is F;

[0289] the amino acid at position 23 is V;

[0290] the amino acid at position 24 is selected from N, Q, and E;

[0291] the amino acid at position 25 is W;

[0292] the amino acid at position 26 is L;

[0293] the amino acid at position 27 is L;

[0294] the amino acid at position 29 is Q; and / or

[0295] the amino acid at position 30 is K or R.

[0296] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X1-X2):

[0297]

[0298] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X2):

[0299]

[0300] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30 X1):

[0301]

[0302] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP3-30):

[0303]

[0304] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP4-30 X2):

[0305]

[0306] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP4-30):

[0307]

[0308] 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.

[0309] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP5-30):

[0310]

[0311] In one embodiment, the present disclosure provides a GIP peptide analog consisting of SEQ ID NO: (GIP6-30):

[0312]

[0313] One feature of the GIP peptide analogs of the present disclosure is the presence of a moiety called 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 (HGEGTFTSDLSKQME EEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO:E). The presence of a Z peptide is advantageous because it improves both the half-life and the antagonistic potency of the GIP peptide analog.

[0314] In an embodiment of the disclosure, Z consists of one or more contiguous amino acid residues of GIP(31-42) (SEQ ID NO: Z).

[0315] In an embodiment of the disclosure, Z consists of one or more contiguous amino acid residues of Exendin-4 (SEQ ID NO: E).

[0316] In an embodiment of the disclosure, Z consists of one or more contiguous amino acid residues of the C-terminus of Exendin-4(30-39) (PSSGAPPPS; SEQ ID NO: CE30-39).

[0317] In an embodiment of the disclosure, Z consists of one or more contiguous amino acid residues of the C-terminus of Exendin-4(29-39) (GPSSGAPPPS; SEQ ID NO: CE29-39).

[0318] In an embodiment of the disclosure, Z comprises at least one G or one P. Without wishing to be bound by theory, it is believed that when Z comprises a G or a P (e.g. like at position 31 and / or 32) then the half-life of the GIP peptide analogue is increased, which can be due to a decrease in degradation from the C-terminus, which increases the in vivo stability of the GIP peptide analogue.

[0319] In an embodiment of the disclosure, Z comprises at least two P.

[0320] In an embodiment of the disclosure, Z is a peptide selected from the group consisting of:

[0321] - glycine or proline,

[0322] - GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0323] - PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, - GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[0324] -GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GKKKDW, GKKNDKGRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues

[0325] variants thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues

[0326] -PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues.

[0327] 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).

[0328] 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).

[0329] 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).

[0330] 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).

[0331] 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).

[0332] In one embodiment, the GIP peptide analog of the disclosure has a free N-terminus. Thus, the N-terminus of the GIP peptide analog comprises an unsubstituted (such as unacetylated, acylated, or alkylated) amino (-NH2) moiety. Thus, the N-terminus of the GIP peptide analog can comprise a free amino (-NH2) moiety.

[0333] 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.

[0334] 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.

[0335] 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 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 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.

[0336] In one embodiment, the fatty acid molecule is attached to an 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 the GIP peptide analogue such as SEQ ID NO:XX or a functional variant thereof.

[0337] In one embodiment, the fatty acid molecule is attached to an 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.

[0338] In one embodiment, the fatty acid molecule is attached to an 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.

[0339] In one embodiment, the fatty acid molecule is attached to an 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.

[0340] 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.

[0341] 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.

[0342] 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.

[0343] In one embodiment, the fatty acid molecule is attached on one or more of the 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 one of these positions can result in a GIP peptide analogue with a particularly long half-life and with a particularly high antagonistic potency.

[0344] In one embodiment, the fatty acid molecule is attached on the epsilon-amino group of a K residue or an 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.

[0345] In one embodiment, the fatty acid molecule is attached on the side chain amino group of the amino acid residue 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.

[0346] In one embodiment, a fatty acid molecule is attached to the side chain amino group of 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 variant thereof, wherein in the GIP peptide analogue the H at position 18 has been replaced by K or Orn. Attachment of a fatty acid to the side chain amino group of the amino acid residue at position 18 can result in a GIP peptide analogue with a particularly long half-life and with a particularly high antagonistic potency.

[0347] In one embodiment, a fatty acid molecule is attached to the side chain amino group of 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 variant thereof, wherein in the GIP peptide analogue the H at position 18 has been replaced by K or Orn. Attachment of a fatty acid to the side chain amino group of the amino acid residue at position 18 can result in a GIP peptide analogue with a particularly long half-life and with a particularly high antagonistic potency.

[0348] In one embodiment, a fatty acid molecule is attached to the side chain amino group of 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 variant thereof, wherein in the GIP peptide analogue the H at position 18 has been replaced by K or Orn. Attachment of a fatty acid to the side chain amino group of the amino acid residue at position 18 can result in a GIP peptide analogue with a particularly long half-life and with a particularly high antagonistic potency.

[0349] In one embodiment, a fatty acid molecule is attached to the side chain amino group of 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 variant thereof, wherein I at position 12 in the GIP peptide analogue has been substituted with K or Orn.

[0350] 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.

[0351] In one embodiment, a 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.

[0352] 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.

[0353] In one embodiment, a fatty acid molecule is attached to the 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.

[0354] 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.

[0355] In one embodiment, a fatty acid molecule is attached on 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.

[0356] In one embodiment, at least one fatty acid molecule is attached on an 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.

[0357] In one embodiment, a fatty acid molecule is attached on 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.

[0358] In one embodiment, at least one fatty acid molecule is attached to a 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 at least two of the amino acids at positions 9, 15, and 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) are E.

[0359] In one embodiment, at least one fatty acid molecule is attached to an amino acid in the middle of the GIP peptide analogue, such as at any one of positions 11 to 18 of the GIP peptide analogue, such as at position 11 or 18.

[0360] In one embodiment, a GIP peptide analogue or functional variant thereof is provided, the peptide being an analogue 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 having a sequence selected from the group consisting of: EGTFISDYSIAMDKIHQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30), EGTFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30)[H18K],

[0361] SGTFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3S; H18K],

[0362] SGTFISDYSIAMDRIKQQDFVNWLLAQR - Z; SEQ ID NO:; GIP(3-30) [E3S; K16R; H18K; K30R],

[0363] EGTFISDYKIAMDKIHQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [S11K],

[0364] EGTFISDYSKAMDKIHQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [I12K],

[0365] EGTFISDYSIAMDKIHQKDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [Q20K],

[0366] EGTFISDYSIAMDKIHQQDFVKWLLAQK - Z; SEQ ID NO:; GIP(3-30) [N24K],

[0367] EGTFISDYSIAMDKKHQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [I17K],

[0368] EGTFISDYSIAMDKIKQQDFVNWLLAQG - Z; SEQ ID NO:; GIP(3-30) [H18K; K30G],

[0369] EGTFISDYSIAMDKIKQQDFVNWLLAGG - Z; SEQ ID NO:; GIP(3-30) [H18K; Q29G; K30G],

[0370] EGTFISEYSIAMEKIKQQEFVQWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; D15E; H18K; D21E; N24Q],

[0371] EGTFISEYSIAMEKIKQQDFVQWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; D15E; H18K; N24Q],

[0372] EGTFISEYSAibANleEKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[0373] EGTFISEYSIAibMEKIKQQDFVEWLLAQK - Z; SEQ ID NO: GIP(3-30) [D9E; A13Aib; D15E; H18K; N24E],

[0374] EGTFISDYSIAMDKIKQQDFVEWLLAQK - Z; SEQ ID NO: GIP(3-30) [H18K; N24E],

[0375] EGTFISDYSIALDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [M14L; H18K],

[0376] EGTFISDYSIANleDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [M14Nle; H18K],

[0377] EGTFISDYSIAEDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [M14E; H18K],

[0378] EGTFISDYSIAKDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [M14K; H18K],

[0379] EGTFISDYSIASDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [M14S; H18K],

[0380] EGTFISDYSIAMDKIKQQDFVEWLLAQA - Z; SEQ ID NO: GIP(3-30) [H18K; N24E; K30A],

[0381] EGTFISDYSIAMDKIKQQDFVNWLLEQK - Z; SEQ ID NO: GIP(3-30) [H18K; A28E],

[0382] VGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO: GIP(3-30) [E3V; H18K],

[0383] AibGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3Aib; H18K],

[0384] PGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3P; H18K],

[0385] VETFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3V; G4E; H18K],

[0386] AibETFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3Aib; G4E; H18K],

[0387] GETFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3G; G4E; H18K],

[0388] PETFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3P; G4E; H18K],

[0389] DTTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3D; G4T; H18K],

[0390] GETFISDYAIALDKIKQQDFVEWLLAQG - Z; SEQ ID NO:; GIP(3-30) [E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[0391] GETFISTYSIALDKIKQQDFVEWLLAQG - Z; SEQ ID NO:; GIP(3-30) [E3G; G4E; D9T; M14L; H18K; N24E],

[0392] EGTFISTYKIALDKIHQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9T; S11K; M14L; N24E],

[0393] EGTFISDYSIAibMDKIKQQDFVEWLLAQK - Z; SEQ ID NO; GIP(3-30) [A13Aib; H18K; N24E],

[0394] EGTFISDYSIAibLDKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [A13Aib; M14L; H18K; N24E],

[0395] EGTFISDYSIAibNleDKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [A13Aib; M14Nle; H18K; N24E],

[0396] EGTFISDYSIALDKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [M14L; H18K; N24E],

[0397] EGTFISDYSIANleDKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [M14Nle; H18K; N24E],

[0398] EGTFISDYSIAKDKIKQQDFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [M14K; H18K; N24E],

[0399] EGTFISDYSIANleDKIKQQDFVNWLLAGG - Z; SEQ ID NO:; GIP(3-30) [M14Nle; H18K; Q29G; K30G],

[0400] EGTFISDYSIANleDKIKQQDFVEWLLAGG - Z; SEQ ID NO:; GIP(3-30) [M14Nle; H18K; N24E; Q29G; K30G],

[0401] EGTFISEYSIAibLEKIKQQEFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], EGTFISEYSIAibNleEKIKQQEFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], yGluGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3 yGlu; H18K], βGluGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3 βGlu; H18K],

[0402] XGTFISDYSIAMDKIKQQDFVNWLLAQK - Z; SEQ ID NO:; GIP(3-30) [E3 glutaroyl (X); H18K],

[0403] EGTFISDYSIALDKIKQQDFVEWLLAGG - Z; SEQ ID NO:; GIP(3-30) [M14L; H18K; N24E; Q29G; K30G],

[0404] EGTFISEYSIALEKIKQQEFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; M14L; D15E; H18K; D21E; N24E],

[0405] EGTFISEYSIANleEKIKQQEFVEWLLAQK - Z; SEQ ID NO:; GIP(3-30) [D9E; M14Nle; D15E; H18K; D21E; N24E],

[0406] yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO: GIP(3-30) [E3 yGlu (L isomer); M14 Nle; H18K; N24E], yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO: GIP(3-30) [E3 yGlu (D isomer); M14 Nle; H18K; N24E], βGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO: GIP(3-30) [E3 βGlu; M14 Nle; H18K; N24E],

[0407] XGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO: GIP(3-30) [E3 glutaric acid (X); M14 Nle; H18K; N24E],

[0408] βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQK-Z; SEQ ID NO: GIP(3-30) [E3 βGlu; A13 Aib; M14 Nle; H18K],

[0409] EGTFISDYSIALDKIKQQDFVNWLLEQK-Z; SEQ ID NO: GIP(3-30) [M14 L; H18K; A28E],

[0410] EGTFISDYSIANleDKIKQQDFVNWLLEQK-Z; SEQ ID NO: GIP(3-30) [M14 Nle; H18K; A28E], and

[0411] EGTFISDYSIALDKIKQQDFVNWLLEGG-Z; SEQ ID NO: GIP(3-30) [M14 L; H18K; A28E; Q29G; K30G]

[0412] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more amino acid residues from position 4 to 29 of any one of the above sequences. And wherein the peptide can be C-terminally carboxylated.

[0413] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, the peptide being an analogue of hGIP5-30 (SEQ ID NO: GIP(5-30)) and having a sequence selected from the group consisting of: TFISDYSIAMDKIHQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30) TFISDYKIAMDKIHQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30) [S11K],

[0414] TFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30) [H18K],

[0415] TFISDYKIAMDRIHQQDFVNWLLAQR -Z; SEQ ID NO:; GIP(5-30) [S11K; K16R; K30R],

[0416] TFISDYSKAMDKIHQQDFVNWLLAQK -Z; SEQ ID NO:; GIP(5-30) [I12K],

[0417] TFISDYSIAMDKIHQKDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30) [Q20K], and

[0418] TFISDYSIAMDKIHQQDFVKWLLAQK -Z; SEQ ID NO:; GIP(5-30) [N24K], wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more amino acid residues from position 4 to 29 of any one of the above sequences. And wherein the peptide can be C-terminally carboxylated.

[0419] In one embodiment, there is provided a GIP peptide analogue or functional variant thereof, the peptide being an analogue of hGIP6-30 (SEQ ID NO: GIP(6-30)) and having a sequence selected from the group consisting of: FISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(6-30) [H18K]. wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more amino acid residues from position 4 to 29 of any one of the above sequences. And wherein the peptide can be C-terminally carboxylated.

[0420] In one embodiment, the GIP peptide analogue of the present disclosure is C-terminally amidated (-NH2).

[0421] In one embodiment, the GIP peptide analog of the present disclosure is C-terminally carboxylated (-COOH), such as where the C-terminus is a free carboxylic acid.

[0422] Functional variants - mutants

[0423] In one embodiment, one or more or all of the amino acid substitutions are conservative amino acid substitutions (or synonymous substitutions). A conservative substitution is the substitution of an amino acid with similar biochemical properties and therefore does not affect the function of the peptide.

[0424] Particular amino acid substitutions as disclosed herein are K to R, A, G; E to D, S, P, G, V, 2-aminoisobutyric acid (Aib), gamma-glutamic acid (yGlu), D-gamma-glutamic acid (D-yGlu), beta-glutamic acid (bGlu), 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.

[0425] In another embodiment, a functional variant as defined herein comprises the sequence: wherein alkyl amino acid is substituted for an alkyl amino acid, wherein aromatic amino acid is substituted for an aromatic amino acid, wherein sulfur-containing amino acid is substituted for a sulfur-containing amino acid, wherein hydroxyl-containing amino acid is substituted for a hydroxyl-containing amino acid, wherein acidic amino acid is substituted for an acidic amino acid, wherein basic amino acid is substituted for a basic amino acid, and / or wherein dibasic monocarboxylic acid amino acid is substituted for a dibasic monocarboxylic acid amino acid.

[0426] Conservative substitutions can be introduced into one or more of the above- specified positions of a GIP peptide analog 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), so long as the resulting variant retains functionality. However, it can also be desirable to introduce non-conservative substitutions (non-synonymous substitutions) at one or more positions.

[0427] In one embodiment, the non-conservative substitution resulting in the formation of a variant of a GIP peptide 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) comprises a substitution of an amino acid residue that: i) is substantially different in polarity, e.g., a residue with a nonpolar side chain (Ala, Leu, Pro, Trp, Val, lie, Leu, Phe, or Met) is substituted for a residue with a polar side chain (such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gin or a charged amino acid (such as Asp, Glu, Arg, or Lys)), or a charged or polar residue is substituted for a nonpolar residue; and / or ii) has a substantially different effect on the orientation of the peptide backbone, such as Pro or Gly being substituted for the other or the other substituted for Pro or Gly; and / or iii) is substantially different in charge, e.g., a negatively charged residue (such as Glu or Asp) is substituted for a positively charged residue (such as Lys, His, or Arg) (and vice versa); and / or iv) is substantially different in steric bulk, e.g., a residue with a bulky side chain (such as His, Trp, Phe, or Tyr) is substituted for a residue with a smaller side chain (e.g., Ala, Gly, or Ser) (and vice versa).

[0428] In one embodiment, substitutions of amino acids can be made on the basis of the hydropathic nature of the amino acids and the relative similarity of the side chain substituents of the amino acids (including charge, size, and so on).

[0429] A GIP peptide analogue or its functional variant counterpart as defined herein comprises proteinogenic or natural amino acids, i.e. the 22 amino acids naturally incorporated into polypeptides. Of these, 20 are encoded by the universal genetic code and the remaining 2 (selenocysteine (Sec, U) and pyrrolysine (Pyl, O) are incorporated into proteins by unique synthetic mechanisms.

[0430] In one embodiment, the 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, beta-2-naphthyl-alanine, trans-3-methylproline, 2,4-methanoproline, cis-4-hydroxyproline, ornithine (Orn), trans-4-hydroxyproline, N-methylglycine, allothreonine, methylthreonine, hydroxyethylcysteine, hydroxyethylhomocysteine, nitroglutamine, homoglutamine, piperidinic acid, thiazolidine carboxylic 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.

[0431] In one embodiment, the amino acid Met is substituted by an antioxidant amino acid analogue, such as norleucine (Nle) or Leu, which preserves the length of the amino acid side chain important for hydrophobic interactions, but not its hydrogen bonding properties; or methoxinine (Mox), which is a non-canonical amino acid with electronic properties more similar to Met than Nle or Lys.

[0432] Standard and / or non-standard amino acids can be linked by peptide bonds (to form linear peptide chains), or by non-peptide bonds (for example via variable side chains of the amino acids). Preferably, the amino acids of the peptides as defined herein are linked by peptide bonds.

[0433] As known in the art, the term peptide also encompasses post-translational modifications introduced by chemical or enzyme-catalysed reactions. These include acetylation, phosphorylation, methylation, glycosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation and sulfation of one or more amino acid residues, and also proteolytic modifications by known proteases, including lysosomal cathepsins as well as calpains, secretases and matrix-metalloproteases.

[0434] Likewise, functional equivalents of the peptides can comprise chemical modifications, such as ubiquitination, labelling (for example with radionuclides, various enzymes etc.), pegylation (derivatisation with polyethylene glycol), or by the insertion (or substitution by chemical synthesis) of amino acids not normally found in human proteins (non-proteinogenic, such as ornithine).

[0435] Spatially similar compounds can be formulated to mimic key portions of the peptide structure. This can be accomplished by 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 will be understood that all such spatially similar constructs fall within the scope of the present application. Peptides with N-terminal and C-terminal alkylations and esterifications are also encompassed within the present application. For example, glutaric acid is a spatially similar compound that mimics glutamic acid.

[0436] In one embodiment, the N-terminal amino acid of the GIP peptide analog of the present disclosure does not have any chemical modification. It can be advantageous for the amino group at the N-terminus of the GIP peptide analog to be free, i.e., unsubstituted, as substitution can result in agonism at the GIPR.

[0437] It appears that lengthening the fatty acid or linker, if present, can decrease antagonistic potency. However, the simultaneous incorporation of an Aib residue at position 13 appears to compensate for some or all of the decreased potency, especially 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.

[0438] Attachment of fatty acid molecules

[0439] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues having a side chain amino-alkyl (-C n H 2n NH2) group.

[0440] In one embodiment, the fatty acid molecule is attached to one or more amino acid residues having a side chain amino (NH2) group.

[0441] In one embodiment, the fatty acid molecule is attached to an amino (NH2) group of an amino acid residue.

[0442] In one embodiment, the fatty acid molecule is attached to a side chain amino group of an amino acid residue.

[0443] In one embodiment, the fatty acid molecule is attached to an epsilon (epsilon) side chain amino group of a lysine residue (Lys, K).

[0444] In one embodiment, the fatty acid molecule is attached to a delta (delta) side chain amino group of an ornithine residue (Orn).

[0445] In one embodiment, the amino acid residue having the attached fatty acid molecule is selected from Lys and Orn.

[0446] In one embodiment, the amino acid residue with the attached fatty acid molecule is Lys.

[0447] In one embodiment, the fatty acid molecule is attached to the delta-amino group of an Orn residue of the GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant comprising an Orn amino acid residue.

[0448] In one embodiment, the fatty acid molecule is attached to the epsilon-amino group of a K residue of the GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant thereof.

[0449] 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 the GIP peptide analogue (such as SEQ ID NO: XX) or a functional variant thereof, wherein the fatty acid is attached to an amino group comprised in the N-terminal amino acid side chain.

[0450] In one embodiment, the fatty acid molecule according to the present disclosure is a straight-chain fatty acid.

[0451] In one embodiment, the fatty acid molecule according to the present disclosure is a branched-chain fatty acid.

[0452] 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.

[0453] For example, a GIP peptide can be conjugated via a linker to a monoacyl fatty acid (such as hexadecanoyl) as depicted in Formula I:

[0454] Formula I

[0455] 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 both carboxyl groups are located at one end or each end of the fatty acid molecule.

[0456] For example, a GIP peptide can be conjugated via a linker to a diacyl fatty acid (also referred to as “diacid”) (such as 15-carboxy-pentadecanoyl) as depicted in Formula II:

[0457] Formula II

[0458] In one embodiment, the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule comprising two fatty acids.

[0459] In one embodiment, the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule containing two carboxylic functional groups.

[0460] In one embodiment, the fatty acid molecule according to the present disclosure comprises an acyl group of formula CH3(CH2) n CO-, wherein n is an integer from 4 to 24.

[0461] In one embodiment, the fatty acid molecule comprises an acyl group selected from the group consisting of CH3(CH2)6CO-, 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-.

[0462] In one embodiment, the fatty acid molecule is a (mono)acyl fatty acid selected from the group consisting of CH3(CH2) 10 CO- (lauric, C12), CH3(CH2) 12 CO- (myristoyl, C14), CH3(CH2) 14 CO- (palmitoyl, C16), CH3(CH2) 16 CO- (stearoyl, C18), CH3(CH2) 18 CO- (arachidyl, C20), and CH3(CH2) 20 CO- (behenyl, C22).

[0463] 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).

[0464] 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-(stearoyl, C18), CH3(CH2) 18 CO-(arachidyl, C20), and CH3(CH2) 20 CO-(behenyl, C22).

[0465] In one embodiment, the fatty acid molecule comprises an acyl group of the formula COOH(CH2) n CO-(dicarboxylic acid), where n is an integer from 4 to 24.

[0466] 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).

[0467] In one embodiment, the fatty acid molecule is selected from the group consisting of C12, C14, C16, C18, C20, and C22.

[0468] In one embodiment, the fatty acid molecule is selected from the group consisting of C14 diacid, C16 diacid, C18 diacid, C20 diacid, and C22 diacid.

[0469] In one embodiment, the fatty acid molecule is palmitoyl.

[0470] In one embodiment, the fatty acid molecule is 1,16-hexadecanedioic acid / hexadecanedioic acid.

[0471] In one embodiment, the fatty acid molecule is 15-carboxy-pentadecanoyl.

[0472] In one embodiment, the fatty acid molecule is stearoyl.

[0473] In one embodiment, the fatty acid molecule is 1,18-octadecanedioic acid / octadecanedioic acid.

[0474] In one embodiment, the fatty acid molecule is 17-carboxy-heptadecanoyl.

[0475] In one embodiment, the fatty acid molecule is arachidyl.

[0476] In one embodiment, the fatty acid molecule is 1,20-eicosanedioic acid / eicosanedioic acid.

[0477] In one embodiment, the fatty acid molecule is 19-carboxy-nonadecanoyl.

[0478] In one embodiment, the fatty acid molecule is behenyl.

[0479] In one embodiment, the fatty acid molecule is 1,22-docosanedioic acid / docosanedioic acid.

[0480] In one embodiment, the fatty acid molecule comprises COOH(CH2) 14 or consists of. In one embodiment, the fatty acid molecule comprises COOH(CH2) 16 or consists of. In one embodiment, the fatty acid molecule comprises COOH(CH2) 18 or consists of.

[0481] The fatty acid molecule can be attached to the amino acid residue in a manner such that the carboxyl group of the fatty acid molecule forms an amide bond with the amino group of the amino acid residue.

[0482] Attachment of fatty acid molecules via linkers

[0483] Attachment of the fatty acid molecule to the peptide herein can occur directly or indirectly (i.e. via a linker or spacer).

[0484] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to an amino acid residue.

[0485] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the a-amino group of an amino acid residue, wherein the amino acid residue is an N-terminal amino acid residue.

[0486] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the e-amino group of a Lys residue.

[0487] In one embodiment, the fatty acid molecule according to the present disclosure is directly attached to the d-amino group of an Orn residue.

[0488] In one embodiment, the fatty acid molecule according to the present disclosure is attached to an amino acid residue via a linker or spacer, as depicted in Formula III:

[0489] Formula III:

[0490] 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 spacer.

[0491] In one embodiment, the fatty acid molecule according to the present disclosure is attached to the δ-amino group of an Orn residue via a linker or spacer.

[0492] In one embodiment, the fatty acid molecule can be attached to an amino acid residue by means of 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.

[0493] In one embodiment, the linker is an α,ω-amino acid. Examples of suitable linkers are succinic acid, Lys, Glu or Asp, or a dipeptide 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 amide bonds 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- asparagyl), Nε-glycyl and Nε-(α-(γ-aminobutyryl)).

[0494] In one embodiment, the linker comprises one or more moieties independently selected from:

[0495] a. an α-amino acid, a γ-amino acid or an ω-amino acid,

[0496] b. one or more amino acids selected from succinic acid, Lys, Glu, Asp,

[0497] c. one or more of γ-aminobutyryl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β- asparagyl), β-Ala (β-alanyl) and Gly, and

[0498] d. [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer between 1 and 50,

[0499] such as between 1-4, 1-3 or 1-2.

[0500] In one embodiment, the linker is a hydrophilic linker. In one embodiment, the linker is a non-natural amino acid hydrophilic linker.

[0501] In one embodiment, the linker is selected from the group consisting of gamma-aminobutyryl (gamma-aminobutyric acid), gamma-glutamyl (gamma-glutamic acid), beta- asparaginyl, beta-alanyl and glycyl. In one embodiment, the linker comprises one or more of gamma-aminobutyryl (gamma-aminobutyric acid), gamma-glutamyl (gamma-glutamic acid), beta-asparaginyl, beta-alanyl and glycyl.

[0502] 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.

[0503] In one embodiment, the linker is gamma-glutamic acid.

[0504] In one embodiment, the linker is gamma-glutamic acid-8-amino-3,6-dioxaoctanoic acid (gamma-Glu)-(AEEAc) or a repeat thereof.

[0505] In one embodiment, the linker comprises one or more repeats of gamma-glutamic acid-8-amino-3,6-dioxaoctanoic acid (gamma-Glu)-(AEEAc n ).

[0506] Examples of linkers disclosed herein are such that they can be attached to an amino acid residue of a GIP peptide analogue via either end of the linker. Thus, if for example the linker comprises one or more repeats of gamma-glutamic acid-8-amino-3,6-dioxaoctanoic acid (gamma-Glu)-(AEEAc n ), the linker can be attached to an amino acid residue of a GIP peptide analogue via the gamma-Glu or via the AEEAc n .

[0507] In one embodiment, the linker is [gamma-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid] n ( gamma-Glu)-(AEEAc n ), wherein n is an integer between 1 and 50.

[0508] In one embodiment, the linker is [gamma-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.

[0509] In one embodiment, the linker is [gamma-glutamic acid-8-amino-3,6-dioxaoctanoic acid] n (γ-Glu)-(AEEAc n ), wherein n is an integer selected from 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.

[0510] 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.

[0511] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer selected from 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.

[0512] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] n AEEAc n wherein n is an integer selected from 1, 2, 3.

[0513] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n wherein n is an integer selected from 1, 2, 3.

[0514] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] (AEEAc) or [8-amino-3,6-dioxaoctanoic acid]-[gamma-glutamic acid] (AEEAc-γ-Glu). For example, a GIP peptide can be conjugated via [8-amino-3,6-dioxaoctanoic acid] to a fatty acid (e.g. C16 or palmitic acid / palmitoyl in Formula IV, but any other fatty acid can be used) as depicted in Formula IV:

[0515]

[0516] Formula IV: The formula does not depict stereochemistry unless otherwise noted, the natural L-form is generally used.

[0517] For example, a GIP peptide can be conjugated via [8-amino-3,6-dioxaoctanoic acid]-[gamma-glutamic acid] to a fatty acid (e.g. C16 or palmitic acid / palmitoyl in Formula IV, but any other fatty acid can be used) as depicted in Formula V:

[0518]

[0519] Formula V: The formula does not depict stereochemistry unless otherwise noted, the natural L-form is generally used.

[0520] In one embodiment, the linker is [8-amino-3,6-dioxaoctanoic acid] 2 (AEEAc)2. For example, the linker can comprise or consist of yGlu-AEEAc-AEEAc- or AEEAc-yGlu-AEEAc- or AEEAc-AEEAc-yGlu-.

[0521] In one embodiment, the linker is [gamma-glutamic acid]-[8-amino-3,6-dioxaoctanoic acid]3 (y-Glu)-(AEEAc)3. For example, the linker can comprise or consist of yGlu-AEEAc-AEEAc-AEEAc- or AEEAc-yGlu-AEEAc-AEEAc- or AEEAc-AEEAc-yGlu-AEEAc- or AEEAc-AEEAc-AEEAc-yGlu-.

[0522] As provided herein, the linker comprising or consisting of one gamma-glutamic acid and one, two or three 8-amino-3,6-dioxaoctanoic acid moieties can form a bridge between the amino group of the parent peptide and the amino group of the fatty acid molecule via the y-Glu or via the AEEAc n attached to an amino acid residue of the GIP peptide analogue.

[0523] 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 y-aminobutyric acid.

[0524] In another embodiment, the linker is a dipeptide, such as a dipeptide of the following, 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, Gin, lie, Leu, Val, Phe and Pro. In one embodiment, the dipeptide linker is Gly-Lys.

[0525] In one embodiment, the linker comprises one or more moieties selected from the group consisting of gamma-aminobutyryl (y-aminobutyric acid), gamma-glutamyl (y-glutamic acid), beta-asparaginyl, beta-alanyl and glycinyl. In one embodiment, the linker comprises gamma-aminobutyryl (y-aminobutyric acid), gamma-glutamyl (y-glutamic acid), beta-asparaginyl, beta-alanyl, glycinyl, gamma-glutamic acid-8-amino-3,6-dioxaoctanoic acid (y-Glu-AEEAc n wherein n is an integer between 1 and 50), an amino acid residue other than Cys, 4-Abu, y-aminobutyric acid and a dipeptide.

[0526] In another embodiment, the linker is a non-branched alkane alpha, omega-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.

[0527] In one embodiment, the GIP peptide analogs disclosed herein comprise a fatty acid, and the fatty acid molecule is attached to an amino acid residue via a linker, such that the combination of the linker and fatty acid is selected from:

[0528] i. Hexadecanoyl-Y-Glu-

[0529] ii. Hexadecanoyl-Y-Glu-Y-Glu-

[0530] iii. Hexadecanoyl-Y-Glu-AEEAc-

[0531] iv. Hexadecanoyl-Y-Glu-AEEAc-AEEAc-

[0532] v. Hexadecanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[0533] vi. [15-carboxy-pentadecanoyl]-Y-Glu-

[0534] vii. [15-carboxy-pentadecanoyl]-Y-Glu-Y-Glu-

[0535] viii. [15-carboxy-pentadecanoyl]-Y-Glu-AEEAc-

[0536] ix. [15-carboxy-pentadecanoyl]-Y-Glu-AEEAc-AEEAc-

[0537] x. [15-carboxy-pentadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-

[0538] xi. Octadecanoyl-Y-Glu-

[0539] xii. Octadecanoyl-Y-Glu-Y-Glu-

[0540] xiii. Octadecanoyl-Y-Glu-AEEAc-

[0541] xiv. Octadecanoyl-Y-Glu-AEEAc-AEEAc-

[0542] xv. Octadecanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[0543] xvi. [17-carboxy-heptadecanoyl]-Y-Glu-

[0544] xvii. [17-carboxy-heptadecanoyl]-Y-Glu-Y-Glu-

[0545] xviii. [17-carboxy-heptadecanoyl]-Y-Glu-AEEAc-

[0546] xix. [17-carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-

[0547] xx. [17-carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc-

[0548] xxi. Eicosanoyl-Y-Glu-

[0549] xxii. Eicosanoyl-Y-Glu-Y-Glu-

[0550] xxiii. Eicosanoyl-Y-Glu-AEEAc-

[0551] xxiv. Eicosanoyl-Y-Glu-AEEAc-AEEAc-

[0552] xxv. Eicosanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[0553] xxvi. [19-carboxy-nonadecanoyl]-Y-Glu-

[0554] xxvii. [19-carboxy-nonadecanoyl]-Y-Glu-Y-Glu-

[0555] xxviii. [19-carboxy-nonadecanoyl]-Y-Glu-AEEAc-

[0556] xxix. [19-carboxy-nonadecanoyl]-Y-Glu-AEEAc-AEEAc-

[0557] xxx. [19-carboxy-nonadecanoyl]-Y-Glu-AEEAc-AEEAc-AEEAc.

[0558] In one embodiment, the GIP peptide analogs disclosed herein comprise a fatty acid, and the fatty acid molecule is attached to an amino acid residue via a linker, such that the combination of the linker and fatty acid is selected from:

[0559] i. [15-carboxypentadecanoyl]-Y-Glu

[0560] ii. [17-carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-, and

[0561] iii. [17-carboxy-heptadecanoyl]-Y-Glu-Y-Glu.

[0562] GIP peptides with fatty acids

[0563] In one embodiment, the GIP analogue as defined herein is selected from the group consisting of:

[0564] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0565] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0566] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C18-diacid / K18; SEQ ID NO: GIP(3-36)[H18K],

[0567] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K],

[0568] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0569] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0570] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0571] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[0572] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18-diacid / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0573] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18 / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0574] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C16-diacid / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0575] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-yGlu-C16-diacid / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0576] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30) + Cex[H18K],

[0577] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc + y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[CexH18K],

[0578] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc + y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[CexH18K],

[0579] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc + y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[CexH18K],

[0580] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[CexH18K],

[0581] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0582] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K],

[0583] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPP-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex(9) [CexH18K],

[0584] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPP-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex(Cex8) [H18K],

[0585] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAP-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex(Cex7) [H18K],

[0586] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGA-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex(Cex6) [H18K],

[0587] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSG-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex(Cex5) [H18K],

[0588] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSS-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex (Cex4) [H18K],

[0589] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPS-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex (Cex3) [H18K],

[0590] EGTFISDYSIAMDKIKQQDFVNWLLAQKGP-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex (Cex2) [H18K],

[0591] EGTFISDYSIAMDKIKQQDFVNWLLAQKG-C16-diacid / K18: SEQ ID NO: GIP(3-31) [H18K],

[0592] EGTFISDYSIAMDKIKQQDFVNWLLAQKGK-C16-diacid / K18: SEQ ID NO: GIP(3-32) [H18K],

[0593] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKK-C16-diacid / K18: SEQ ID NO: GIP(3-33) [H18K],

[0594] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKN-C16-diacid / K18: SEQ ID NO: GIP(3-34) [H18K],

[0595] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKND-C16-diacid / K18: SEQ ID NO: GIP(3-35) [H18K],

[0596] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-C16-diacid / K18: SEQ ID NO: GIP(3-36) [H18K],

[0597] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWK-C16-diacid / K18: SEQ ID NO: GIP(3-37) [H18K],

[0598] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKH-C16-diacid / K18: SEQ ID NO: GIP(3-38) [H18K],

[0599] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN-C16-diacid / K18: SEQ ID NO: GIP(3-39) [H18K],

[0600] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNI-C16-diacid / K18: SEQ ID NO: GIP(3-40) [H18K],

[0601] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNIT-C16-diacid / K18: SEQ ID NO: GIP(3-41) [H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ-C16-diacid / K18: SEQ ID NO: GIP(3-42) [H18K],

[0602] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36) [E3S; H18K],

[0603] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36) [E3S; H18K],

[0604] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C18-diacid / K18; SEQ ID NO: GIP(3-36) [E3S; H18K],

[0605] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex [E3S; H18K],

[0606] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[Cex E3S; H18K],

[0607] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[Cex E3S; H18K],

[0608] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[Cex E3S; H18K],

[0609] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-2xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[0610] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[0611] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C18-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[0612] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[E3S; K16R; H18K; K30R],

[0613] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex[Cex E3S; K16R; H18K; K30R],

[0614] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30) + Cex [CexE3S; K16R; H18K; K30R],

[0615] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30) + Cex [CexE3S; K16R; H18K; K30R],

[0616] EGTFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-diacid / K11; SEQ ID NO: GIP(3-36) [S11K],

[0617] EGTFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-diacid / K12; SEQ ID NO: GIP(3-36) [I12K],

[0618] EGTFISDYSIAMDKIHQKDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K20; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexQ20K],

[0619] EGTFISDYSIAMDKKHQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K17; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexI17K],

[0620] EGTFISDYSIAMDKIKQQDFVNWLLAQGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid; SEQ ID NO: GIP(3-30) + Cex(31-39) [CexH18K; K30G],

[0621] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS (NH2)-2xAEEAc + yGlu-C18-diacid; SEQ ID NO: GIP(3-30) + Cex(31-39) [Cex H18K; Q29G; K30G],

[0622] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS-2xAEEAc + yGlu-C18-diacid; SEQ ID NO: GIP(3-30) + Cex(31-39) [Cex H18K; Q29G; K30G],

[0623] EGTFISEYSIAMEKIKQQEFVQWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30) + Cex(31-39) [Cex D9E; D15E; H18K; D21E; N24Q],

[0624] EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; D15E; H18K; N24E],

[0625] EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[0626] EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; A13Aib; D15E; H18K; N24E],

[0627] EGTFISDYSIAMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [H18K; N24E],

[0628] EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14E; H18K],

[0629] EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C18-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14E; H18K],

[0630] EGTFISDYSIANleDKIKQQDFVNWLLAQKPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14Nle; H18K],

[0631] EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14E; H18K],

[0632] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14K; H18K],

[0633] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C18-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14K; H18K],

[0634] EGTFISDYSIASDKIKQQDFVNWLLAQKPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14S; H18K],

[0635] EGTFISDYSIAMDKIKQQDFVEWLLAQAPSSGAPPPS-C16-Diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [H18K; N24E; K30A],

[0636] EGTFISDYSIAMDKIKQQDFVNWLEAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [H18K; L27E],

[0637] EGTFISDYSIAMDKIKQQDFVNWLLEQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [H18K; A28E],

[0638] VGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3V; H18K],

[0639] AibGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3Aib; H18K],

[0640] PGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3P; H18K],

[0641] VETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3V; G4E; H18K],

[0642] AibETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3Aib; G4E; H18K],

[0643] GETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS - C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3G; G4E; H18K],

[0644] PETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3P; G4E; H18K],

[0645] DTTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3D; G4T; H18K],

[0646] GETFISDYAIALDKIKQQDFVEWLLAQGPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[0647] GETFISTYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3G; G4E; D9T; M14L; H18K; N24E],

[0648] EGTFISTYKIALDKIHQQDFVEWLLAQKPSSGAPPPS-yGlu-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9T; S11K; M14L; N24E],

[0649] GETFISDYAIALDKIKQQDFVEWLLAQG(NH2)PSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[0650] EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [A13Aib; H18K; N24E],

[0651] EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [A13 Aib; M14L; H18K; N24E],

[0652] EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [A13 Aib; M14L; H18K; N24E],

[0653] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [A13 Aib; M14Nle; H18K; N24E],

[0654] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [A13 Aib; M14Nle; H18K; N24E],

[0655] EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14L; H18K; N24E],

[0656] EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc + yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14L; H18K; N24E],

[0657] EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14Nle; H18K; N24E],

[0658] EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14Nle; H18K; N24E],

[0659] EGTFISDYSIAKDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14K; H18K; N24E],

[0660] EGTFISDYSIANleDKIKQQDFVNWLLAGGPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14Nle; H18K; Q29G; K30G],

[0661] EGTFISDYSIANleDKIKQQDFVEWLLAGGPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14Nle; H18K; N24E; Q29G; K30G],

[0662] EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E],

[0663] EGTFISEYSIAibLEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; A13Aib; M14L; D15E; H18K; D21E; N24E],

[0664] EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E],

[0665] EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E],

[0666] yGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3yGlu; H18K],

[0667] βGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3βGlu; H18K],

[0668] XGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 glutaric acid (X); H18K],

[0669] EGTFISDYSIALDKIKQQDFVEWLLAGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [M14L; H18K; N24E; Q29G; K30G],

[0670] EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; M14L; D15E; H18K; D21E; N24E],

[0671] EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [D9E; M14Nle; D15E; H18K; D21E N24E],

[0672] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 yGlu (L isomer); M14 Nle; H18K; N24E],

[0673] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 yGlu (D isomer); M14 Nle; H18K; N24E],

[0674] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 yGlu (D isomer); M14 Nle; H18K; N24E],

[0675] yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 yGlu (D isomer); M14 Nle; H18K; N24E],

[0676] XGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 glutaric acid (X); M14 Nle; H18K; N24E],

[0677] XGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 glutaric acid (X); M14 Nle; H18K; N24E],

[0678] yGluGTFISDYSIAibNleDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30) + Cex(31-39) [E3 yGlu; A13 Aib; M14 Nle; H18K],

[0679] EGTFISDYSIAMDKIKQQDFVNWLLAQPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)+Cex(32-39) [H18K; Q29G; K30P]),

[0680] EGTFISDYSIALDKIKQQDFVNWLLEQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39) [M14L; H18K; A28E],

[0681] EGTFISDYSIANleDKIKQQDFVNWLLEQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39) [M14Nle; H18K; A28E],

[0682] EGTFISDYSIALDKIKQQDFVNWLLEGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:; GIP(3-30)Cex(31-39) [M14L; H18K; A28E; Q29G; K30G], AT691,

[0683] EGTFISDYSIAMDKIKQQDFVNWLLAQK(NH2)PSSGAPPPS C16-diacid / 18K; GIP(3-30+CEX31-39 [H18K], AT650

[0684] EGTFISDYSIAMDKIKQQDFVNWLLEGGPSSGAPPPS-C16-diacid / K18; GIP(3-30)+Cex(31-39), AT626

[0685] or a functional variant thereof,

[0686] wherein the fatty acid is attached directly or via a linker / spacer as defined herein.

[0687] Thus, C16 is the fatty acid CH3(CH2) 14 CO-(palmitoyl) and C18 is the fatty acid CH3(CH2) 16 CO-(stearoyl). The suffix“-diacid” means that the fatty acid molecule is a diacyl fatty acid molecule. Without such a suffix it refers to a monoacyl fatty acid molecule.

[0688] Thus 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. Without such a suffix refers to a monoacyl fatty acid molecule.

[0689] Thus 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. Without such a suffix refers to a monoacyl fatty acid molecule.

[0690] In one embodiment, the GIP analogue as defined herein is selected from:

[0691] TFISDYKIAMDKIHQQDFVNWLLAQKGKK-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-33) [S11K],

[0692] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-36) [S11K],

[0693] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-diacid / K11, SEQ ID NO: GIP(5-36) [S11K],

[0694] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW(NH2)-2xAEEAc+yGlu-C18-diacid / K11, SEQ ID NO: GIP(5-36) [S11K],

[0695] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18 / K11, SEQ ID NO: GIP(5-36) [S11K],

[0696] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-yGlu-yGlu-C18 / K11, SEQ ID NO: GIP(5-36) [S11K],

[0697] TFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18 diacid / K12 SEQ ID NO: GIP(5-36) [I12K],

[0698] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHN-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-39) [S11K],

[0699] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-42) [S11K],

[0700] TFISDYKIAMDKIHQQDFVNWLLAQKG-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-31) [S11K],

[0701] TFISDYKIAMDKIHQQDFVNWLLAQKGK-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-32) [S11K],

[0702] TFISDYKIAMDKIHQQDFVNWLLAQKGKKN-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-34) [S11K],

[0703] TFISDYKIAMDKIHQQDFVNWLLAQKGKKND-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-35) [S11K],

[0704] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWK-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-37) [S11K],

[0705] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKH-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-38) [S11K],

[0706] TFISDYKIAMDKIHQQDFVNWLLAQKGKKNDWKHNI-y-glu-C16 diacid / K11 SEQ ID NO: GIP(5-40) [S11K],

[0707] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0708] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0709] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0710] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0711] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0712] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0713] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0714] TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C16 diacid / K11; SEQ ID NO: GIP(5-30)+Cex[S11K; K16R; K30R],

[0715] TFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW - 2xAEEAc + y-glu-C18 diacid / K18; SEQ ID NO: GIP(5-36) [H18K],

[0716] TFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)2xPEG + yGlu-C18 diacid / K11 AT632, and

[0717] TFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)2xPEG + yGlu-C18 diacid / K11 AT632, and

[0718] TFISDYSIAMDKIHQKDFVNWLLAQKGKKNDW - 2xAEEAc + y-glu-C18 diacid / K20; SEQ ID NO: GIP(5-36) [Q20K],

[0719] TFISDYSIAMDKIHQKDFVNWLLAQKGKKNDW - 2xAEEAc + y-glu-C18 diacid / K20; SEQ ID NO: GIP(5-36) [Q20K],

[0720] TFISDYSIAMDKIHQQDFVKWLLAQKGKKNDW - 2xAEEAc + y-glu-C18 diacid / K24; SEQ ID NO: GIP(5-36) [N24K],

[0721] TFISDYKIAMDKIHQQDFVNWLLAQKPSSGAPPPS(NH2)2xPEG + yGlu-C18 diacid / K11 AT632, and

[0722] TFISDYKIAMDKIHQQDFVNWLLAQKPSSGAPPPS(NH2)2xPEG + yGlu-C18 diacid / K11 AT632, and

[0723] or a functional variant thereof.

[0724] In one embodiment, the GIP analog is selected from the group consisting of:

[0725] FISDYSIAMDKIKQQDFVNWLLAQKGKK-C16 diacid / K18; SEQ ID NO: GIP(6-33) [H18K],

[0726] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-C16 diacid / K18; SEQ ID NO: GIP(6-36) [H18K],

[0727] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN-C16 diacid / K18; SEQ ID NO: GIP(6-39) [H18K],

[0728] FISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ-C16 diacid / K18; SEQ ID NO: GIP(6-42) [H18K], and

[0729] FISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-C16 diacid / K18; SEQ ID NO: GIP(6-30) + Cex [H18K],

[0730] or a functional variant thereof,

[0731] wherein the fatty acid is attached directly or via a linker / spacer as defined herein.

[0732] Compounds

[0733] 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), while in another embodiment the compound is formulated as a peptide multimer.

[0734] Multimeric compounds

[0735] In one embodiment, the peptide according to the present disclosure is formulated as a multimer. A multimer is a protein comprising or consisting of a plurality of peptide monomers. A multimer is an aggregate of multiple molecules, usually 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.

[0736] In one embodiment, the peptide sequence of the present disclosure is linked to another (identical or different) peptide sequence of the present disclosure, either 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 as defined according to the present disclosure.

[0737] Thus, in one embodiment, the multimeric compound according to the present disclosure is a polymer comprising two or more peptide sequences of the present disclosure, which are identical or different, wherein at least one of the two or more peptide sequences is a peptide according to the present disclosure. Preferably, both peptide sequences are peptides according to the present disclosure.

[0738] In one embodiment, the multimeric compound is a dimer comprising two peptides according to the present disclosure, which are identical or different with respect to each other.

[0739] In another embodiment, the multimeric compound is a trimer comprising three peptides according to the present disclosure, which are identical or different with respect to each other.

[0740] In another embodiment, the multimeric compound is a tetramer comprising four peptides according to the present disclosure, which are identical or different with respect to each other.

[0741] In one embodiment, the multimeric compound is a dendrimer, such as a tetra- or octa-dendrimer. Dendrimers are roughly spherical macromolecules with repeated branching, typically symmetric around a core, often adopting a globular three-dimensional morphology.

[0742] The dendrimers according to the present disclosure can comprise 4 peptides, 8 peptides, 16 peptides or 32 peptides. In one particular embodiment, the dendrimers comprise four peptides (i.e. tetra-dendrimers) or eight peptides (octa-dendrimers).

[0743] In some particular embodiments, the multimeric compound comprises two identical amino acid sequences of the present disclosure (dimer) or the compound comprises four identical copies of the amino acid sequence of the present disclosure (tetra-dendrimer).

[0744] In one embodiment, the multimers according to the present disclosure are prepared by linking two or more peptide monomers via peptide bonds or linker groups. In one embodiment, they are linked to a lysine scaffold, such as a lysine residue (each peptide chain is linked to a single lysine residue), or coupled to a polymeric carrier, e.g. a protein carrier. In one embodiment, the linker groups comprise a plurality of lysine residues, such as a core portion with a plurality of lysine residues, such as seen in lysine-based dendritic structures containing three, seven, fifteen and more lysine residues, however, any other linkage of the peptide monomers known to the skilled person is conceivable.

[0745] In one embodiment, the linkage occurs at the N-terminus and / or the C-terminus of the peptide monomers.

[0746] In one embodiment, there is provided a multimeric compound consisting of:

[0747] A) one or more glucose-dependent insulinotropic peptide (GIP) analogues selected from the group consisting of:

[0748] - a glucose-dependent insulinotropic peptide (GIP) analogue

[0749] consisting of the amino acid sequence of SEQ ID NO: XX:

[0750]

[0751] wherein X1and X2are independently any amino acid or are omitted;

[0752] 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,

[0753] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more amino acid residues of positions 3 to 29 of SEQ ID NO XX or the 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

[0754] - a glucose-dependent insulinotropic peptide (GIP) analogue selected from the group consisting of:

[0755] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0756]

[0757]

[0758] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0759]

[0760] and

[0761] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0762]

[0763] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions in any one of SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more amino acid residues from 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),

[0764] wherein Z is:

[0765] a. glycine or proline,

[0766] b. a fragment selected from the group consisting of:

[0767] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, and GPSSGAPPPS,

[0768] b1. a fragment selected from the group consisting of:

[0769] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS,

[0770] c. a fragment selected from the group consisting of:

[0771] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKH

[0772] NITQ, or

[0773] d. a fragment selected from the group consisting of:

[0774] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAP

[0775] PPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKK

[0776] NDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI,

[0777] GKKNDWKHNIT and GKKNDWKHNITQ,

[0778] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues, or

[0779] e. a fragment selected from the group consisting of:

[0780] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAP

[0781] PPS,

[0782] or a variant thereof comprising 1 or 2 single amino acid substitutions at any of said amino acid residues;

[0783] B) optionally, one or more linker groups.

[0784] Determining antagonist properties and affinities

[0785] To determine whether a peptide is an antagonist of GIPR, methods known in the art can be employed, for example by determining the IC50 of the peptide. This can be done by constructing a dose response curve and examining the effect of different concentrations of the peptide on reversing the activity of an agonist. The agonist can be GIP1-42, for example hGIP-1-42 or hGIP1-30. The GIPR can be hGIPR, rGIPR, mGIPR, canine GIPR, porcine GIPR or Macaca mulatta GIPR. The IC50 value for a given antagonist can be calculated by determining the concentration required to inhibit half of the maximal biological response of the agonist. Methods of determining whether a peptide is an antagonist are described in Example 4, but other methods known in the art can also be used. For example, Schild plot analysis can be performed on hGIP1-42 cAMP dose response curves as the concentration of GIP-derived peptide is increased. In this way, the type of antagonist activity can also be determined.

[0786] GIP peptide analogs of the present disclosure are characterized by having antagonistic activity on GIPR. In particular, GIP peptide analogs of the present disclosure are potent antagonists of GIPR, largely due to the presence of a fatty acid in the core of the GIP peptide (residues 3 to 29 of GIP) and the presence of a lengthening at the C-terminus of the GIP peptide.

[0787] In one embodiment, GIP peptide analogs of the present disclosure are antagonists of GIPR.

[0788] In one embodiment, the GIP peptide analogs of the present disclosure inhibit, such as are capable of inhibiting, 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% of GIPR activity as determined via an assay that determines reduction of intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which are described in the “Materials and Methods”).

[0789] In one embodiment, the GIP peptide analogs of the present disclosure inhibit at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100% of GIPR activity, wherein the inhibition of GIPR activity is determined as reduction of intracellular cAMP, e.g., via an assay that determines reduction of intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which are described in the “Materials and Methods”). % inhibition is % inhibition of Emax, which means that if a peptide inhibits 85% of Emax, GIPR remains 15% of activity.

[0790] In one embodiment, the GIP peptide analogs of the present disclosure have an IC50 for GIPR antagonistic activity corresponding to 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 antagonistic activity (also referred to as “potency”) is measured via an assay that determines reduction of intracellular cAMP, such as via the CisBio cAMP assay and / or via the DiscoveRx cAMP assay (which are described in the “Materials and Methods”).

[0791] Methods for determining antagonistic activity of a compound, such as a GIP peptide analog, are known to the person skilled in the art. Exemplary methods that can be used to determine antagonistic activity of a compound, such as a GIP peptide analog, 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 a GIP peptide analog.

[0792] GIP peptide analogs of the present disclosure are further 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, of agonistic activity are also referred to as “silent antagonists”.

[0793] In one embodiment, the GIP peptide analogue of the disclosure is capable of stimulating at most 30%, such as at most 25%, such as at most 20%, such as at most 15%, such as at most 10%, such as at most 5% of GIPR activity, in one embodiment the GIP peptide analogue of the disclosure has no agonistic activity on GIPR, i.e. it stimulates about 0% of GIPR activity.

[0794] Agonistic activity of a GIP peptide analogue on GIPR can be determined in the same way as antagonistic activity, but measuring an increase rather than a decrease in intracellular cAMP, as described in “Materials and Methods”.

[0795] Methods of treatment

[0796] In one aspect there is provided a peptide as defined herein, or a composition comprising said peptide, for use as a medicament.

[0797] In one embodiment there is provided a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

[0798]

[0799] wherein X1and X2are independently any amino acid or are omitted;

[0800] 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,

[0801] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues in positions 3 to 29 of SEQ ID NO XX or the functional variant,

[0802] 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E), for use as a medicament.

[0803] In one embodiment there is provided a GIP analogue selected from the group consisting of:

[0804] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0805]

[0806] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0807]

[0808] and

[0809] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0810]

[0811] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any 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),

[0812] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of the amino acid residues 6 to 29 of any 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 of the amino acid residues of any of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0813] glycine or proline,

[0814] a fragment selected from the group consisting of:

[0815] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0816] a fragment selected from the group consisting of:

[0817] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, a fragment selected from the group consisting of:

[0818] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ, or

[0819] a fragment selected from the group consisting of:

[0820] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, or

[0821] a fragment selected from the group consisting of:

[0822] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, for use as a medicament.

[0823] In one embodiment, there is provided a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO: XX:

[0824]

[0825] wherein X1and X2are independently any amino acid or are omitted;

[0826] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any of the amino acids of SEQ ID NO: XX,

[0827] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues in positions 3 to 29 of SEQ ID NO XX or the functional variant,

[0828] 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E) for use in a method of inhibiting or reducing one or more of: 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, viii) 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 decrease in appetite suppressive effects of GLP-1, xiii) GIP-induced leptin resistance.

[0829] In one embodiment, a GIP analogue is provided selected from the group consisting of:

[0830] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0831]

[0832] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0833]

[0834]

[0835] and

[0836] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0837]

[0838] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any 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),

[0839] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of amino acid residues 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 in 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:

[0840] glycine or proline,

[0841] a fragment selected from the group consisting of:

[0842] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0843] a fragment selected from the group consisting of:

[0844] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, a fragment selected from the group consisting of:

[0845] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ, or

[0846] a fragment selected from the group consisting of:

[0847] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any one of said amino acid residues, or

[0848] a fragment selected from the group consisting of:

[0849] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, for use in a method of inhibiting or reducing one or more of: 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, viii) serum levels of free fatty acids and / or triglycerides, ix) GIP-induced reduction of bone resorption.

[0850] In one embodiment, there is provided a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

[0851]

[0852] wherein Xi and X2 are independently any amino acid or are omitted;

[0853] 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,

[0854] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues in positions 3 to 29 of SEQ ID NO XX or the functional variant,

[0855] 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 treating a disorder selected from the group consisting of metabolic syndrome, obesity, prediabetes, type I diabetes, type 2 diabetes, insulin resistance, elevated fasting glucose, hyperglycemia, elevated fasting serum triglyceride levels, very low density lipoprotein (VLDL) levels low, high density lipoprotein (HDL) levels low, dyslipidemia, low density lipoprotein (LDL) elevated / reduced, high cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure, and atherosclerosis.

[0856] In one embodiment, there is provided a GIP analogue selected from the group consisting of:

[0857] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0858]

[0859] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0860]

[0861] and

[0862] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0863]

[0864] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any 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),

[0865] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of the amino acid residues 6 to 29 of any 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 of the amino acid residues of any of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), wherein Z is:

[0866] glycine or proline,

[0867] a fragment selected from the group consisting of:

[0868] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,

[0869] a fragment selected from the group consisting of:

[0870] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, a fragment selected from the group consisting of:

[0871] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues,

[0872] a fragment selected from the group consisting of:

[0873] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues,

[0874] a fragment selected from the group consisting of:

[0875] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, 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 I diabetes, type 2 diabetes, diabetes-related disorders, insulin resistance, elevated fasting plasma glucose, hyperglycemia, elevated fasting serum triglyceride levels, very low-density lipoprotein (VLDL) levels low, high-density lipoprotein (HDL) levels low, dyslipidemia, low-density lipoprotein (LDL) elevated / reduced, high cholesterol levels, abnormal deposition of lipids, cardiovascular disease, elevated blood pressure, and atherosclerosis.

[0876] In one embodiment, there is provided a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO:XX:

[0877]

[0878] wherein X1and X2are independently any amino acid or are omitted;

[0879] or a functional variant thereof, wherein the variant has 1 to 8 (such as 1 to 4) individual amino acid substitutions at any of the amino acids of SEQ ID NO:XX,

[0880] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues at positions 3 to 29 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 SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30), and SEQ ID NO: hGIP(6-30), wherein Z is:

[0881] 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO: E) for use in a method of inducing weight loss.

[0882] In one embodiment, a GIP analogue is provided selected from the group consisting of:

[0883] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0884]

[0885] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0886]

[0887] and

[0888] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0889]

[0890] 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),

[0891] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of the amino acid residues at positions 6 to 29 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 SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30), and SEQ ID NO: hGIP(6-30), wherein Z is:

[0892] glycine or proline,

[0893] a fragment selected from the group consisting of:

[0894] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, and GPSSGAPPPS,

[0895] a fragment selected from the group consisting of:

[0896] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, a fragment selected from the group consisting of:

[0897] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or

[0898] a fragment selected from the group consisting of:

[0899] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, or

[0900] a fragment selected from the group consisting of:

[0901] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, for use in a method of inducing weight loss.

[0902] In one embodiment, there is provided a glucose-dependent insulinotropic peptide (GIP) analogue consisting of the amino acid sequence of SEQ ID NO: XX:

[0903]

[0904] wherein X1and X2are independently any amino acid or are omitted;

[0905] 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,

[0906] wherein the peptide is modified by attachment of at least one fatty acid molecule at one or more of the amino acid residues in positions 3 to 29 of SEQ ID NO XX or the functional variant,

[0907] 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 (HGEGTFTSDLSKQMEEEAVRLFIEWLKN GGPSSGAPPPS; SEQ ID NO:E) for the manufacture of a medicament for:

[0908] - the treatment of a disorder selected from the group consisting of metabolic syndrome, obesity, overweight, obesity related disorders, prediabetes, type I diabetes, type 2 diabetes, diabetes related disorders, insulin resistance, elevated fasting plasma glucose, hyperglycemia, elevated fasting serum triglyceride levels, very low density lipoprotein (VLDL) levels low, high density lipoprotein (HDL) levels low, dyslipidemia, low density lipoprotein (LDL) elevated / reduced, high cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure, and atherosclerosis, or

[0909] - the induction of weight loss, or the treatment of cancer, including but not limited to colon cancer, neuroendocrine cancer, and adrenal adenoma.

[0910] In one embodiment, a GIP analogue selected from the group consisting of:

[0911] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):

[0912]

[0913] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(5-30):

[0914]

[0915] and

[0916] a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(6-30):

[0917]

[0918] or a functional variant thereof, wherein the variant has 1 to 4 individual amino acid substitutions at any 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),

[0919] wherein the peptide is modified by attachment of at least one fatty acid molecule (with or without a linker) at one or more of the amino acid residues 6 to 29 of 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 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30), and SEQ ID NO: hGIP(6-30) comprising between 1 and 4 amino acid substitutions at any 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:

[0920] glycine or proline,

[0921] a fragment selected from the group consisting of:

[0922] GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, and GPSSGAPPPS,

[0923] a fragment selected from the group consisting of:

[0924] PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP, and PSSGAPPPS, a fragment selected from the group consisting of:

[0925] GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or

[0926] a fragment selected from the group consisting of:

[0927] GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, or

[0928] a fragment selected from the group consisting of:

[0929] PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any of the amino acid residues, for use in the manufacture of a medicament for:

[0930] - the treatment of a condition selected from the group consisting of metabolic syndrome, obesity, overweight, obesity related disorders, prediabetes, type I diabetes, type 2 diabetes, diabetes related disorders, insulin resistance, elevated fasting plasma glucose, hyperglycemia, elevated fasting serum triglyceride levels, very low density lipoprotein (VLDL) levels, high density lipoprotein (HDL) levels, dyslipidemia, low density lipoprotein (LDL) elevated / reduced, high cholesterol levels, abnormal lipid deposition, cardiovascular disease, elevated blood pressure and atherosclerosis, or

[0931] - inducing weight loss, or

[0932] - the treatment of cancer, including but not limited to colon cancer, neuroendocrine cancer and adrenal adenoma.

[0933] In a particular embodiment, there is provided a GIP peptide analogue as defined herein for use in a method of treating obesity.

[0934] In a particular 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.

[0935] In a particular embodiment, there is provided a GIP peptide analogue as defined herein for use in a method of treating insulin resistance.

[0936] In another aspect there is provided a GIP peptide analogue as defined herein for use in a method of treating cancer.

[0937] The obesity related disorder can be any one of: increased food intake, increased appetite, binge eating, bulimia nervosa, obesity caused by administration of anti-psychotic drugs or steroids, decreased / increased gastric motility, delayed / increased gastric emptying, decreased physical activity capacity, osteoarthritis, dyslipidemia, low density lipoprotein (LDL) elevated / reduced, high cholesterol levels, and abnormal lipid deposition.

[0938] In some embodiments, dyslipidemia, low density lipoprotein (LDL) elevated / reduced, cholesterol, and abnormal lipid deposition are referred to as fatty acid metabolic disorders.

[0939] The diabetes-related disorder can be any one of impaired glucose tolerance (IGT), progression from IGT to type 2 diabetes, progression of type 2 diabetes that does not require insulin to type 2 diabetes that requires insulin, reduced beta cell function, reduced beta cell mass, increased beta cell apoptosis, reduced glucose sensitivity of beta cells.

[0940] The cardiovascular disease can be any one of coronary heart disease, myocardial infarction, reperfusion injury, stroke, cerebral ischaemia, left ventricular hypertrophy, coronary artery disease, hypertension, essential hypertension, acute hypertensive crisis, cardiomyopathy, cardiac insufficiency, exercise intolerance, acute and / or chronic heart failure, arrhythmia, cardiac arrhythmia, syncope, angina pectoris, cardiac bypass and / or stent re-occlusion, intermittent claudication (also known as atherosclerotic occlusion), diastolic dysfunction and systolic dysfunction and combinations thereof.

[0941] In one embodiment, the cancer is selected from colon cancer, neuroendocrine cancer and adrenal adenoma.

[0942] 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).

[0943] In one embodiment there is provided a GIP peptide analogue as defined herein for use in a method of inhibiting bone cell activity. In one embodiment there is provided a peptide as defined herein for use in a method of inhibiting (or antagonising) GIP-induced reduction in post-prandial bone resorption. In one embodiment there is provided a peptide as defined herein for use in a method of treating bone cancer.

[0944] In one embodiment, the bone density (or volume) disorder is selected from osteoporosis, a disorder characterised by reduced bone density and / or bone volume, a disorder characterised by increased bone density and / or bone volume and osteoporosis.

[0945] In another aspect there is provided a GIP peptide analogue as defined herein for use in a method of characterising or investigating aspects of a disorder and / or characterising or investigating aspects of human physiology associated with a 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 application relates to methods of treating cancer, such as colon cancer or adrenal adenoma. In other aspects, the present application relates to methods of treating a bone density disorder characterised by increased bone density and / or bone volume or osteoporosis. In other aspects, the present application relates to methods of treating atherosclerosis.

[0946] 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.

[0947] An individual in need referred to herein is an individual who can benefit from the administration of a peptide or a pharmaceutical composition according to the present disclosure. Such an individual can have metabolic syndrome, and / or have a metabolic disorder, such as 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, or be at risk of having such a disorder. The individual can be any human, male or female, infant, middle-aged or elderly. The disorder to be treated or prevented in the individual can be related to the age of the individual, the general health condition of the individual, the medication used to treat the individual, and whether the individual has a previous history of a disease or disorder that can induce or has induced metabolic syndrome and / or a metabolic disorder, such as 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, atherosclerosis, a bone density disorder. In some embodiments, the disorder to be treated is related to 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 "higher" is to be interpreted as referring to levels that are higher than the respective levels observed in an individual not in need of treatment.

[0948] Methods of preparation (peptides)

[0949] A peptide according to the present disclosure can be prepared by any method known in the art. Thus, a GIP-derived peptide can be prepared by standard peptide preparation techniques, such as solution synthesis or Merrifield-type solid phase synthesis.

[0950] 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).

[0951] In one embodiment, the peptide according to the present disclosure is purified from its naturally occurring source, 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 usually a biological tissue. Individual steps in the purification process can free the protein from the matrix that defines it, separate the protein from non-protein parts of the mixture, and finally isolate the desired protein from all other proteins. The separation steps can exploit differences in, for example, protein size, physicochemical properties, binding affinities, and biological activities.

[0952] In one embodiment, the peptide according to the present disclosure is synthetically manufactured or produced.

[0953] Methods for the synthetic production of peptides are well known in the art. Detailed instructions and practical advice for the production of synthetic peptides can be found in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), edited by Grant G. A., Oxford University Press, 2002, or in Pharmaceutical Formulation: Development of Peptides and Proteins, edited by Frokjaer and Hovgaard, Taylor and Francis, 1999.

[0954] In one embodiment, the peptide or peptide sequence of the present application is synthetically produced, 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 the peptide operably linked to a second nucleic acid capable of directing expression in the host cell) or enzymatic synthesis. These are well known to the person skilled in the art.

[0955] Peptides can be synthesized batch-wise on a fully automated peptide synthesizer using 9-fluorenylmethyloxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc) as N-a-amino protecting group and appropriate common side chain functional group protecting groups.

[0956] After purification, such as by reverse phase HPLC, the peptides can be further processed to obtain, for example, a cyclic or C-terminal or N-terminal modified isoform. Methods for cyclization and terminal modification are well known in the art.

[0957] The peptides according to the present application can be synthesized as monomers or multimers, such as dimers or tetramers.

[0958] Pharmaceutical compositions and formulations

[0959] Although the biologically active agents of the present disclosure can be administered as the chemical (peptide) itself, it is sometimes preferable to present the agent in the form of a pharmaceutical formulation. Such pharmaceutical formulations can be referred to as pharmaceutical compositions, pharmaceutically acceptable compositions, or pharmaceutically safe compositions.

[0960] Accordingly, there is further provided a pharmaceutical formulation comprising a biologically active 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.

[0961] The present invention is also intended to cover pharmaceutically acceptable salts of the peptide compounds of the present invention, where they can be made. These salts will be acceptable salts in the application of their pharmaceutical use. This means that the salts will retain the biological activity of the parent compound and the salts will not have an adverse or deleterious effect in their application and use in the treatment of disease.

[0962] Pharmaceutically acceptable salts are prepared in standard ways. 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.

[0963] The peptide compounds as disclosed herein can be administered in an effective amount in the form of their alkali or alkaline earth salts, in parallel, simultaneously 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) route.

[0964] For example, examples of pharmaceutically acceptable acid addition salts for use in the pharmaceutical compositions of the present invention include those derived from mineral acids (such as hydrochloric, hydrobromic, phosphoric, metaphosphoric, nitric and sulphuric acids) and organic acids (such as tartaric, acetic, citric, malic, lactic, fumaric, benzoic, glycolic, gluconic, succinic, p-toluenesulphonic and aromatic sulphonic acids).

[0965] In particular embodiments, the peptides according to the present disclosure are formulated as acetate, HC1 (hydrochloride) or TFA (trifluoroacetate) salts.

[0966] Administration and dosage

[0967] 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. The dose requirements will vary with the particular pharmaceutical composition employed, the route of administration and the particular subject being treated, depending on the severity and kind of the disorder and the subject's body weight and general condition. The skilled artisan will also recognize that the optimal number and spacing of individual doses of the peptide compound will depend upon the nature and extent of the condition being treated, the form, route and site of administration, and the particular patient being treated, and that such optimal values can be determined by routine clinical trial determination. The skilled artisan will also appreciate that routine course of treatment determination testing can be used to determine the optimal course of treatment, i.e., the dose of the compound to be administered each day for a defined number of days.

[0968] In one embodiment, the biologically active 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.

[0969] The doses can also be administered at intermittent intervals or at intervals, thus not every day. Rather, one or more doses can 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.

[0970] In one embodiment, the dose is administered once a week, such as once a week, such as one dose per week.

[0971] Routes of administration

[0972] 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 of the tissue to be treated in the body, and the active ingredients selected.

[0973] Systemic treatment

[0974] For systemic treatment according to the present disclosure, the route of administration is capable of introducing the biologically active agent into the bloodstream for eventual targeting to the site of the desired effect.

[0975] These routes of administration are any suitable route, 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).

[0976] Parenteral administration

[0977] Parenteral administration means any administration route other than the oral / enteral route, whereby the medicament is spared first-pass degradation in the liver. Thus, parenteral administration includes any injection and infusion, e.g. bolus injection or continuous infusion, such as intravenous, intramuscular or subcutaneous administration. Furthermore, parenteral administration includes inhalation and topical administration.

[0978] Thus, the biologically active agent can be administered topically to penetrate any mucosa of the animal to which the biologically active substance is to be administered, e.g. mucosa in the nose, vagina, eye, mouth, reproductive tract, lung, gastrointestinal tract or rectum, preferably mucosa of the nose or mouth, and thus, parenteral administration can also include buccal, sublingual, transnasal, transrectal, vaginal and intraperitoneal administration as well as pulmonary and bronchial administration by inhalation or installation. Furthermore, the medicament can also be administered topically to penetrate the skin.

[0979] According to an advantageous embodiment of the present application, the GIP analogue is administered subcutaneously.

[0980] Topical treatment

[0981] In one embodiment, the biologically active agent according to the present application can be used as a topical treatment, i.e. introduced directly into one or more sites of action. Thus, the biologically active agent can be applied directly onto the skin or mucosa, or the biologically active agent can be injected into the site of action, e.g. into the diseased tissue or directly into the terminal artery leading to the diseased tissue. These administration forms preferably avoid the blood-brain barrier.

[0982] Multi-component kits

[0983] 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 further component, such as one or more second active ingredients.

[0984] References

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[1013] 31.Fulurija A,Lutz TA,Sladko K et al.Vaccination against GIP fortheTreatment of Obesity.PLoS ONE 2008;3(9):e3163.

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[1015] 33.Hinke SA,Manhart S,Pamir N et al.Identification of abioactivedomain in the amino-terminus of glucose-dependentinsulinotropicpolypeptide(GIP).Biochimica et Biophysica Acta(BBA)-ProteinStructure and Molecular Enzymology 2001;1547(1):143-155.34.Tseng CC,KiefferTJ,Jarboe LA,Usdin TB,Wolfe MM.Postprandial stimulation of insulin release byglucose-dependent insulinotropic polypeptide(GIP).Effect of a specificglucose-dependent insulinotropic polypeptide receptor antagonist in the rat.JClin Invest 1996;98(11):2440-2445.

[1016] 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.

[1017] 36.Kerr BD,Flatt AJS,Flatt PR,Gault VA.Characterization andbiological actions of N-terminal truncated forms of glucose-dependentinsulinotropic polypeptide.Biochemical and BiophysicalResearchCommunications 2011;404(3):870-876.

[1018] 37.Gelling RW,Coy DH,Pederson RA et al.GIP(6-30amide)contains thehigh affinity binding region of GIP and is a potent inhibitor of GIP1-42action in vitro.Regulatory Peptides 1997;69(3):151-154.

[1019] 38.Deacon CFP.GIP-(3-42)does not antagonize insulinotropic effectsofGIP at physiological concentrations.American Journal of Physiology-Endocrinology and Metabolism 2006;291(3):E468-E475.39.Gault VA,O'Harte FPM,Harriott P,Flatt PR.Characterization ofthe Cellular and Metabolic Effects ofa Novel Enzyme-ResistantAntagonist of Glucose-Dependent InsulinotropicPolypeptide.Biochemical and Biophysical Research Communications 2002;290(5):1420-1426.

[1020] 40.Ravn P,Madhurantakam C,Kunze S et al.Structural andPharmacological Characterization of Novel Potent and Selective MonoclonalAntibody Antagonists of Glucose-dependent Insulinotropic PolypeptideReceptor.Journal of Biological Chemistry 2013;288(27):19760-19772.

[1021] 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.

[1022] 42.Goetze JP,Hunter I,Lippert SK,Bardram L,Rehfeld JF.Processing-independent analysis of peptide hormones and prohormones inplasma.FrontBiosci 2012;17:1804-1815.

[1023] 43.Goetze JP,Rehfeld JF.Peptide hormones and their prohormones asbiomarkers.Biomarkers Med 2009;3(4):335-338.

[1024] 44.Fujita Y,Asadi A,Yang GK,Kwok YN,Kieffer TJ.Differentialprocessingof pro-glucose-dependent insulinotropic polypeptide ingut.American Journal ofPhysiology-Gastrointestinal and LiverPhysiology 2010;298(5):G608-G614.

[1025] 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.

[1026] 46.Graham FL,van der Eb AJ.A new technique for the assay ofinfectivity of human adenovirus 5DNA.Virology 1973;52(2):456-467.

[1027] 47.Kissow H,Hartmann B,Holst JJ et al.Glucagon-like peptide-1(GLP-1)receptor agonism or DPP-4inhibition does not accelerateneoplasia incarcinogen treated mice.Regulatory Peptides 2012;179(1-3):91-100.

[1028] 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 with type 2diabetes. Diabetologia 2009;52(2):199-207.

[1029] 49. Hansen LS, Sparre-Ulrich AH, et al. N-terminally and C-terminally truncated forms of glucose-dependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor. British Journal of Pharmacology 2016; 173 826–838. Example: This example supports the following conclusion:

[1030] 1) Individual amino acid substitutions at certain sites lead to improved antagonistic profiles.

[1031] 2) Several acylation sites show great potential in both GIP(3-30)+ and GIP(5-30)+ extensions.

[1032] 3) Extension of the C-terminal amino acid residues from GIP(1-42) or scorpion exopeptide-4 leads to improved effects, such as antagonistic effects and / or prolonged in vivo half-life and / or selectivity.

[1033] 4) The GIP peptide analogs according to embodiments of the present invention have increased physical stability, such as increased solubility.

[1034] 5) The GIP peptide analogue according to the embodiments of the present invention has a reducing GIPR agonistic activity.

[1035] Sexual activity or lack of excitatory activity.

[1036] Materials and Methods

[1037] WO 2016 / 034186 discloses the generation and function of GIP(3-30) and GIP(5-30) peptides themselves.

[1038] Material

[1039] Human GIPs (1-42) were purchased from Bachem (Bubdendorf, Switzerland (H5645)), while the remaining ligands were purchased from Caslo. TM Synthesized by Almac Group (Kregavin, UK), Peptides & Elephants GmbH (Hennihisdorf, Germany), and WuXi AppTec (China). Human GIP receptor cDNA was purchased from Origene (Rockville, MD, USA (SC110906)) and cloned into the pCMV-Script vector. Iodinated human GIPs (1-42) were purchased from PerkinElmer LifeSciences (Scholend, Denmark (NEX402025UC)).

[1040] animal

[1041] Göttingen miniature pigs or male Wistar rats were housed in the animal facility of the Faculty of Health and Medical Sciences.

[1042] Transfection and tissue culture

[1043] COS-7 cells were cultured in Durbeco Modified Iger Medium 1885 (supplemented with 10% fetal bovine serum, 2 mM glutamine, 180 IU / ml penicillin, and 45 g / ml streptomycin) at 10% CO2 and 37°C. Transient transfection of COS-7 cells for cAMP accumulation and competitive binding was performed using the calcium phosphate precipitation method and the addition of chloroquine. 46-47 .

[1044] cAMP assay

[1045] Alternative Option 1 (also known as DiscoveRx measurement):

[1046] Transiently transfected COS-7 cells expressing the human GIP receptor were seeded in white 96-well plates at a density of 3.5 x 10⁶ cells / well. 4 / well. The next day, cells were washed twice with Hepes-buffered saline (HBS) buffer and incubated at 37°C for 30 min with HBS and 1 mM 3-isobutyl-1-methylxanthine (IBMX). To test agonist properties, ligands were added and incubated at 37°C for 30 min. To test antagonist properties, cells were pre-incubated with the antagonist for 10 min, then the agonist was added and incubated for another 20 min. HitHunter™ cAMP XS assay (DiscoveRx) was performed according to the manufacturer's instructions.

[1047] Alternative 2 (also known as CisBio assay):

[1048] The in vitro functional activity of the compound against the human GIP receptor can also be determined in HEK-293 cells transiently expressing the receptor. On the day of 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 analog of this disclosure was diluted in HBSS buffer supplemented with 20 mM HEPES, 0.1% pluronic, 0.1% casein, and 500 μM IBMX. To test antagonistic properties, the GIP peptide analogs to be tested were independently added to cells and incubated at 37°C for 20 min, followed by the addition of an agonist (GIP1-42) at an EC50 concentration and incubation at 37°C for 30 min. The resulting reduction in intracellular cAMP was quantified using the CisBiocAMP Dynamic 2HTRF assay kit. The assay was based on competition between cell-produced native cAMP and cAMP labeled with dye d2 for binding to an antibody labeled with a cryptate compound. A specific signal (i.e., an energy transfer signal) was inversely proportional to the concentration of cAMP in the sample.

[1049] Following the manufacturer's instructions, cAMP-d2 conjugate and antibody-anti-cAMP-crystalloid compound (both diluted in the lysis buffer provided in the kit) were added to the cells. The resulting competitive assay was incubated at room temperature for 60 minutes and analyzed using PerkinElmer. The instrument detects the signal using 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 the HTRF ratio is converted to nM cAMP / well using a cAMP standard curve. The pIC50 value is estimated by fitting the dose-response curve using nonlinear regression analysis (four-logistic equations) in GraphPad Prism.

[1050] To test the agonistic properties of the GIP receptor, the compound was diluted and added to cells as described above, and incubated at 37°C for 30 min. The resulting increase in intracellular cAMP was determined using the CisBio cAMP Dynamic 2HTRF assay kit, as described above.

[1051] The estimated elimination half-life (T) in Göttingen miniature pigs 1 / 2 )

[1052] One GIP analog of the present invention (1-10 nmol / kg, total volume 2-6 mL) was subcutaneously administered to 2-3 Göttingen miniature pigs 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 for analysis.

[1053] The estimated elimination half-life (T0) in Wistar rats 1 / 2 )

[1054] Three Wistar rats were intravenously administered a GIP analog of the present invention (7 nmol / kg, total dose volume 1 ml / kg), and blood samples were collected from the tail tip prior to administration and up to 72 hours thereafter. Blood was collected into cold EDTA tubes, centrifuged, and plasma was kept at -20°C for analysis.

[1055] Determination of plasma concentrations of modified GIP peptide analogs

[1056] Plasma concentrations of the GIP analogs according to the invention from Göttingen miniature pigs or male Wistar rats were analyzed by radioimmunoassay (RIA) or by liquid chromatography-mass spectrometry (LC / MS). For RIA-based determinations, the immunoreactivity of the analogs was determined using antiserum Ab95234, Ab95235, or Ab95236 (polyclonal internal antibodies generated in rabbits that are specific to the intermediate 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 ethanol and then mixing thoroughly. The supernatant was centrifuged and diluted, and the sample was analyzed by LC-MS / MS and compared with a 9-point calibration curve prepared in a juvenile plasma matrix from Göttingen miniature pigs. LC / MS was performed using Red Glead Discovery AB (Lund, Sweden).

[1057] Data Analysis

[1058] IC is determined by nonlinear regression. 50 EC 50 And Emax. These were achieved using GraphPad Prism 6.0 software (GraphPad, San Diego, California, USA) and Microsoft Excel. TM The pharmacokinetic parameters, including the elimination of T, were calculated using the software PKsolutions 2.0 (Summit Research services, USA). 1 / 2.

[1059] 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 sarcophagus exopeptide-4 were retained or improved after the addition of additional C-terminal amino acid residues.

[1060] As described below, the addition of 1 to 12 additional C-terminal amino acid residues to GIP(3-30) and GIP(5-30) was tested to assess their antagonistic activity and T. 1 / 2 effect. GIP analogs are also acylated with or without a linker at, for example, positions 11, 12, 17, 18 or 20, where serine-11, isoleucine-12, isoleucine-17, histidine-18 or glutamine-20 has previously been replaced by lysine.

[1061] Results:

[1062] Compared to, for example, AT158, GIP(3-36) analogs (e.g., AT361, whose 18th position is C16 diacidized) exhibit a 2 nM IC. 50 Value. The AT361 also has a very high T31h. 1 / 2 The half-life is surprisingly long compared to analogs of GIP (3-30) with C16 diacid esterification at position 18 (such as AT158, which has a half-life of only 14 hours). This long half-life is achieved without N-terminus capping or other types of stabilization, as in, for example, AT361 with a free amino group at the N-terminus.

[1063] GIP(3-30)+ amino acids derived from the C-terminal portion of tarantula exopeptide-4 (such as AT631) are typically potent antagonists. AT631 exhibits an improved IC50 at 1.9 nM compared to, for example, AT158. 50 Value. The half-life of AT631 in vivo also exceeds 30 hours, as a very long T5 of 56 hours was determined. 1 / 2, and with, for example, AT158 (see Figure 1 It has a surprisingly long half-life compared to liraglutide (which also has a C16 fatty acid). The long half-life is achieved without N-terminus capping or other types of stabilization, such as AT631 which has a free amino group at the N-terminus.

[1064] Together with GIP (3-30) antagonists with C-terminal extensions, such as AT361 and AT631, these are better antagonists than those reported in PCT / EP2018 / 064355. In use for T 1 / 2 The antagonists tested in the pigs studied were significantly better than those reported in PCT / EP 2018 / 064355. They were comparable to, for example, GIP(3-30) analogues AT158 (see Table 1B and...). Figure 1 Compared to other C16 esterified peptides known in the art (such as liraglutide (a once-daily GLP-1 analog)), both AT361 and AT631 also exhibit an ultralong T+1 duration exceeding 30 hours. 1 / 2 AT437, AT632, AT587, AT589, AT614, AT616, AT618, and 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., attaching a fatty acid at a specific position (such as on lysine at position 18)) can produce surprisingly long half-lives.

[1065] Unbound by any theory, the presence of a carboxylic acid at the C-terminus (as in AT361 and AT631) can also help improve half-life.

[1066] 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 is shorter in rats than in miniature pigs, our pharmacokinetic findings in rats will be discussed below. From Tables 3A and 3B, the mean and time-dependent plasma concentrations in Wistar rats, it can be seen that analogs where the fatty acid is attached to the middle region of the peptide have significantly higher exposure and half-life compared to, for example, GIP analogs with a fatty acid attached at position 40 of the C-terminus (such as in AT651). For all peptides tested according to embodiments of the invention, significantly higher exposure was also observed at each time point compared to, for example, GIP analogs with a fatty acid attached at position 40 of the C-terminus (such as in AT651). Therefore, attaching a fatty acid to the middle region (e.g., positions 11 and 18) of a GIP (3-30) with C-terminal extension produces a pharmacokinetically superior analog than attaching the fatty acid to position 40 of the C-terminus. It is equally important to note that although many of the tested analogues have attached C16 fatty acids (AT361, AT631, AT366, AT632, AT447), when compared with analog peptides having the same attached fatty acid length (e.g., liraglutide, which has a 4-hour Tg in rats), 1 / 2) In comparison, the tested analogues have a surprisingly long T0. 1 / 2 (11h, 7h, 7h, 8h, 5.8h respectively). Unbound by any theory, C-terminal extended GIP peptides can be esterified to form molecules that are beneficial for extending half-life.

[1067] As can also be seen from Table 2B, specific substitutions may be advantageous. Introducing α-helix stabilizing amino acids, such as E, L, K, A, and Aib, at specific positions (such as any one of the 9th, 13th, 14th, 15th, 18th, 21st, and 24th positions independently) may be particularly beneficial for increasing antagonistic potency.

[1068] For example, replacing the 24th position with E retains or increases its effectiveness.

[1069] As seen in, for example, AT618, AT619, and AT621, substitution at position 14 with L, Nle, or K retains or even increases potency. As seen in, for example, AT613, AT614, AT616, and AT617, and for example, AT693, AT695, AT696, and AT700, substitution of D at positions 9 and / or 15 and / or 21 with E appears to increase potency. It is also generally observed that a free C-terminal carboxylic acid increases potency. Potency typically decreases as the length of the fatty acid increases (e.g., from a C16 diacid to a C18 diacid). However, certain substitutions may compensate for this. For example, Aib at position 13 or substitution with E at, for example, positions 9 and / or 15 and / or 21. Substitution with E at position 24 produces retained or improved antagonistic potency and improved solubility, for example, at a physiological pH of approximately 7.5. As can also be seen from Table 2B, various Z-type molecules retain or increase their potency, such as AT467, AT468, AT469, AT470, AT471, AT472, AT473, and AT474. As can be seen from AT633 and AT635, N-terminal acetylation leads to (partial) agonistic activity towards GIPR.

[1070] Table 1A: Names and structures of GIP antagonists with extensions. When the linker consists of more than one unit, it is designed so 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 arranged in a different order without affecting the function of the linker or with little effect.

[1071]

[1072]

[1073]

[1074]

[1075]

[1076]

[1077]

[1078]

[1079] Table 1B: Antagonistic properties, agonistic properties, and half-life (T) of extended GIP antagonists. 1 / 2. Data were obtained using cAMP assays (Discove Rx assays).

[1080]

[1081]

[1082] Table 1C: Antagonistic properties, agonistic properties, and half-life of some GIP antagonists with extended durations, and elimination of T 1 / 2. The CisBio assay (alternative to the above 2) is used to determine the antagonistic and agonistic activities of the GIP peptide analogs listed in Table 1B.

[1083]

[1084]

[1085] Table 1C. Continued

[1086]

[1087]

[1088]

[1089] 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”).

[1090] Table 2A: Mean and time-dependent plasma concentrations in Wistar rats are shown for selected numbers of compounds. Plasma concentrations were determined by LC / MS (see “Materials and Methods”).

[1091]

[1092]

[1093] na: Indicates that no plasma sample was collected at this time point and is therefore unavailable.

[1094] Table 2B: For selected amounts of the compound, the elimination of T in Wistar rats is shown. 1 / 2, where the dataset enables computation (see "Materials and Methods").

[1095] ID T 1 / 2 (hours) AT361 11 AT631 7 AT366 7 AT632 8 AT433 8 AT447 5.8 AT449 4.1 AT452 4

[1096] Example 2 - Selective cAMP assay - Selective

[1097] COS-7 cells transiently transfected with any one of the following receptors (GLP1R, GLP2R, GcgR, or SCTR) were fed at 3.5 x 10⁻⁶ cells per cell line. 4Cells were seeded at a density of / wells in white 96-well plates. The next day, cells were washed twice with Hepes-buffered saline (HBS) buffer and incubated at 37°C for 30 min with HBS and 1 mM 3-isobutyl-1-methylxanthine (IBMX). To test agonist properties, ligands were added and incubated at 37°C for 30 min. To test antagonist properties, cells were pre-incubated with the antagonist for 10 min, then the natural agonists targeting the expressed receptors (GLP1 for GLP1R-expressing cells, GLP2 for GLP2R-expressing cells, glucagon for GcgR, and secretin for SCTR) were added and incubated for another 20 min. To determine IC50, concentrations of the natural agonist corresponding to 50%–80% of maximum cAMP accumulation were used. HitHunter™ cAMP XS assay (DiscoveRx) was performed according to the manufacturer's instructions.

[1098] Results:

[1099] We compared the selectivity data of the best antagonist from PCT / EP 2018 / 064355 with that of the best antagonist in this application. This was done by determining the antagonistic properties of the peptide against GIPR, glucagon receptor, and GLP-1 receptor. As the data in Table 3 show, the antagonist in this application is more selective than the antagonist from PCT / EP 2018 / 064355. The combination of C-terminal extension of GIP (3-30) (as in, for example, AT361 and AT631) with acylation at, for example, lysine at position 18 appears to produce a surprisingly selective antagonist.

[1100] Table 3A. Antagonistic properties of GIP antagonists in this disclosure and previously described in PCT / EP 2018 / 064355 with respect to GIPR, glucagon receptor and GLP-1 receptor.

[1101]

[1102] NA = Unavailable

[1103] Italics indicate the previously described antagonists.

[1104] Furthermore, the antagonistic properties of the peptides against GIPR, GLP-2 receptors, and secretin receptors were determined. As shown in the data in Table 3B, the GIP analogs of the present invention, such as AT361 and AT631, do not antagonize GLP-2 or secretin receptors and are therefore highly selective for GIP receptors.

[1105] Table 3B. Antagonistic properties of the GIP antagonists of this disclosure with respect to GIPR, GLP-2 receptors and secretin receptors.

[1106] Sequence Listing

[1107] <SEQ ID NO:1; PRT1; Artificial Sequence> XXTFISDYSIAMDKIHQQDFVNWLLA QK (SEQ ID NO:XX)

[1108] <SEQ ID NO:2; PRT1; Artificial Sequence> GKKNDWKHNITQ GIP(31-42) (SEQ ID NO:Z)

[1109] <SEQ ID NO:3; PRT1; Artificial Sequence> HGEGTFTSDLSKQMEEEAVRLFIEW LKNGGPSSGAPPPS Exendin-4 (; SEQ ID NO:E)

[1110] <SEQ ID NO:4; PRT1; Artificial Sequence> PSSGAPPPS (; SEQ ID NO:CE31-39)

[1111] <SEQ ID NO:5; PRT1; Artificial Sequence> GPSSGAPPPS (; SEQ ID NO:CE30-39)

[1112] <SEQ ID NO:6; PRT1; Artificial Sequence> GPSS

[1113] <SEQ ID NO:7; PRT1; Artificial Sequence> GPSSG

[1114] <SEQ ID NO:8; PRT1; Artificial Sequence> GPSSGA

[1115] <SEQ ID NO:9; PRT1; Artificial Sequence> GPSSGAP

[1116] <SEQ ID NO:10; PRT1; Artificial Sequence> GPSSGAPP

[1117] <SEQ ID NO:11; PRT1; Artificial Sequence> GPSSGAPPP

[1118] <SEQ ID NO:12; PRT1; Artificial Sequence> PSSG

[1119] <SEQ ID NO:13; PRT1; Artificial Sequence> PSSGA

[1120] [[ID=DI=44]]<SEQ ID NO:14; PRT1; Artificial Sequence> PSSGAP

[1121] <SEQ ID NO:15; PRT1; Artificial Sequence>PSSGAPP

[1122] <SEQ ID NO:16; PRT1; Artificial Sequence>PSSGAPPP

[1123] <SEQ ID NO:17; PRT1; Artificial Sequence>GKKN

[1124] <SEQ ID NO:18; PRT1; Artificial Sequence>GKKND

[1125] <SEQ ID NO:19; PRT1; Artificial Sequence>GKKNDW

[1126] <SEQ ID NO:20; PRT1; Artificial Sequence>GRKNDW

[1127] <SEQ ID NO:21; PRT1; Artificial Sequence>GKRNDW

[1128] <SEQ ID NO:22; PRT1; Artificial Sequence>GRRNDW

[1129] <SEQ ID NO:23; PRT1; Artificial Sequence>GKKNDWK

[1130] <SEQ ID NO:24; PRT1; Artificial Sequence>GKKNDWKH

[1131] <SEQ ID NO:25; PRT1; Artificial Sequence>GKKNDWKHN

[1132] <SEQ ID NO:26; PRT1; Artificial Sequence>GKKNDWKHNI

[1133] <SEQ ID NO:27; PRT1; Artificial Sequence>GKKNDWKHNIT

[1134] <SEQ ID NO:28; PRT1; Artificial Sequence>GKKKDW

[1135] <SEQ ID NO:29; PRT1; Artificial Sequence>GKKNDK

[1136] <SEQ ID NO:30; PRT1; Artificial Sequence>EXTFISDYSIAMDKIHQQDFVNWL LAQK SEQ ID NO:(GIP3-30 X2),

[1137] <SEQ ID NO:31; PRT1; Artificial Sequence> XGTFISDYSIAMDKIHQQDFVNWL LAQK SEQ ID NO: (GIP3-30 X1),

[1138] <SEQ ID NO:32; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVNWL LAQK SEQ ID NO: (GIP3-30),

[1139] <SEQ ID NO:33; PRT1; Artificial Sequence> XTFISDYSIAMDKIHQQDFVNWLL AQK SEQ ID NO: (GIP4-30 X2),

[1140] <SEQ ID NO:34; PRT1; Artificial Sequence> GTFISDYSIAMDKIHQQDFVNWLL AQK SEQ ID NO: (GIP4-30),

[1141] <SEQ ID NO:35; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVNWLLA QK SEQ ID NO: (GIP5-30),

[1142] <SEQ ID NO:36; PRT1; Artificial Sequence> FISDYSIAMDKIHQQDFVNWLLAQ K SEQ ID NO: (GIP6-30),

[1143] <SEQ ID NO:37; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVNWL LAQK SEQ ID NO:; GIP(3-30),

[1144] <SEQ ID NO:38; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQK SEQ ID NO:; GIP(3-30)[H18K],

[1145] <SEQ ID NO:39; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWL LAQK SEQ ID NO:; GIP(3-30)[E3S; H18K],

[1146] <SEQ ID NO:40; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLL EQK GIP(3-30)Cex(31-39)[M14L; H18K; A28E]

[1147] <SEQ ID NO:41; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-diacid / K18; (3-30+CEX32-39[H18K][Q29G][K30P]), AT593

[1148] <SEQ ID NO:42; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWL LAQR GIP(3-30)[E3S; K16R; H18K; K30R]

[1149] <SEQ ID NO:43; PRT1; Artificial Sequence> EGTFISDYKIAMDKIHQQDFVNWL LAQK GIP(3-30)[S11K]

[1150] <SEQ ID NO:44; PRT1; Artificial Sequence> EGTFISDYSKAMDKIHQQDFVNWL LAQK GIP(3-30)[I12K]

[1151] <SEQ ID NO:45; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQKDFVNWL LAQK GIP(3-30)[Q20K]

[1152] <SEQ ID NO:46; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQQDFVKWL LAQK GIP(3-30)[N24K]

[1153] <SEQ ID NO:47; PRT1; Artificial Sequence> EGTFISDYSIAMDKKHQQDFVNWL LAQK GIP(3-30)[I17K]

[1154] <SEQ ID NO:48; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQG GIP(3-30)[H18K; K30G]

[1155] <SEQ ID NO:49; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAGG GIP(3-30)[H18K; Q29G; K30G],

[1156] <SEQ ID NO:50; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQEFVQWLL AQK GIP(3-30)[D9E; D15E; H18K; D21E; N24Q],

[1157] <SEQ ID NO:51; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQDFVQWLL AQK GIP(3-30)[D9E; D15E; H18K; N24Q],

[1158] <SEQ ID NO:52; PRT1; Artificial Sequence> EGTFISEYSAibANleEKIKQQDFVE WLLAQK GIP(3-30)[D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[1159] <SEQ ID NO:53; PRT1; Artificial Sequence> EGTFISEYSIAibMEKIKQQDFVEWL LAQK GIP(3-30)[D9E; A13Aib; D15E; H18K; N24E],

[1160] <SEQ ID NO:54; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWL LAQK GIP(3-30)[H18K; N24E],

[1161] <SEQ ID NO:55; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLL AQK GIP(3-30)[M14L; H18K],

[1162] <SEQ ID NO:56; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWL LAQK GIP(3-30)[M14Nle;; H18K],

[1163] <SEQ ID NO:57; PRT1; Artificial Sequence> EGTFISDYSIAEDKIKQQDFVNWLL AQK GIP(3-30)[M14E; H18K],

[1164] <SEQ ID NO:58; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVNWLL AQK GIP(3-30)[M14K; H18K],

[1165] <SEQ ID NO:59; PRT1; Artificial Sequence> EGTFISDYSIASDKIKQQDFVNWLL AQK GIP(3-30)[M14S; H18K],

[1166] <SEQ ID NO:60; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWL LAQA GIP(3-30)[H18K; N24E; K30A],

[1167] <SEQ ID NO:61; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LEQK GIP(3-30)[H18K; A28E],

[1168] <SEQ ID NO:62; PRT1; Artificial Sequence> VGTFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30)[E3V; H18K],

[1169] <SEQ ID NO:63; PRT1; Artificial Sequence> AibGTFISDYSIAMDKIKQQDFVNW LLAQK GIP(3-30)[E3Aib; H18K],

[1170] <SEQ ID NO:64; PRT1; Artificial Sequence> PGTFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30)[E3P; H18K],

[1171] <SEQ ID NO:65; PRT1; Artificial Sequence> VETFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30)[E3V; G4E; H18K],

[1172] <SEQ ID NO:66; PRT1; Artificial Sequence> AibETFISDYSIAMDKIKQQDFVNW LLAQK GIP(3-30)[E3Aib; G4E; H18K],

[1173] <SEQ ID NO:67; PRT1; Artificial Sequence>GETFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30)[E3G; G4E; H18K],

[1174] <SEQ ID NO:68; PRT1; Artificial Sequence>PETFISDYSIAMDKIKQQDFVNWLL AQK GIP(3-30)[E3P; G4E; H18K],

[1175] <SEQ ID NO:69; PRT1; Artificial Sequence>DTTFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30)[E3D; G4T; H18K],

[1176] <SEQ ID NO:70; PRT1; Artificial Sequence>GETFISDYAIALDKIKQQDFVEWLL AQG GIP(3-30)[E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[1177] <SEQ ID NO:71; PRT1; Artificial Sequence>GETFISTYSIALDKIKQQDFVEWLL AQG GIP(3-30)[E3G; G4E; D9T; M14L; H18K; N24E],

[1178] <SEQ ID NO:72; PRT1; Artificial Sequence>EGTFISTYKIALDKIHQQDFVEWLL AQK GIP(3-30)[D9T; S11K; M14L; N24E],

[1179] <SEQ ID NO:73; PRT1; Artificial Sequence>EGTFISDYSIAibMDKIKQQDFVEW LLAQK GIP(3-30)[A13Aib; H18K; N24E],

[1180] <SEQ ID NO:74; PRT1; Artificial Sequence>EGTFISDYSIAibLDKIKQQDFVEWL LAQK GIP(3-30)[A13Aib; M14L; H18K; N24E],

[1181] <SEQ ID NO:75; PRT1; Artificial Sequence>EGTFISDYSIAibNleDKIKQQDFVE WLLAQK GIP(3-30)[A13Aib; M14Nle; H18K; N24E],

[1182] <SEQ ID NO:76; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLL AQK GIP(3-30)[M14L; H18K; N24E],

[1183] <SEQ ID NO:77; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWL LAQK GIP(3-30)[M14Nle; H18K; N24E],

[1184] <SEQ ID NO:78; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVEWLL AQK GIP(3-30)[M14K; H18K; N24E],

[1185] <SEQ ID NO:79; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWL LAGG GIP(3-30)[M14Nle; H18K; Q29G; K30G],

[1186] <SEQ ID NO:80; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEWL LAGG GIP(3-30)[M14Nle; H18K; N24E; Q29G; K30G],

[1187] <SEQ ID NO:81; PRT1; Artificial Sequence> EGTFISEYSIAibLEKIKQQEFVEWL LAQK GIP(3-30)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], <SEQ ID NO:82; PRT1; Artificial Sequence> EGTFISEYSIAibNleEKIKQQEFVEW LLAQK GIP(3-30)[D9E; A13Aib; M14Nle; D15E; H18K; D21E; N24E], <SEQ ID NO:83; PRT1; Artificial Sequence> yGluGTFISDYSIAMDKIKQQDFVN WLLAQK GIP(3-30)[E3yGlu; H18K],

[1188] <SEQ ID NO:84; PRT1; Artificial Sequence> βGluGTFISDYSIAMDKIKQQDFVN WLLAQK GIP(3-30)[E3βGlu; H18K],

[1189] <SEQ ID NO:85; PRT1; Artificial Sequence> XGTFISDYSIAMDKIKQQDFVNWL LAQK GIP(3-30) [E3 Glutaric Acid (X); H18K],

[1190] <SEQ ID NO:86; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLL AGG GIP(3-30) [M14L; H18K; N24E; Q29G; K30G],

[1191] <SEQ ID NO:87; PRT1; Artificial Sequence> EGTFISEYSIALEKIKQQEFVEWLL AQK GIP(3-30) [D9E; M14L; D15E; H18K; D21E; N24E],

[1192] <SEQ ID NO:88; PRT1; Artificial Sequence> EGTFISEYSIANleEKIKQQEFVEWL LAQK GIP(3-30) [D9E; M14Nle; D15E; H18K; D21E; N24E],

[1193] <SEQ ID NO:89; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVE WLLAQK GIP(3-30) [E3 yGlu (L-isomer); M14Nle; H18K; N24E],

[1194] <SEQ ID NO:90; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVE WLLAQK GIP(3-30) [E3 yGlu (D-isomer); M14Nle; H18K; N24E],

[1195] <SEQ ID NO:91; PRT1; Artificial Sequence> βGluGTFISDYSIANleDKIKQQDFVE WLLAQK GIP(3-30) [E3 βGlu; M14Nle; H18K; N24E],

[1196] <SEQ ID NO:92; PRT1; Artificial Sequence> XGTFISDYSIANleDKIKQQDFVEW LLAQK GIP(3-30) [E3 Glutaric Acid (X); M14Nle; H18K; N24E],

[1197] <SEQ ID NO:93; PRT1; Artificial Sequence> βGluGTFISDYSIAibNleDKIKQQDFV NWLLAQK(3-30E3βGlu A13Aib M14Nle H18K)

[1198] <SEQ ID NO:94; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVNWLL EGG GIP(3-30)[M14L; H18K; A28E; Q29G; K30G]

[1199] <SEQ ID NO:95; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNWL LEQK GIP(3-30)Cex(31-39)[M14Nle; H18K; A28E]

[1200] <SEQ ID NO:96; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVNWLLA QK GIP(5-30)

[1201] <SEQ ID NO:97; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLLA QK GIP(5-30)[S11K],

[1202] <SEQ ID NO:98; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSK(NH2)C16-diacid / K40; GIP(3-30+CEX31-39+K), phenyl lactic acid at the N-terminus, AT651

[1203] <SEQ ID NO:99; PRT1; Artificial Sequence> PGTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSK(NH2)C16-diacid / K40; GIP(3-30+CEX31-39+K), phenyl lactic acid at the N-terminus, AT652

[1204] <SEQ ID NO:100; PRT1; Artificial Sequence> TFISDYSIAMDKIKQQDFVNWLL AQK GIP(5-30)[H18K],

[1205] <SEQ ID NO:101; PRT1; Artificial Sequence> TFISDYKIAMDRIHQQDFVNWLL AQR GIP(5-30)[S11K; K16R; K30R],

[1206] <SEQ ID NO:102; PRT1; Artificial Sequence> TFISDYSKAMDKIHQQDFVNWLL AQK GIP(5-30)[I12K],

[1207] <SEQ ID NO:103; PRT1; Artificial Sequence> TFISDYSIAMDKIHQKDFVNWLL AQK GIP(5-30)[Q20K], and

[1208] <SEQ ID NO:104; PRT1; Artificial Sequence> TFISDYSIAMDKIHQQDFVKWLL AQK GIP(5-30)[N24K],

[1209] <SEQ ID NO:105; PRT1; Artificial Sequence> FISDYSIAMDKIKQQDFVNWLLA QK GIP(6-30)[H18K],

[1210] <SEQ ID NO:106; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDW2xAEEAc+y-glu-C16-dioic acid / K18; GIP(3-36H18K), AT415 <SEQ ID NO:107; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPS-C16-dioic acid / K18; GIP(3-30+CEX31-39 H18K), AT631, <SEQ ID NO:108; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid / K18; GIP(3-30+CEX31-39H18K), AT587

[1211] <SEQ ID NO:109; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAPPPS

[1212] 2xAEEAc+y-glu-C16-dioic acid / K18:GIP(3-30+CEX H18K), AT:431 <s

[1213] <SEQ ID NO:110; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAPPPS(NH2)

[1214] 2xAEEAc + yGlu - C18 - diacid / K18; GIP(3 - 31 + CEX31 - 39 H18K), AT588,

[1215] <SEQ ID NO:111; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAPPPC16 - diacid / K18; GIP(3 - 30 + CEX 9H18K), AT467

[1216] <SEQ ID NO:112; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAPPC16 - diacid / K18; GIP(3 - 30 + CEX 8H18K), AT468

[1217] <SEQ ID NO:113; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAPC16 - diacid / K18; GIP(3 - 30 + CEX 7H18K), AT469

[1218] <SEQ ID NO:114; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSGAC16 - diacid / K18; GIP(3 - 30 + CEX 6H18K), AT470

[1219] <SEQ ID NO:115; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSSG C16 - diacid / K18; GIP(3 - 30 + CEX 5H18K), AT471

[1220] <SEQ ID NO:116; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPSS C16 - diacid / K18; GIP(3 - 30 + CEX 4H18K), AT472

[1221] <SEQ ID NO:117; PRT1; artificial sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQKGPS C16 - diacid / K18 GIP(3 - 30 + CEX 3H18K), AT473

[1222] <SEQ ID NO:118; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGP C16-diacid / K18 GIP(3-30+CEX 2H18K), AT474

[1223] <SEQ ID NO:119; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKG-C16-diacid / K18 GIP(3-31H18K), AT447

[1224] <SEQ ID NO:120; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGK C16-diacid / K18 GIP(3-32H18K), AT448

[1225] <SEQ ID NO:121; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKK C16-diacid / K18 GIP(3-33H18K), AT360

[1226] <SEQ ID NO:122; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKN C16-diacid / K18 GIP(3-34H18K), AT449

[1227] <SEQ ID NO:123; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKND C16-diacid / K18 GIP(3-35H18K), AT450

[1228] <SEQ ID NO:124; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKC16-diacid / K18 GIP(3-37H18K), AT451

[1229] <SEQ ID NO:125; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKHC16-diacid / K18 GIP(3-38H18K), AT452

[1230] <SEQ ID NO:126; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKHNC16 - diacid / K18 GIP(3 - 39H18K), AT462

[1231] <SEQ ID NO:127; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKHNIC16 - diacid / K18 GIP(3 - 40H18K), AT453

[1232] <SEQ ID NO:128; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKHNITC16 - diacid / K18:SEQ ID NO:(3 - 41H18K), AT454 <SEQ ID NO:129; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDWKHNITQ C16 - diacid / K18 GIP(3 - 42H18K), AT363

[1233] <SEQ ID NO:130; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWL LAQKGKKNDW2xAEEAc + y - glu - C16 - diacid / K18; GIP(3 - 30E3S H18K), AT419

[1234] <SEQ ID NO:131; PRT1; Artificial Sequence> SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS2xAEEAc + y - glu - C16 - diacid / K18 GIP(3 - 30 + CEX E3S H18K), AT435

[1235] <SEQ ID NO:132; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWL LAQRGRRNDW2xAEEAc + y - glu - C16 - diacid / K18; GIP(3 - 30E3S K16R H18K K30R), AT423

[1236] <SEQ ID NO:133; PRT1; Artificial Sequence> SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS2xAEEAc+y-glu-C16-dioic acid / K18 GIP(3-30+CEX E3S K16R H18K K30R), AT439

[1237] <SEQ ID NO:134; PRT1; Artificial Sequence> EGTFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW2xAEEAc+yGlu-C18-dioic acid / K11; GIP(3-36S11K), AT543

[1238] <SEQ ID NO:135; PRT1; Artificial Sequence> EGTFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW2xAEEAc+yGlu-C18-dioic acid / K12; GIP(3-36I12K), AT544

[1239] <SEQ ID NO:136; PRT1; Artificial Sequence> EGTFISDYSIAMDKIHQKDFVNWLLAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid / K20; GIP(3-30+CEX31-39Q20K), AT594

[1240] <SEQ ID NO:137; PRT1; Artificial Sequence> EGTFISDYSIAMDKKHQQDFVNWLLAQKPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid / K17; GIP(3-30+CEX31-39I17K), AT586

[1241] <SEQ ID NO:138; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAQGPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid; GIP(3-30+CEX31-39H18K K30G), AT590 <t

[1242] <SEQ ID NO:139; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS(NH2)2xAEEAc+yGlu-C18-dioic acid; GIP(3-30+CEX31-39H18K Q29G K30G), AT591

[1243] <SEQ ID NO:140; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS2xAEEAc+yGlu-C18-diacid; GIP(3-30+CEX31-39 H18KQ29G K30G), AT592

[1244] <SEQ ID NO:141; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQEFVQWL LAQKPSSGAPPPSC16-diacid; GIP(3-30+CEX31-39 D9E; D15E; H18K; D21E; N24Q), AT613,

[1245] <SEQ ID NO:142; PRT1; Artificial Sequence> EGTFISEYSIAMEKIKQQDFVEWL LAQKPSSGAPPPSC16-diacid; GIP(3-30)Cex(31-39)[D9E; D15E; H18K; N24E], AT614

[1246] <SEQ ID NO:143; PRT1; Artificial Sequence> EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30+CEX31-39 D9E; I12Aib; M14Nle; D15E; H18K; N24E), AT615,

[1247] <SEQ ID NO:144; PRT1; Artificial Sequence> EGTFISEYSIAibMEKIKQQDFVE WLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 D9E; A13Aib; D15E; H18K; N24E), AT616,

[1248] <SEQ ID NO:145; PRT1; Artificial Sequence> EGTFISDYSIAMDKIKQQDFVEWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K N24E), AT 617,

[1249] <SEQ ID NO:146; PRT1; Artificial Sequence>EGTFISDYSIALDKIKQQDFVNWL LAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 M14L H18K), AT 618,

[1250] <SEQ ID NO:147; PRT1; Artificial Sequence>EGTFISDYSIANleDKIKQQDFVNW LLAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 M14Nle H18K), AT619,

[1251] <SEQ ID NO:148; PRT1; Artificial Sequence>EGTFISDYSIAEDKIKQQDFVNWL LAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 M14E H18K), AT 620,

[1252] <SEQ ID NO:149; PRT1; Artificial Sequence>EGTFISDYSIAKDKIKQQDFVNWL LAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 M14K H18K), AT 621,

[1253] <SEQ ID NO:150; PRT1; Artificial Sequence>EGTFISDYSIASDKIKQQDFVNWL LAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 M14S H18K), AT 622

[1254] <SEQ ID NO:151; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVEWL LAQAPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 H18K N24E K30A), AT623,

[1255] <SEQ ID NO:152; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWL EAQKPSSGAPPPSC16-Diacid / 18K; GIP(3-30+CEX31-39 H18K L27E), AT624,

[1256] <SEQ ID NO:153; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWL LEQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 H18K A28E), AT625,

[1257] <SEQ ID NO:154; PRT1; Artificial Sequence>VGTFISDYSIAMDKIKQQDFVNW LLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3V H18K), AT 636,

[1258] <SEQ ID NO:155; PRT1; Artificial Sequence>AibGTFISDYSIAMDKIKQQDFVN WLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3Aib H18K), AT637,

[1259] <SEQ ID NO:156; PRT1; Artificial Sequence>PGTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3P H18K), AT638,

[1260] <SEQ ID NO:157; PRT1; Artificial Sequence>VETFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3V G4E H18K), AT639,

[1261] <SEQ ID NO:158; PRT1; Artificial Sequence>AibETFISDYSIAMDKIKQQDFVN WLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3Aib G4E H18K), AT640,

[1262] <SEQ ID NO:159; PRT1; Artificial Sequence>GETFISDYSIAMDKIKQQDFVNW LLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3G G4E H18K), AT641,

[1263] <SEQ ID NO:160; PRT1; Artificial Sequence>PETFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3P G4E H18K), AT642,

[1264] <SEQ ID NO:161; PRT1; Artificial Sequence>DTTFISDYSIAMDKIKQQDFVNWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3D G4T H18K), AT643,

[1265] <SEQ ID NO:162; PRT1; Artificial Sequence>GETFISDYAIALDKIKQQDFVEWL LAQGPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3G; G4E; S11A; M14L; H18K; N24E; K30G), AT644,

[1266] <SEQ ID NO:163; PRT1; Artificial Sequence>GETFISTYSIALDKIKQQDFVEWL LAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 E3G; G4E; D9T; M14L; H18K; N24E), AT646,

[1267] <SEQ ID NO:164; PRT1; Artificial Sequence>EGTFISTYKIALDKIHQQDFVEWL LAQKPSSGAPPPSyGlu-C16-diacid / 18K; GIP(3-30+CEX31-39 D9T; S11K; M14L; N24E), AT647,

[1268] <SEQ ID NO:165; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWL LAQK(NH2)PSSGAPPPS C16-diacid / 18K; GIP(3-30+CEX31-39[H18K], AT 650,

[1269] <SEQ ID NO:166; PRT1; Artificial Sequence>EGTFISDYSIAibMDKIKQQDFVE WLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30+CEX31-39 A13Aib H18KN24E), AT665,

[1270] <SEQ ID NO:167; PRT1; Artificial Sequence> EGTFISDYSIAibLDKIKQQDFVEW LLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30+CEX31-39 A13Aib M14L H18K N24E), AT666,

[1271] <SEQ ID NO:168; PRT1; Artificial Sequence> EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30+CEX31-39 A13Aib M14Nle H18K N24E), AT667,

[1272] <SEQ ID NO:169; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWL LAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30+CEX31-39 M14L H18K N24E), AT668,

[1273] <SEQ ID NO:170; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEW LLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30+CEX31-39 M14Nle H18K N24E), AT669,

[1274] <SEQ ID NO:171; PRT1; Artificial Sequence> EGTFISDYSIAKDKIKQQDFVEWL LAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[M14K H18K N24E], AT670,

[1275] <SEQ ID NO:172; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVNW LLAGGPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[M14Nle H18KQ29G K30G], AT671,

[1276] <SEQ ID NO:173; PRT1; Artificial Sequence> EGTFISDYSIANleDKIKQQDFVEW LLAGGPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[M14Nle H18KN24E Q29G K30G], AT672,

[1277] <SEQ ID NO:174; PRT1; Artificial Sequence> EGTFISEYSIAibLEKIKQQEFVEW LLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[D9E A13Aib M14L D15E H18K D21E N24E], AT673,

[1278] <SEQ ID NO:175; PRT1; Artificial Sequence> EGTFISEYSIAibNleEKIKQQEFVEWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[D9E A13Aib M14Nle D15E H18KD21E N24E], AT674,

[1279] <SEQ ID NO:176; PRT1; Artificial Sequence> yGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu H18K], AT675,

[1280] <SEQ ID NO:177; PRT1; Artificial Sequence> βGluGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS C16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3βGlu H18K], AT676,

[1281] <SEQ ID NO:178; PRT1; Artificial Sequence> XGTFISDYSIAMDKIKQQDFVNW LLAQKPSSGAPPPSC16-dioic acid / 18K; GIP(3-30)+Cex(31-39)[E3glutaric acid(X)H18K], AT677,

[1282] <SEQ ID NO:179; PRT1; Artificial Sequence> EGTFISDYSIALDKIKQQDFVEWLLAGGPSSGAPPPS2xAEEAc+yGlu-C18-diacid / 18K; GIP(3-30)+Cex(31-39)[M14L H18K N24EQ29G K30G], AT687,

[1283] <SEQ ID NO:180; PRT1; Artificial Sequence> EGTFISEYSIALEKIKQQEFVEWLLAQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / 18K; GIP(3-30)+Cex(31-39)[D9E M14L D15EH18K D21E N24E], AT693,

[1284] <SEQ ID NO:181; PRT1; Artificial Sequence> EGTFISEYSIANleEKIKQQEFVEWLLAQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / 18K; GIP(3-30)+Cex(31-39)[D9E M14Nle D15EH18K D21E N24E], AT694,

[1285] <SEQ ID NO:182; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu (L-isomer) M14Nle H18KN24E], AT697,

[1286] <SEQ ID NO:183; PRT1; Artificial Sequence> yGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3yGlu (D-isomer) M14Nle H18KN24E], AT698,

[1287] <SEQ ID NO:184; PRT1; Artificial Sequence> βGluGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3βGlu M14Nle H18K N24E], AT699,

[1288] <SEQ ID NO:185; PRT1; Artificial Sequence> XGTFISDYSIANleDKIKQQDFVE WLLAQKPSSGAPPPSC16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3 Glutaric acid(X)M14Nle H18K N24E], AT700,

[1289] <SEQ ID NO:186; PRT1; Artificial Sequence> βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQKPSSGAPPPS C16-diacid / 18K; GIP(3-30)+Cex(31-39)[E3βGlu A13Aib M14NleH18K], AT703,

[1290] <SEQ ID NO:187; PRT1; Artificial Sequence> Ac-EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS

[1291] -C16-diacid / K18; GIP(3-30+CEX31-39 H18K), AT 633

[1292] <SEQ ID NO:188; PRT1; Artificial Sequence> Ac-EGTFISEYSIAMEKIKQQDFVNWLLAQKPSSGAPPPS

[1293] -C16-diacid / K18; GIP(3-30+CEX31-39 D9E; D15E; H18K), AT635

[1294] <SEQ ID NO:189; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKK y-glu-C16 diacid / K11 GIP(5-33S11K), AT365

[1295] <SEQ ID NO:190; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDW y-glu-C16 diacid / K11 GIP(5-36S11K), AT366

[1296] <SEQ ID NO:191; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDW(NH2)2xAEEAc+yGlu-C18-diacid / K11, GIP(5-36S11K), AT559

[1297] <SEQ ID NO:192; PRT1; Artificial Sequence> TFISDYSKAMDKIHQQDFVNWLLA QKGKKNDW2xAEEAc+yGlu-C18 diacid / K12 GIP(5-36I12K), AT562

[1298] <SEQ ID NO:193; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWKHN-y-glu-C16 diacid / K11 GIP(5-39S11K), AT367

[1299] <SEQ ID NO:194; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWKHNITQy-glu-C16 diacid / K11 GIP(5-42S11K), AT368

[1300] <SEQ ID NO:195; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKG y-glu-C16 diacid / K11 GIP(5-31S11K), AT455

[1301] <SEQ ID NO:196; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGK y-glu-C16 diacid / K11 GIP(5-32S11K), AT456

[1302] <SEQ ID NO:197; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKN y-glu-C16 diacid / K11 GIP(5-34S11K), AT457

[1303] <SEQ ID NO:198; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDy-glu-C16 diacid / K11 GIP(5-35S11K), AT458

[1304] <SEQ ID NO:199; PRT1; Artificial Sequence> TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWK y-glu-C16 diacid / K11 GIP(5-37S11K), AT459

[1305] <SEQ ID NO:200; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWKH y-glu-C16 diacid / K11 GIP(5-38S11K), AT460

[1306] <SEQ ID NO:201; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWKHNI y-glu-C16 diacid / K11 GIP(5-40S11K), AT461

[1307] <SEQ ID NO:202; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQKGKKNDWKHNITy-glu-C16 diacid / K11 GIP(5-41S11K), AT462

[1308] <SEQ ID NO:203; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQK PSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39S11K), AT597,

[1309] <SEQ ID NO:204; PRT1; Artificial Sequence>TFISDYKIAMDRIHQQDFVNWLL AQRGRRNDW3xAEEAc+y-glu-C16 diacid / K11; GIP(5-36S11K K16R K30R K32R K33R), AT428

[1310] <SEQ ID NO:205; PRT1; Artificial Sequence>TFISDYKIAMDRIHQQDFVNWLLAQRGPSSGAPPPS2xAEEAc+y-glu-C16 diacid / K11; GIP(5-30+CEX S11KK16R K30R), AT443

[1311] <SEQ ID NO:206; PRT1; Artificial Sequence>TFISDYSIAMDKIKQQDFVNWLL AQKGKKNDW2xAEEAc+y-glu-C18 diacid / K18; GIP(5-36H18K), AT563 <SEQ ID NO:207; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQKGPSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39S11K), AT605,

[1312] <SEQ ID NO:208; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AQKPSSGAPPPSyGlu-C16-diacid / K11; GIP(5-30+CEX31-39 S11K), AT632,

[1313] <SEQ ID NO:209; PRT1; Artificial Sequence>TFISDYSIAMDKIHQKDFVNWLL AQKGKKNDW2xAEEAc+y-glu-C18 diacid / K20; GIP(5-36Q20K), AT564 <SEQ ID NO:210; PRT1; Artificial Sequence>TFISDYSIAMDKIHQQDFVKWLL AQKGKKNDW 2xAEEAc+y-glu-C18 diacid / K24; GIP(5-36N24K), AT566 <SEQ ID NO:211; PRT1; Artificial Sequence>FISDYSIAMDKIKQQDFVNWLLA QKGKK C16 diacid / K18; GIP(6-33H18K), AT463

[1314] <SEQ ID NO:212; PRT1; Artificial Sequence>FISDYSIAMDKIKQQDFVNWLLA QKGKKNDW C16 diacid / K18; GIP(6-36H18K), AT464

[1315] <SEQ ID NO:213; PRT1; Artificial Sequence>FISDYSIAMDKIKQQDFVNWLLA QKGKKNDWKHN C16 diacid / K18; GIP(6-39H18K), AT465

[1316] <SEQ ID NO:214; PRT1; Artificial Sequence>FISDYSIAMDKIKQQDFVNWLLA QKGKKNDWKHNITQC16 diacid / K18; GIP(6-342H18K), AT466

[1317] <SEQ ID NO:215; PRT1; Artificial Sequence>FISDYSIAMDKIKQQDFVNWLLA QKGPSSGAPPPS C16 diacid / K18; GIP(6-30+CEX H18K), AT475

[1318] <SEQ ID NO:216; PRT1; Artificial Sequence>TFISDYKIAMDKIHQQDFVNWLL AGGPSSGAPPPS(NH2)2xPEG+yGlu-C18-diacid / K11; GIP(5-30+CEX31-39[S11K Q29G K30G]), AT602,

[1319] <SEQ ID NO:218; PRT1; Artificial Sequence>EGTFISDYSIALDKIKQQDFVNWLLEQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30)Cex(31-39)[M14L; H18K; A28E], AT689

[1320] <SEQ ID NO:219; PRT1; Artificial Sequence>EGTFISDYSIANleDKIKQQDFVNWLLEQKPSSGAPPPS2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30)Cex(31-39)[M14Nle; H18K; A28E], AT690

[1321] <SEQ ID NO:220; PRT1; Artificial Sequence>EGTFISDYSIALDKIKQQDFVNWL LEGGPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / K18; GIP(3-30)Cex(31-39)[M14L; H18K; A28E; Q29G; K30G], AT691

[1322] <SEQ ID NO:221; PRT1; Artificial Sequence>EGTFISDYSIAMDKIKQQDFVNWL LEGGPSSGAPPPS-C16-diacid / K18; GIP(3-30)+Cex(31-39)[H18K; A28E; Q29G; K30G]

[1323] This disclosure relates to the following implementation plan:

[1324] 1. A glucose-dependent insulinotropic peptide (GIP) analogue

[1325] It consists of the amino acid sequence SEQ ID NO:XX:

[1326]

[1327]

[1328] Where X1 and X2 are either any amino acids or are omitted;

[1329] Or functional variants thereof, wherein the variants have 1 to 8 individual amino acid substitutions at any amino acid in SEQ ID NO:XX.

[1330] The peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX or the functional variant.

[1331] Z is a peptide containing one or more amino acid residues of GIP(31-42)(GKKNDWKHNITQ;SEQ ID NO:Z) or one or more amino acid residues of lizard exopeptide-4(HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS;SEQ ID NO:E).

[1332] 2. A glucose-dependent insulinotropic peptide (GIP) analogue

[1333] It consists of the amino acid sequence SEQ ID NO:XX:

[1334]

[1335] Where X1 and X2 are either any amino acids or are omitted;

[1336] Or functional variants thereof, wherein the variants have 1 to 4 individual amino acid substitutions at any amino acid in SEQ ID NO:XX.

[1337] The peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX or the functional variant.

[1338] Z is a peptide containing one or more amino acid residues of GIP(31-42)(GKKNDWKHNITQ;SEQ ID NO:Z) or one or more amino acid residues of lizard exopeptide-4(HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS;SEQ ID NO:E).

[1339] 3. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog is a GIPR antagonist.

[1340] 4. The GIP peptide analog according to any one of the preceding items, wherein the GIP peptide analog inhibits at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100% of GIPR activity.

[1341] 5. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog inhibits at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100% of GIPR activity, wherein the inhibition of GIPR activity is determined to be a decrease in intracellular cAMP.

[1342] 6. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog has GIPR antagonistic potency corresponding to an IC50 value of 50 nM or less.

[1343] 7. The GIP peptide analog according to any one of the preceding items, wherein:

[1344] The fifth amino acid is T or is omitted;

[1345] The amino acid at position 9 is selected from D, E, and T;

[1346] The 11th amino acid is selected from S, K, and A;

[1347] The amino acid at position 12 is selected from I, K, and 2-aminoisobutyric acid (Aib);

[1348] The amino acid at position 13 is selected from A and Aib;

[1349] The amino acid at position 14 is selected from M, K, E, S, L, and Nle;

[1350] The amino acid at position 15 is selected from D and E;

[1351] The amino acid at position 16 is selected from K and R;

[1352] The amino acid at position 17 is selected from I and K;

[1353] The amino acid at position 18 is selected from H and K;

[1354] The 20th amino acid is selected from Q and K;

[1355] The amino acid at position 21 is selected from D and E;

[1356] The amino acid at position 24 is selected from N, K, Q, and E;

[1357] The amino acid at position 28 is selected from A and E;

[1358] The amino acid at position 29 is selected from Q and G; and / or

[1359] The 30th amino acid is selected from K, R, G, and A.

[1360] 8. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has a single amino acid substitution at any amino acid residue of SEQ ID NO:XX, such as two single amino acid substitutions, such as three single amino acid substitutions, such as four single amino acid substitutions.

[1361] 9. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has 1 to 2 individual amino acid substitutions at any amino acid residue of SEQ ID NO:XX, 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.

[1362] 10. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has a single amino acid substitution, such as two single amino acid substitutions, such as three single amino acid substitutions, such as four single amino acid substitutions, at any amino acid residue of SEQ ID NO:XX, wherein the substitution is a conserved amino acid substitution.

[1363] 11. The GIP peptide analog according to any one of the preceding items, wherein X1 and X2 are omitted.

[1364] 12. The GIP peptide analog according to any one of the preceding items, wherein the amino acid residues at positions X1, X2 and 5 are omitted.

[1365] 13. The GIP peptide analog according to any one of the preceding claims, wherein the variant is in SEQ ID NO:

[1366] The amino acid residues 3 to 30 of XX have 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.

[1367] 14. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has 1 to 2 individual amino acid substitutions at any of amino acid residues 3 to 30 of SEQ ID NO:XX, 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.

[1368] 15. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has one to two individual amino acid substitutions, such as two to three individual amino acid substitutions, such as three to four individual amino acid substitutions, such as four to five individual amino acid substitutions, such as five to six individual amino acid substitutions, such as six to seven individual amino acid substitutions, such as seven to eight individual amino acid substitutions, at any 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.

[1369] 16. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant is in SEQ ID NO:GIP(3-30)X1-X2, SEQ ID NO:GIP(3-30)X2, SEQ ID NO:

[1370] The amino acid residues 4 to 10 of 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), and SEQ ID NO:GIP(6-30) have one or two individual amino acid substitutions.

[1371] 17. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has one or two, such as one or three, such as two or three individual amino acid substitutions at any of amino acid residues 19 to 27 of SEQ ID NO: XX.

[1372] 18. The GIP peptide analog according to any one of the preceding claims, wherein at least one amino acid residue of the GIP peptide analog of SEQ ID NO:XX is substituted with E, such as wherein SEQ ID NO:XX

[1373] At least one amino acid residue at any of the 9th, 15th, 21st and 24th positions is replaced by E.

[1374] 19. The GIP peptide analog according to any one of the preceding claims, wherein X1 is selected from E, S, G, V, ...

[1375] Amino acid residues of 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.

[1376] 20. The GIP peptide analog according to any one of the preceding items, wherein X1 is E.

[1377] 21. The GIP peptide analog according to any one of the preceding claims, wherein X2 is an amino acid residue selected from G, E, T, K and Orn.

[1378] 22. The GIP peptide analog according to any one of the preceding claims, wherein the 9th D of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from E and T.

[1379] 23. The GIP peptide analog according to any one of the preceding claims, wherein the 11th S of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from A, K and Orn.

[1380] 24. The GIP peptide analog according to any one of the preceding claims, wherein the 12th position I of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from K, Orn and 2-aminoisobutyric acid (Aib).

[1381] 25. The GIP peptide analog according to any one of the preceding claims, wherein the 13th position A of said SEQ ID NO:XX or a functional variant thereof is replaced by any amino acid, such as a conserved amino acid, such as being replaced by 2-aminoisobutyric acid (Aib).

[1382] 26. The GIP peptide analog according to any one of the preceding claims, wherein the 14th M of said SEQ ID NO:XX or a functional variant thereof is replaced by any amino acid, such as a conserved amino acid substitution, such as being replaced by an amino acid residue selected from L, ortholeucine (Nle), E, ​​S, K and Orn.

[1383] 27. The GIP peptide analog according to any one of the preceding claims, wherein the 14th position M of SEQ ID NO:XX or a functional variant thereof is replaced by an amino acid residue selected from L, ortholeucine (Nle) and K.

[1384] 28. The GIP peptide analog according to any one of the preceding claims, wherein the 15th D of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with E.

[1385] 29. The GIP peptide analog according to any one of the preceding claims, wherein the 16th K of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with R.

[1386] 30. The GIP peptide analog according to any one of the preceding claims, wherein the 17th position I of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from K or Orn.

[1387] 31. The GIP peptide analog according to any one of the preceding claims, wherein the 18th H of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from K and Orn.

[1388] 32. The GIP peptide analog according to any one of the preceding claims, wherein the 20th position Q of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from K and Orn.

[1389] 33. The GIP peptide analog according to any one of the preceding claims, wherein the 21st D of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with E.

[1390] 34. The GIP peptide analog according to any one of the preceding claims, wherein the 24th N of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from Q and E.

[1391] 35. The GIP peptide analog according to any one of the preceding claims, wherein the 24th N of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with E.

[1392] 36. The GIP peptide analog according to any one of the preceding claims, wherein the 28th position A of said SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with E.

[1393] 37. The GIP peptide analog according to any one of the preceding claims, wherein the 29th position Q of the SEQ ID NO:XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as being substituted with G.

[1394] 38. The GIP peptide analog according to any one of the preceding claims, wherein the 30th K of the SEQ ID NO: XX or a functional variant thereof is substituted with any amino acid, such as a conserved amino acid substitution, such as substitution with an amino acid residue selected from R, A and G.

[1395] 39. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog comprises at least one K substitution and one E or Aib substitution at any one of amino acid residues 3 to 30 of SEQ ID NO: XX.

[1396] 40. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO:(GIP3-30 X1-X2):

[1397]

[1398] 41. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO:(GIP3-30 X2):

[1399]

[1400] 42. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO:(GIP3-30 X1):

[1401]

[1402] 43. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO: (GIP3-30):

[1403]

[1404] 44. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO:(GIP4-30 X2):

[1405]

[1406] 45. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO: (GIP4-30):

[1407]

[1408] 46. ​​The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO: (GIP5-30):

[1409]

[1410] 47. The GIP peptide analog according to claim 1, wherein the peptide comprises SEQ ID NO: (GIP6-30):

[1411]

[1412] 48. The GIP peptide analog according to any one of the preceding claims, wherein Z consists of one or more consecutive amino acid residues of GIP (31-42) (SEQ ID NO: Z).

[1413] 49. The GIP peptide analog according to any one of the preceding claims, wherein Z consists of one or more consecutive amino acid residues of sarcophagus exopeptide-4 (SEQ ID NO:E).

[1414] 50. The GIP peptide analog according to any one of the preceding claims, wherein Z is derived from sarcophagus exopeptide-4 (30-39).

[1415] (PSSGAPPPS; SEQ ID NO: CE31-39) consists of one or more amino acid residues at the C-terminus.

[1416] 51. The GIP peptide analog according to any one of the preceding claims, wherein Z is derived from sarcophagus exopeptide-4 (29-39).

[1417] (GPSSGAPPPS; SEQ ID NO: CE30-39) consists of one or more amino acid residues at the C-terminus.

[1418] 52. The GIP peptide analog according to any one of the preceding items, wherein Z comprises at least one G or one P.

[1419] 53. The GIP peptide analog according to any one of the preceding items, wherein Z comprises at least two Ps.

[1420] 54. The GIP peptide analog according to any one of the preceding claims, wherein Z is a peptide selected from:

[1421] - Glycine or proline,

[1422] –GP, GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP,

[1423] GPSSGAPPP and GPSSGAPPPS

[1424] – PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[1425] –GK, GKK, GKKN, GKKND, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,

[1426] – GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GKKKDW, GKKNDKGRKNDW, GKRNDW, GRNDW, GKKNDWK, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT, and GKKNDWKHNITQ, or variants thereof containing one or two separate amino acid substitutions at any of the amino acid residues, or

[1427] –PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,

[1428] – or variants thereof containing one or two separate amino acid substitutions at any of the amino acid residues.

[1429] 55. The GIP peptide analog according to any one of the preceding claims, wherein fatty acid molecules are not attached to

[1430] On the 3rd amino acid residue of SEQ ID NO:XX or its variants.

[1431] 56. The GIP peptide analog according to any one of the preceding claims, wherein fatty acid molecules are not attached to SEQ ID NO:(GIP3-30 X1-X2), SEQ ID NO:(GIP3-30 X1), or SEQ ID NO:

[1432] The N-terminal amino group of the third amino acid residue in (GIP3-30 X2).

[1433] 57. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is not attached to the N-terminal amino group of the fourth amino acid residue in SEQ ID NO:(GIP4-30 X2) or SEQ ID NO:(GIP4-30).

[1434] 58. The GIP peptide analog according to any one of the preceding claims, wherein fatty acid molecules are not attached to

[1435] On the N-terminal amino group of the 5th amino acid residue in SEQ ID NO:(GIP5-30).

[1436] 59. The GIP peptide analog according to any one of the preceding items, wherein fatty acid molecules are not attached to the amino acid residues of Z.

[1437] 60. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog has a free N-terminus.

[1438] 61. A GIP peptide analog according to any one of the preceding claims, wherein one or more fatty acid molecules are attached to the side chain of the GIP peptide analog, such as SEQ ID NO:XX or a functional variant thereof, at positions 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 an amino acid residue.

[1439] 62. The GIP peptide analog according to any one of the preceding claims, wherein the at least one fatty acid molecule is attached to one or more amino acid residues in the middle region of SEQ ID NO:XX or a functional variant thereof; such as being attached to one or more amino acid residues at any one of positions 11 to 21 of SEQ ID NO:XX or a functional variant thereof.

[1440] 63. The GIP peptide analog according to any one of the preceding claims, wherein the at least one fatty acid molecule is attached to one or more amino acid residues at any one of positions 11, 12, 17 and 18 of SEQ ID NO:XX or a functional variant thereof.

[1441] 64. The GIP peptide analog according to any one of the preceding claims, wherein a fatty acid molecule is attached to the GIP peptide analog, such as SEQ ID NO:XX or an ε-amino group of a functional variant containing at least one K or Orn residue.

[1442] 65. The GIP peptide analog according to any one of the preceding claims, wherein a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 18 of SEQ ID NO:XX or a variant thereof, wherein in SEQ ID NO:XX, the H at position 18 has been substituted with K or Orn.

[1443] 66. The GIP peptide analog according to any one of the preceding claims, wherein a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 11 of SEQ ID NO:XX or a variant thereof, wherein in SEQ ID NO:XX, the S at position 11 has been substituted with K or Orn.

[1444] 67. The GIP peptide analog according to any one of the preceding claims, wherein a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 12 of SEQ ID NO:XX or a functional variant thereof, wherein

[1445] In SEQ ID NO:XX, the 12th I has been replaced by K or Orn.

[1446] 68. The GIP peptide analog according to any one of the preceding claims, wherein the 30th position K of SEQ ID NO:XX or a functional variant thereof is replaced by any amino acid residue, and a fatty acid molecule is attached to an amino acid residue at a position other than the 30th position of SEQ ID NO:XX or a functional variant thereof.

[1447] 69. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog has an amino acid sequence selected from:

[1448] EGTFISDYSIAMDKIHQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(3-30),EGTFISDYSIAMDKIKQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(3-30)[H18K],

[1449] SGTFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3S; H18K]

[1450] SGTFISDYSIAMDRIKQQDFVNWLLAQR–Z; SEQ ID NO:; GIP(3-30)[E3S; K16R; H18K; K30R]

[1451] EGTFISDYKIAMDKIHQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[S11K],

[1452] EGTFISDYSKAMDKIHQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[I12K],

[1453] EGTFISDYSIAMDKIHQKDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[Q20K],

[1454] EGTFISDYSIAMDKIHQQDFVKWLLAQK–Z; SEQ ID NO:; GIP(3-30)[N24K],

[1455] EGTFISDYSIAMDKKHQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[I17K],

[1456] EGTFISDYSIAMDKIKQQDFVNWLLAQG–Z; SEQ ID NO:; GIP(3-30)[H18K; K30G]

[1457] EGTFISDYSIAMDKIKQQDFVNWLLAGG–Z;SEQ ID NO:;GIP(3-30)[H18K;Q29G;K30G],

[1458] EGTFISEYSIAMEKIKQQEFVQWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; D15E; H18K; D21E; N24Q]

[1459] EGTFISEYSIAMEKIKQQDFVQWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; D15E; H18K; N24Q]

[1460] EGTFISEYSAibANleEKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; I12Aib; M14Nle; D15E; H18K; N24E], EGTFISEYSIAibMEKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; A13Aib; D15E; H18K; N24E],

[1461] EGTFISDYSIAMDKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[H18K; N24E]

[1462] EGTFISDYSIALDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K]

[1463] EGTFISDYSIANleDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K],

[1464] EGTFISDYSIAEDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14E;H18K],

[1465] EGTFISDYSIAKDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[M14K; H18K]

[1466] EGTFISDYSIASDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14S;H18K],

[1467] EGTFISDYSIAMDKIKQQDFVEWLLAQA–Z; SEQ ID NO:; GIP(3-30)[H18K; N24E; K30A]

[1468] EGTFISDYSIAMDKIKQQDFVNWLLEQK–Z; SEQ ID NO:; GIP(3-30)[H18K; A28E]

[1469] VGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3V; H18K]

[1470] AibGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3Aib; H18K]

[1471] PGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3P; H18K]

[1472] VETFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3V; G4E; H18K]

[1473] AibETFISDYSIAMDKIKQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(3-30)[E3Aib;G4E;H18K],

[1474] GETFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3G; G4E; H18K]

[1475] PETFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3P; G4E; H18K]

[1476] DTTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3D; G4T; H18K]

[1477] GETFISDYAIALDKIKQQDFVEWLLAQG–Z; SEQ ID NO:; GIP(3-30)[E3G; G4E; S11A; M14L; H18K; N24E; K30G], GETFISTYSIALDKIKQQDFVEWLLAQG–Z; SEQ ID NO:; GIP(3-30)[E3G; G4E; D9T; M14L; H18K; N24E],

[1478] EGTFISTYKIALDKIHQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9T; S11K; M14L; N24E]

[1479] EGTFISDYSIAibMDKIKQQDFVEWLLAQK–Z; SEQ ID NO; GIP(3-30)[A13Aib; H18K; N24E]

[1480] EGTFISDYSIAibLDKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[A13Aib; M14L; H18K; N24E]

[1481] EGTFISDYSIAibNleDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[A13Aib;M14Nle;H18K;N24E],EGTFISDYSIALDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14L;H18K;N24E],

[1482] EGTFISDYSIANleDKIKQQDFVEWLLAQK–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;N24E],

[1483] EGTFISDYSIAKDKIKQQDFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[M14K; H18K; N24E]

[1484] EGTFISDYSIANleDKIKQQDFVNWLLAGG–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;Q29G;K30G],

[1485] EGTFISDYSIANleDKIKQQDFVEWLLAGG–Z;SEQ ID NO:;GIP(3-30)[M14Nle;H18K;N24E;Q29G;K30G],

[1486] EGTFISEYSIAibLEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; A13Aib; M14L; D15E; H18K; D21E; N24E], 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],

[1487] βGluGTFISDYSIAMDKIKQQDFVNWLLAQK–Z; SEQ ID NO:; GIP(3-30)[E3βGlu; H18K],

[1488] XGTFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3 glutaric acid (X); H18K],

[1489] EGTFISDYSIALDKIKQQDFVEWLLAGG–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K; N24E; Q29G; K30G],

[1490] EGTFISEYSIALEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; M14L; D15E; H18K; D21E; N24E],

[1491] EGTFISEYSIANleEKIKQQEFVEWLLAQK–Z; SEQ ID NO:; GIP(3-30)[D9E; M14Nle; D15E; H18K; D21E; N24E],

[1492] yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3yGlu (L-isomer); M14Nle; H18K; N24E], yGluGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3yGlu (D-isomer); M14Nle; H18K; N24E], βGluGTFISDYSIANleDKIKQQDFVEWLLAQK–Z; SEQID NO:; GIP(3-30)[E3βGlu; M14Nle; H18K; N24E], XGTFISDYSIANleDKIKQQDFVEWLLAQK-Z; SEQ ID NO:; GIP(3-30)[E3 glutaric acid (X); M14Nle; H18K; N24E], βGluGTFISDYSIAibNleDKIKQQDFVNWLLAQK–Z; SEQ ID NO:GIP(3-30)[E3βGlu; A13Aib; M14Nle; H18K], EGTFISDYSIALDKIKQQDFVNWLLEQK–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K; A28E],

[1493] EGTFISDYSIANleDKIKQQDFVNWLLEQK–Z; SEQ ID NO:; GIP(3-30)[M14Nle; H18K; A28E],

[1494] EGTFISDYSIALDKIKQQDFVNWLLEGG–Z; SEQ ID NO:; GIP(3-30)[M14L; H18K; A28E; Q29G; K30G],

[1495] TFISDYSIAMDKIHQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30)TFISDYKIAMDKIHQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30)[S11K],

[1496] TFISDYSIAMDKIKQQDFVNWLLAQK-Z; SEQ ID NO:; GIP(5-30)[H18K],

[1497] TFISDYKIAMDRIHQQDFVNWLLAQR–Z; SEQ ID NO:; GIP(5-30)[S11K; K16R; K30R],

[1498] TFISDYSKAMDKIHQQDFVNWLLAQK–Z;SEQ ID NO:;GIP(5-30)

[1499] [I12K],

[1500] TFISDYSIAMDKIHQKDFVNWLLAQK–Z;SEQ ID NO:;GIP(5-30)

[1501] [Q20K],

[1502] TFISDYSIAMDKIHQQDFVKWLLAQK-Z;SEQ ID NO:;GIP(5-30)

[1503] [N24K], and

[1504] FISDYSIAMDKIKQQDFVNWLLAQK-Z;SEQ ID NO:;GIP(6-30)

[1505] [H18K].

[1506] 70. The GIP peptide analog according to any one of the preceding claims, wherein the peptide is C-terminally amidated (-NH2) or C-terminally carboxylated (-COOH).

[1507] 71. The GIP peptide analog according to any one of the preceding claims, wherein the peptide is C-terminally carboxylated (-COOH).

[1508] 72. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is a straight-chain fatty acid.

[1509] 73. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is a branched-chain fatty acid.

[1510] 74. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is a monoacyl fatty acid molecule containing one fatty acid.

[1511] 75. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is a diacyl fatty acid molecule.

[1512] 76. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises the formula...

[1513] CH3(CH2) n The acyl group of CO-, where n is an integer from 4 to 24.

[1514] 77. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises a subset selected from 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

[1515] (CH2) 22 One or more acyl groups of CO-.

[1516] 78. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises a component selected from CH3(CH2). 10 CO-(lauryl, C12), CH3(CH2) 12 CO-(myristoyl, C14), CH3(CH2) 14 CO-(palmitoyl, C16), CH3(CH2) 16 CO-(stearoyl, C18), CH3(CH2) 18 CO-(arachidoyl, C20) and CH3(CH2) 20 The acyl group of CO-(behenyl, C22).

[1517] 79. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises two acyl groups selected from HOOC-CH3(CH2). 10 CO-(dodecanoyl, C12), HOOC-CH3(CH2) 12 CO-(1-Tetradecanoyl, C14), HOOC-CH3(CH2) 14 CO-(hexadecyl, C16), HOOC-CH3(CH2) 15 CO-(15-carboxy-pentadecanoyl, C17), HOOC-CH3(CH2) 16 CO-(octadecyl, C18), HOOC-CH3(CH2) 17 CO-(17-carboxy-heptadecanoyl, C19), HOOC-CH3(CH2) 18 CO-(eicosyl, C20), HOOC-CH3(CH2) 19 CO-(19-carboxy-nonadecanoyl, C21) and HOOC-CH3(CH2) 20CO-(Yamyuki, C22).

[1518] 80. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises the formula...

[1519] COOH(CH2) n The acyl group of CO-(dicarboxylic acid), where n is an integer from 4 to 24.

[1520] 81. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises a component selected from COOH(CH2). 14 CO-, COOH(CH2) 16 CO-, COOH(CH2) 18 CO- and

[1521] COOH(CH2) 20 Acyl group of CO-.

[1522] 82. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises

[1523] COOH(CH2) 14 CO- or composed of it.

[1524] 83. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises

[1525] COOH(CH2) 16 CO- or composed of it.

[1526] 84. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule comprises

[1527] COOH(CH2) 18 CO- or composed of it.

[1528] 85. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is directly attached to the ε-amino group of the side chain of the amino acid residue of the GIP peptide analog.

[1529] 86. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker.

[1530] 87. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker such that the carboxyl group of the fatty acid molecule forms an amide bond with the amino group of the linker.

[1531] 88. The GIP peptide analog according to any one of the preceding claims, wherein the linker comprises one or more

[1532] Each of the one or more parts is individually selected from:

[1533] a. One or more α,ω-amino acids,

[1534] b. One or more amino acids selected from succinic acid, Lys, Glu, and Asp.

[1535] c.4-Abu,

[1536] dy-aminobutyric acid

[1537] e. A dipeptide, such as 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 Ala, Arg, Asp, Asn, Gly,

[1538] Dipeptides of Glu, Gln, Ile, Leu, Val, Phe, and Pro, such as Gly-Lys,

[1539] f. One or more of γ-aminobutyryl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparagine acyl, β-alanyl, and glycyl, and

[1540] g. γ-Glutamic acid-[8-amino-3,6-dioxanoic acid] n (γGlu-AEEAc n ), where n

[1541] Integers between 1 and 50, such as 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.

[1542] Integers between 20-25, 25-30, 30-35, 35-40, 40-45, and 45-50.

[1543] 89. The GIP peptide analog according to any one of the preceding claims, wherein the linker comprises one or more

[1544] Each of the one or more parts is individually selected from:

[1545] a. α-amino acids, γ-amino acids, or ω-amino acids,

[1546] b. One or more amino acids selected from succinic acid, Lys, Glu, and Asp.

[1547] c. One or more of γ-aminobutyryl (γ-aminobutyric acid), γ-Glu (γ-glutamic acid), β-Asp (β-asparagine acyl), β-Ala (β-alanyl), and Gly, and

[1548] d. [8-Amino-3,6-dioxanoic 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.

[1549] 90. The GIP peptide analog according to any one of the preceding claims, wherein the linker comprises γ-Glu, one or more 8-amino-3,6-dioxanoic acid (AEEAc), or a combination thereof.

[1550] 91. The GIP peptide analog according to any one of the preceding items, wherein the linker comprises or is composed of γ-Glu.

[1551] 92. The GIP peptide analog according to any one of the preceding claims, wherein the linker comprises [8-amino-3,6-dioxanoic acid]. n (AEEAc) n Or composed of, where 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, preferably where n is 1, 2 or 3.

[1552] 93. The GIP peptide analog according to any one of the preceding items, wherein the linker comprises one γ-Glu and one AEEAc, such as one γ-Glu and two AEEAc, for example one γ-Glu and three AEEAc, or consists thereof.

[1553] 94. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker, and wherein the combination of the linker and the fatty acid is selected from:

[1554] i. hexadecanoyl-Y-Glu-

[1555] ii. Hexadecyl-Y-Glu-Y-Glu-

[1556] iii. Hexadecyl-Y-Glu-AEEAc-

[1557] iv. Hexadecyl-Y-Glu-AEEAc-AEEAc-

[1558] v. Hexadecanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[1559] vi. [15-Carboxy-pentadecanoyl]-Y-Glu-

[1560] vii. [15-Carboxy-pentadecanoyl]-Y-Glu-Y-Glu-

[1561] viii. [15-Carboxy-pentadecanoyl]-Y-Glu-AEEAc-

[1562] ix.[15-Carboxy-pentadecanoyl]-Y-Glu-AEEAc-AEEAc-

[1563] x.[15-Carboxyl-pentadecanyl]-Y-Glu-AEEAc-AEEAc-AEEAc-

[1564] xi.octadecyl-Y-Glu-

[1565] xii. Octyl-Y-Glu-Y-Glu-

[1566] xiii. Octyl-Y-Glu-AEEAc-

[1567] xiv. Octyl-Y-Glu-AEEAc-AEEAc-

[1568] xv.octadecyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[1569] xvi.[17-Carboxy-heptadecanoyl]-Y-Glu-

[1570] xvii.[17-Carboxy-heptadecanoyl]-Y-Glu-Y-Glu-

[1571] xviii.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-

[1572] xix.[17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-

[1573] xx.[17-Carboxy-Heptadecanyl]-Y-Glu-AEEAc-AEEAc-AEEAc-

[1574] xxi. Eicosyl-Y-Glu-

[1575] xxii. Eicosyl-Y-Glu-Y-Glu-

[1576] xxiii. Eicosyl-Y-Glu-AEEAc-

[1577] xxiv. Eicosyl-Y-Glu-AEEAc-AEEAc-

[1578] xxv. icosanoyl-Y-Glu-AEEAc-AEEAc-AEEAc-

[1579] xxvi.[19-carboxy-nonadecanoyl]-Y-Glu-

[1580] xxvii.[19-Carboxy-Ninedecyl]-Y-Glu-Y-Glu-

[1581] xxviii.[19-carboxy-nonadecanoyl]-Y-Glu-AEEAc-

[1582] xxix[19-carboxy-nonadecanoyl]-Y-Glu-AEEAc-AEEAc-

[1583] xxx.[19-Carboxyl-Ninedecyl]-Y-Glu-AEEAc-AEEAc-AEEAc-.

[1584] 95. The GIP peptide analog according to any one of the preceding claims, wherein the fatty acid molecule is attached to an amino acid residue via a linker, and wherein the combination of the linker and the fatty acid is selected from:

[1585] i. [15-Carboxypentadecanoyl-yGlu]

[1586] ii. [17-Carboxy-heptadecanoyl]-Y-Glu-AEEAc-AEEAc-, and

[1587] iii.[17-Carboxy-heptadecanoyl]-yGlu-yGlu.

[1588] 96. The GIP peptide analogue according to any one of the preceding items, wherein the analogue is selected from:

[1589] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-

[1590] C16-diacid / K18; SEQ ID NO:GIP(3-36)[H18K],

[1591] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-

[1592] C16-diacid / K18; SEQ ID NO: GIP(3-36)[H18K],

[1593] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-

[1594] C18-diacid / K18; SEQ ID NO: GIP(3-36)[H18K],

[1595] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K],

[1596] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc

[1597] + yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu

[1598] -C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1599] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc

[1600] + yGlu-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1601] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18-diacid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1602] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C18 / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1603] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu

[1604] -C16-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1605] EGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-yGlu-C16-dioic acid / K18; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K],

[1606] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-C16-diacid / K18; SEQ ID NO: GIP(3-30)+Cex[H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30)+Cex[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C16-diacid / K18: SEQ ID SEQ ID NO:GIP(3-30)+Cex[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO:GIP(3-30)+Cex[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO:GIP(3-30)+Cex[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K18; SEQ ID NO:GIP(3-30)+Cex(31-39)[CexH18K), EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+yG lu-C18-diacid / K18;SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPP-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(9)[CexH18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPP-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex8)[H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAP-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex7)[H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGA-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex6)[H18K], EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSG-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex5)[H18K],;

[1607] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSS-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex4)[H18K],

[1608] EGTFISDYSIAMDKIKQQDFVNWLLAQKGPS-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex3)[H18K],

[1609] EGTFISDYSIAMDKIKQQDFVNWLLAQKGP-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex(Cex2)[H18K],

[1610] EGTFISDYSIAMDKIKQQDFVNWLLAQKG-C16-dioic acid / K18: SEQ ID NO: GIP(3-31)[H18K],

[1611] EGTFISDYSIAMDKIKQQDFVNWLLAQKGK-C16-dioic acid / K18: SEQ IDNO: GIP(3-32)[H18K],

[1612] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKK-C16-diacid / K18:SEQ ID NO:GIP(3-33)[H18K],

[1613] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKN-C16-diacid / K18: SEQ ID NO: GIP(3-34)[H18K],

[1614] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKND-C16-diacid / K18: SEQ ID NO: GIP(3-35)[H18K],

[1615] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-C16-diacid / K18: SEQ ID NO: GIP(3-36)[H18K],

[1616] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWK-C16-diacid / K18: SEQ ID NO: GIP(3-37)[H18K],

[1617] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKH-C16-diacid / K18:SEQ ID NO:GIP(3-38)[H18K],

[1618] EGTFYSIAMDKIKQQDFVNWLLAQKGKKNDWKHN-C16-diacid / K18:SEQ ID NO:GIP(3-39)[H18K],

[1619] EGTFYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNI-C16-diacid / K18:SEQ ID NO:GIP(3-40)[H18K],

[1620] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNIT-C16-diacid / K18: SEQ ID NO: GIP(3-41)[H18K],

[1621] EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ-C16-diacid / K18:SEQ ID NO:GIP(3-42)[H18K],

[1622] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-2xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; H18K],

[1623] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; H18K],

[1624] SGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDW-3xAEEAc+y-glu-C18-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; H18K],

[1625] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30)+Cex[E3S; H18K],

[1626] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C16-diacid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; H18K],

[1627] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-2xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; H18K],

[1628] SGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAPPPS-3xAEEAc+y-glu-C18-diacid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; H18K],

[1629] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-2xAEEAc+y-glu-C16-diacid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[1630] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C16-dioic acid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[1631] SGTFISDYSIAMDRIKQQDFVNWLLAQRGRRNDW-3xAEEAc+y-glu-C18-dioic acid / K18; SEQ ID NO: GIP(3-36)[E3S; K16R; H18K; K30R],

[1632] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex[E3S; K16R; H18K; K30R],

[1633] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C18-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; K?6R; H18K; K30R],

[1634] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-2xAEEAc+y-glu-C16-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; K16R; H18K; K30R],

[1635] SGTFISDYSIAMDRIKQQDFVNWLLAQRGPSSGAPPPS-3xAEEAc+y-glu-C18-dioic acid / K18: SEQ ID NO: GIP(3-30)+Cex[CexE3S; K16R; H18K; K30R],

[1636] EGTFISDYKIAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-dioic acid / K11; SEQ ID NO: GIP(3-36)[S11K],

[1637] EGTFISDYSKAMDKIHQQDFVNWLLAQKGKKNDW-2xAEEAc+yGlu-C18-dioic acid / K12; SEQ ID NO: GIP(3-36)[I12K], It should be noted that there seems to be a "K?6R" in the translation of line 9 which might be a typo in the original text. If it's a misprint, it should be corrected to "K16R" for a more accurate translation.

[1638] EGTFISDYSIAMDKIHQKDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K20; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexQ20K],

[1639] EGTFISDYSIAMDKKHQQDFVNWLLAQKPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid / K17; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexI17K], dGTFISDYSIAMDKIKQQDFVNWLLAQGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexH18K; K30G],

[1640] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS(NH2)-2xAEEAc+yGlu-C18-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39) [CexH18K; Q29G; K30G],

[1641] EGTFISDYSIAMDKIKQQDFVNWLLAGGPSSGAPPPS-2xAEEAc+yGl u-C18-diacid; SEQ IDNO:GIP(3-30)+Cex(31-39)[CexH18K; Q29G; K30G],

[1642] EGTFISEYSIAMEKIKQQEFVQWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39)[CexD9E; D15E; H18K; D21E; N24Q],

[1643] EGTFISEYSIAMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; D15E; H18K; N24E],

[1644] EGTFISEYSAibANleEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; I12Aib; M14Nle; D15E; H18K; N24E],

[1645] EGTFISEYSIAibMEKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9E; A13Aib; D15E; H18K; N24E],

[1646] EGTFISDYSIAMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K; N24E],

[1647] EGTFISDYSIALDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K],

[1648] EGTFISDYSIALDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L;H18K]

[1649] EGTFISDYSIANleDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K],

[1650] EGTFISDYSIAEDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14E;H18K],

[1651] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K;H18K],

[1652] EGTFISDYSIAKDKIKQQDFVNWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K;H18K]

[1653] EGTFISDYSIASDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14S;H18K],

[1654] EGTFISDYSIAMDKIKQQDFVEWLLAQAPSSGAPPPS-C16-diacid / 18K; SEQ ID NO:GIP(3-30)+Cex(31-39)[H18K; N24E; K30A],

[1655] EGTFISDYSIAMDKIKQQDFVNWLEAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K;L27E],

[1656] EGTFISDYSIAMDKIKQQDFVNWLLEQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[H18K; A28E],

[1657] VGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3V;H18K],

[1658] AibGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3Aib; H18K]

[1659] PGTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3P; H18K],

[1660] VETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3V; G4E; H18K],

[1661] AibETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3Aib; G4E; H18K]

[1662] GETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3G; G4E; H18K],

[1663] PETFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3P;G4E;H18K],

[1664] DTTFISDYSIAMDKIKQQDFVNWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3D; G4T; H18K],

[1665] GETFISDYAIALDKIKQQDFVEWLLAQGPSSGAPPPS-C16-diacid / 18K;SEQ ID NO:(GIP(3-30)+Cex(31-39)[E3G;G4E;S11A;M14L;H18K;N24E;K30G],

[1666] GETFISTYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K;SEQ ID NO:GIP(3-30)+Cex(31-39)[E3G;G4E;D9T;M14L;H18K;N24E],

[1667] EGTFISTYKIALDKIHQQDFVEWLLAQKPSSGAPPPS-yGlu-C16-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[D9T; S11K; M14L; N24E], GETFISDYAIALDKIKQQDFVEWLLAQG(NH2)PSSGAPPPS-C16-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[E3G; G4E; S11A; M14L; H18K; N24E; K30G],

[1668] EGTFISDYSIAibMDKIKQQDFVEWLLAQKPSSGAPPPS-C16-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; H18K; N24E], EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-C16-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14L; H18K; N24E],

[1669] EGTFISDYSIAibLDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14L; H18K; N24E],

[1670] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14Nle; H18K; N24E],

[1671] EGTFISDYSIAibNleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-dioic acid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[A13Aib; M14Nle; H18K; N24E],

[1672] EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L; H18K; N24E], EGTFISDYSIALDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGlu-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14L; H18K; N24E],

[1673] EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K;N24E], EGTFISDYSIANleDKIKQQDFVEWLLAQKPSSGAPPPS-2xAEEAc+yGl u-C18-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14Nle;H18K;N24E],

[1674] EGTFISDYSIAKDKIKQQDFVEWLLAQKPSSGAPPPS-C16-diacid / 18K; SEQ ID NO: GIP(3-30)+Cex(31-39)[M14K; H18K; N24E], EGTFISDYSIANleDKIKQQDFVNWLLAGGPSSGAPPPS-C16-diacid / 18K; SEQ ID ...

Claims

1. A glucose-dependent insulinotropic peptide (GIP) analogue It consists of the amino acid sequence SEQ ID NO:XX: Where X1 and X2 are either any amino acids or are omitted; Or functional variants thereof, wherein the variants have 1 to 8 individual amino acid substitutions at any amino acid in SEQ ID NO:XX. The peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX or the functional variant, wherein Z is a peptide containing one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of sarcophagus exopeptide-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E).

2. A glucose-dependent insulinotropic peptide (GIP) analogue It consists of the amino acid sequence SEQ ID NO:XX: Where X1 and X2 are either any amino acids or are omitted; Or functional variants thereof, wherein the variants have 1 to 4 individual amino acid substitutions at any amino acid in SEQ ID NO:XX. The peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX or the functional variant, wherein Z is a peptide containing one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of sarcophagus exopeptide-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E).

3. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog is a GIPR antagonist.

4. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog inhibits at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100% of GIPR activity.

5. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog inhibits at least 80%, such as at least 85%, such as at least 90%, such as at least 95%, such as about 100% of GIPR activity, wherein the inhibition of GIPR activity is determined to be a decrease in intracellular cAMP.

6. The GIP peptide analog according to any one of the preceding claims, wherein the GIP peptide analog has GIPR antagonistic potency corresponding to an IC50 value of 50 nM or less.

7. The GIP peptide analog according to any one of the preceding claims, wherein: The fifth amino acid is T or is omitted; The amino acid at position 9 is selected from D, E, and T; The 11th amino acid is selected from S, K, and A; The amino acid at position 12 is selected from I, K, and 2-aminoisobutyric acid (Aib); The amino acid at position 13 is selected from A and Aib; The amino acid at position 14 is selected from M, K, E, S, L, and Nle; The amino acid at position 15 is selected from D and E; The amino acid at position 16 is selected from K and R; The amino acid at position 17 is selected from I and K; The amino acid at position 18 is selected from H and K; The 20th amino acid is selected from Q and K; The amino acid at position 21 is selected from D and E; The amino acid at position 24 is selected from N, K, Q, and E; The amino acid at position 28 is selected from A and E; The amino acid at position 29 is selected from Q and G; and / or The 30th amino acid is selected from K, R, G, and A.

8. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has a single amino acid substitution at any amino acid residue of SEQ IDNO:XX, such as two single amino acid substitutions, such as three single amino acid substitutions, such as four single amino acid substitutions.

9. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has 1 to 2 individual amino acid substitutions at any amino acid residue of SEQ IDNO:XX, 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.

10. The GIP peptide analog according to any one of the preceding claims, wherein the functional variant has one single amino acid substitution, such as two single amino acid substitutions, such as three single amino acid substitutions, such as four single amino acid substitutions, at any amino acid residue of SEQ IDNO:XX, wherein the substitution is a conserved amino acid substitution.

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