Dual peptide agonist of GIPR and GLP-2R

Abstract

The present invention relates to peptide dual agonists or co-agonists of GIPR (glucose-dependent insulinotropic polypeptide receptor) and GLP-2R (glucagon-like peptide-2 receptor) and their use for the treatment of bone disorders such as osteoporosis.

Description

[Technical field]

[0001] The present invention relates to peptide dual agonists or co-agonists of GIPR (glucose-dependent insulinotropic polypeptide receptor) and GLP-2R (glucagon-like peptide-2 receptor) and their use for the treatment of bone disorders such as osteoporosis. [Background technology]

[0002] Gastrointestinal peptides and adipokines are important signaling molecules involved in the control of whole-body energy homeostasis. These circulating hormones regulate various biological responses such as hunger, satiety, and glucose uptake. In vivo experiments have demonstrated that these hormones also regulate bone metabolism, while associations between these hormones and bone mass have been observed in human clinical studies.

[0003] Incretins are gastrointestinal hormones that help regulate carbohydrate metabolism in response to food intake. The two major incretins are glucose-dependent insulinotropic polypeptide (GIP) and glucagon-like peptide-1 (GLP-1), both of which are secreted by intestinal epithelial cells. Intestinal glucagon-like peptide-2 (GLP-2) is co-secreted with GLP-1 upon nutrient intake.

[0004] Gastrointestinal hormones released after meal intake, such as GIP and GLP-2, have been shown to regulate bone turnover: GIP has a positive effect on bone, and GLP-2 regulates bone homeostasis and has a positive contribution to bone mass.

[0005] Osteoporosis can be defined as a combination of reduced bone mass and altered bone quality, resulting in reduced bone strength and increased risk of fracture. Gastrointestinal hormones, including GIP and GLP-2, are involved in bone metabolism and as potential therapeutics for treating osteoporosis, respectively.

[0006] Although WO2018 / 069442 and WO2020 / 169792 both disclose dual peptide agonists of GIPR and GLP-2R, it is desirable that peptide agonists with higher potency for GIPR and GLP-2R be developed for clinical use. Summary of the Invention

[0007] Dual agonists are provided herein that combine the properties of GIP and GLP-2 receptor (GIPR and GLP-2R) agonists. The inventors have designed the peptide dual agonists provided herein to selectively target GIPR and GLP-2R by not targeting GLP-1R or targeting GLP-1R to a lesser extent as a result of the presence of fatty acids at the indicated positions. The peptide dual agonists disclosed herein may also have higher potency compared to previously known peptide dual agonists of GIPR and GLP-2R as a result of specific amino acid substitutions. Furthermore, the dual GIPR and GLP-2R agonists of the present invention have reduced ability to recruit β-arrestin to GIPR compared to natural GIP and GLP-2, and previously known dual agonist peptides, and fatty acid positioning as a result of specific amino acid substitutions, and induce less GIPR internalization compared to human GIP. This may result in prolonged activation of GIPR and thus a sustained effect.

[0008] The role of GLP-1R in bone is unclear. On the other hand, its role in obesity / diabetes is clear. Therefore, when used for bone-related indications, it is better to avoid potential side effects / unwanted effects by removing GLP-1R agonism, especially in patients with, for example, unnecessary or unfavorable glucose control. However, it has been difficult to reduce or remove GLP-1R agonism without affecting the potency on GIPR and GLP-2R.

[0009] One aspect of the present disclosure is a method for the preparation of a compound of the sequence HX2X3GX5FX7X8X9X 10 X11 X 12 X 13 X 14 X 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (sequence number 68) wherein X2 is Aib, X3 is D, K, or E; X5 is T, K, or S; X7 is K or I; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S, K, or N, X 12 is K or T, X 13 is A, Aib, K, or I; X 14 is L or K, X 15 is K, D, or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T, K, or omitted, X 33 is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); The peptide is modified by attaching at least one fatty acid molecule to the N-terminus of SEQ ID NO:66 and / or to one or more lysine residues at any one of positions 1 to 15, and the peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor); The present invention relates to a peptide dual agonist comprising or consisting of said sequence.

[0010] Another aspect of the present disclosure relates to a peptide dual agonist according to any one of the preceding claims for use as a medicament.

[0011] Further aspects of the present disclosure relate to a peptide dual agonist as described in any of the preceding for use in a method of inhibiting bone resorption and / or stimulating bone formation, and / or for use in a method of treating a bone disorder, and / or for use in a method of treating osteoporosis in an individual suffering from Duchenne muscular dystrophy (DMD) or cerebral palsy. [Brief description of the drawings]

[0012] [Figure 1] β-arrestin2 recruitment and receptor internalization of two selected dual GIPR / GLP-2R compounds of the invention. (A) Human GIPR was transiently expressed in HEK293 cells and assessed for β-arrestin2 recruitment, and (B) N-terminally SNAP-tagged human GIPR was transiently expressed in HEK293A cells and assessed for internalization after stimulation with two selected peptide dual agonists. Data are shown as mean ± SEM. For β-arrestin2 recruitment, data are n=3 independent experiments performed in duplicate. [Figure 2A] Time-dependent changes in the bone turnover marker CTX (resorption) following SC injection of Compound #11 or vehicle presented as individual percentages of the baseline sample taken at 10 am. P value=0.4. All data presented as mean±SEM. n=4. [Figure 2B]Time-dependent changes in bone turnover marker P1NP (formation) following SC injection of Compound #11 or vehicle presented as individual percentages of baseline samples taken at 10 am. P value=0.4. All data presented as mean±SEM. n=4. [Figure 2C] Area under the curve (AUC) of CTX calculated using y=70% (nadir) as baseline and individual percentages of baseline. P value=0.4. All data presented as mean±SEM. n=4. [Figure 2D] Area under the curve for P1NP calculated using y=0% as baseline and individual percentages of baseline. P value=0.4. All data presented as mean±SEM. n=4. [Diagram 3] Human GIPR expression after ligand incubation. Human GIPR was transiently expressed in COS-7 cells and pre-incubated with human GIP or two selected peptide dual agonist compounds. The receptor present on the cell surface was then labeled with 125I-GIP. Data are shown as mean ± SD from n=1 experiment performed in duplicate. DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

[0013] definition The term "affinity" refers to the strength of binding between a ligand and its receptor.

[0014] The term "agonist" in the present context refers to a peptide, as defined herein, that is capable of binding to and activating a receptor.

[0015] The term "dual agonist" or "co-agonist" refers to a peptide as defined herein that can bind and activate at least two receptors, where the at least two receptors are different receptors. In this context, a dual agonist is an agonist of GIPR and an agonist of GLP-2R. A dual agonist as defined herein may also have agonist activity on additional receptors, so that a dual agonist is at least an agonist of GIPR and GLP-2R.

[0016] An "amino acid residue" may be a natural or unnatural amino acid residue linked by a peptide bond or a bond other than a peptide bond. The amino acid residue may be in the D or L configuration. An amino acid residue comprises an amino terminal portion (NH2) and a carboxy terminal portion (COOH) separated by a central portion comprising a carbon atom or a chain of carbon atoms, at least one of which comprises at least one side chain or comprises a functional group. NH2 refers to the amino group present at the amino terminus of an amino acid or peptide, and COOH refers to the carboxy group present at the carboxy terminus of an amino acid or peptide. The collective term amino acid includes both natural and unnatural amino acids. Naturally occurring amino acids, as listed in J. Biol. Chem., 243:3552-59 (1969) and as adopted in 37 CFR, section 1.822(b)(2), are of the following groups of amino acids listed herein: Y, G, F, M, A, S, I, L, T, V, P, K, H, Q, E, W, R, D, N, and C. Non-naturally occurring amino acids are those not listed immediately above. Non-naturally occurring amino acid residues also include, but are not limited to, modified amino acid residues, L-amino acid residues, and stereoisomers of D-amino acid residues.

[0017] An "equivalent amino acid residue" refers to an amino acid residue that can replace another amino acid residue in a polypeptide without substantially changing the structure and / or functionality of the polypeptide. Thus, equivalent amino acids have similar properties, such as side chain bulkiness, side chain polarity (polar or non-polar), hydrophobicity (hydrophobic or hydrophilic), pH (acidic, neutral or basic), and side chain organization of carbon molecules (aromatic / aliphatic). Thus, an "equivalent amino acid residue" can be considered a "conservative amino acid substitution."

[0018] Within the meaning of the term "equivalent amino acid substitution" as applied herein, in one embodiment, one amino acid may be substituted with another amino acid within the group of amino acids set forth herein below: Amino acids with polar side chains (Asp, Glu, Lys, Arg, His, Asn, Gln, Ser, Thr, Pro, and Cys); amino acids with nonpolar side chains (Gly, Ala, Val, Leu, Ile, Phe, Trp, Tyr, and Met); amino acids with aliphatic side chains (Gly, Ala, Val, Leu, Ile); amino acids with cyclic side chains (Trp, His, Pro); amino acids with aromatic side chains (Phe, Tyr, Trp); acidic, e.g., negatively charged amino acids with side chains (Asp, Glu); amino acids with basic, e.g. positively charged, side chains (Lys, Arg, His); amino acids with amide side chains (Asn, Gln); amino acids with hydroxy side chains (Ser, Thr); amino acids with sulfur-containing side chains (Cys, Met); neutral and slightly hydrophobic amino acids (Pro, Ala, Gly, Ser, Thr); hydrophilic acidic amino acids (Gln, Asn, Glu, Asp); and hydrophobic amino acids (Leu, Ile, Val).

[0019] Where L- or D-form (optical isomer) is not specified, it is understood that the amino acid in question has the naturally occurring L-form (see, e.g., Pure & Appl. Chem. Vol. (56(5) pp 595-624 (1984)) or D-form, and that the peptide formed may be composed of L-, D-, or mixed L- and D-form sequences of amino acids.

[0020] A "functional variant" of a peptide is a peptide that is capable of performing essentially the same function as the peptide of which it is a functional variant. In particular, a functional variant is capable of binding to the same molecule, preferably with the same affinity, as the peptide of which it is a functional variant.

[0021] A "bioactive agent" (i.e., a biologically active substance / drug) is any agent, drug, compound, composition, or mixture of substances that provides some pharmacological effect, often a beneficial effect, that can be demonstrated in vivo or in vitro. It refers to peptide sequences as defined herein, compounds or compositions that contain them, and nucleic acid constructs that encode the peptides. As used herein, the term further includes any physiologically or pharmacologically active substance that produces a local or systemic effect in an individual. As used herein, "bioactive agent" collectively refers to peptides, nucleic acid constructs that encode the peptides, and compositions that contain the peptides.

[0022] As used herein, the terms "drug" and "medicine" include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body.

[0023] 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. This term is intended to include the full range of treatments, such as the administration of a peptide or composition for a given condition from which a patient suffers, with the aim of alleviating or relieving symptoms or complications, slowing the progression of a condition, partially arresting clinical symptoms, disease or disorder, curing or eliminating a condition, disease or disorder, improving or alleviating a condition or symptom, whether detectable or undetectable, and remission (whether partial or total), and / or preventing or reducing the risk of contracting a condition, disease or disorder, and refers equally to curative therapy, prophylactic or preventative therapy, and ameliorative or palliative therapy, and "preventing" or "prevention" is understood to refer to the management and care of a patient for the purpose of preventing the onset of a condition, disease or disorder, and includes the administration of an active compound to prevent or reduce the risk of developing a condition or complication. The term "amelioration" and variations thereof, as used herein, means that the severity and / or undesirable symptoms of a physiological condition or symptom are reduced and / or the time of progression is slowed or prolonged as compared to when a composition of the invention is not administered.

[0024] The term "individual" refers to a vertebrate, a particular member of a mammalian species, preferably a primate, including a human. As used herein, "subject" and "individual" may be used interchangeably. However, treatment of animals such as mice, rats, dogs, cats, cows, horses, sheep and pigs is also within the scope of the invention.

[0025] "Individual in need thereof" refers to an individual who may benefit from treatment. In one embodiment, the individual in need thereof is an individual who has a disease, which may be a bone disorder.

[0026] A "therapeutic effect" or "therapeutic effect" is manifested when there is a change in the condition being treated, as measured by the criteria constituting the definition of the terms "treating" and "treatment". There is a "change" in the condition being treated when there is at least a 5% improvement, preferably a 10% improvement, more preferably at least a 25%, even more preferably at least a 50%, such as at least a 75% improvement, and most preferably at least a 100% improvement. This change may be based on an improvement in the severity of the treated condition in individuals with and without treatment with a bioactive agent, or with a bioactive agent in combination with a pharmaceutical composition of the invention, or on the difference in the frequency of the improved condition in a population of individuals.

[0027] Treatment according to the invention may be prophylactic, ameliorative and / or curative.

[0028] A "pharmacologically effective amount," "pharmacologically effective amount," or "physiologically effective amount" of a "bioactive agent" is the amount of bioactive agent present in a pharmaceutical composition described herein that is necessary to provide a desired level of active agent in the bloodstream or at the site of action (e.g., lungs, gastric system, colorectal system, prostate, etc.) of a treated individual so as to give the expected physiological response when such composition is administered.

[0029] As used herein, "co-administering" or "co-administration" refers to the administration of one or more agonists with the state-of-the-art pharmaceutical composition. The at least two components can be administered separately, sequentially, or simultaneously.

[0030] As used herein, "N-terminal region" refers to amino acid residues 1-15 of the peptide dual agonists of the present disclosure.

[0031] GIP refers to glucose-dependent insulinotropic polypeptide, also known as gastric inhibitory peptide (or polypeptide). As used herein, the abbreviation hGIP is human GIP (Uniprot Accession No. P09681). GIP is derived from a 153 amino acid proprotein and circulates as a biologically active 42 amino acid peptide (positions 52-93). GIP is synthesized by K cells in the duodenal and jejunal mucosa of the gastrointestinal tract.

[0032] Under physiological conditions, GIP, a 42-amino acid hormone, is degraded by the enzyme dipeptidyl peptidase 4 (DPP-4), which cleaves the GIP molecule at position 3 to give GIP3-42. GIP1-30 is generated as a result of post-translational processing. When GIP1-30 is secreted into the human circulation, DPP-4-catalyzed cleavage leads to GIP3-30.

[0033] The sequence of hGIP is YAEGTFISDYSIAMDKIHQQDFVNWLLAQKGKKNDWKHNITQ (sequence number 56).

[0034] GIPR (or GIP receptor) refers to glucose-dependent insulinotropic polypeptide receptor(s). These seven-transmembrane proteins are found at least on the beta cells of the pancreas. As used herein, the abbreviation hGIPR is human GIPR (Uniprot accession number P48546).

[0035] Several physiological effects of GIP have been identified. GIP is secreted from enteroendocrine K cells after nutrient ingestion and induces insulin secretion. More insulin is secreted when glucose is administered orally than intravenously. GIP is also thought to have a profound effect on fatty acid metabolism via stimulation of lipoprotein lipase activity in adipocytes. GIP has recently been noted as a key player in bone remodeling, and deficiency of the GIP receptor has been associated with a dramatic reduction in bone quality and subsequent increased risk of fracture.

[0036] Glucagon-like peptide-2 (GLP-2) is a 33 amino acid peptide in humans that is created by specific post-translational proteolytic cleavage of proglucagon in a process that also liberates the related glucagon-like peptide-1 (GLP-1) and glucagon itself. GLP-2 is produced by enteroendocrine L-cells and by various neurons in the central nervous system. Intestinal GLP-2 is co-secreted with GLP-1 upon nutrient ingestion. When administered exogenously, GLP-2 provides many effects in humans and rodents, including intestinal growth, enhanced intestinal function, reduced bone degradation, and neuroprotection. GLP-2 and related analogs have potential as treatments for short bowel syndrome, Crohn's disease, osteoporosis, and as adjunctive therapy during cancer chemotherapy.

[0037] The sequence of hGLP-2 is HADGSFSDEMNTILDNLAARDFINWLIQTKITD (sequence number 57).

[0038] GLP-2 receptor (GLP-2R) is a member of the G protein-coupled receptor superfamily. GLP-2R is expressed in the intestine and is closely related to glucagon receptor (GCGR) and receptor for GLP-1 (GLP-1R). As used herein, the abbreviation hGLP-2R is human GLP-2R (e.g., Uniprot accession number O95838). As used herein, the abbreviation hGLP-2 is human GLP-2 (no Uniprot accession number). As used herein, the abbreviation hGLP-1R is human GLP-1R (GLP-1 receptor) (e.g., Uniprot accession number P43220).

[0039] GIPR and GLP-2R dual peptide agonist The present inventors have designed novel GIP and GLP-2 peptide analogs, in which the peptides are agonists of GIPR and GLP-2R, i.e., dual agonists of GIPR and GLP-2R. By dual agonists of GIPR and GLP-2R, we mean that the peptides bind to and / or activate at least GIPR and GLP-2R, which may make them useful in a variety of therapeutic applications.

[0040] These peptides are designed by combining amino acids / stretches of amino acids derived from GIP peptide (SEQ ID NO:56) and GLP-2 peptide (SEQ ID NO:57). These amino acids are preferably involved in one or more of receptor binding, receptor affinity, receptor activity, and / or are otherwise related to the agonist activity of the peptide. In some embodiments, the peptides are designed to include amino acid residues that are not derived from either GIP peptide (SEQ ID NO:56) or GLP-2 peptide (SEQ ID NO:57), but may make the peptides of the present disclosure more stable and / or more potent and / or more selective compared to a peptide dual agonist that includes residues derived only from GIP peptide (SEQ ID NO:56) and GLP-2 peptide (SEQ ID NO:57).

[0041] array HX2X3GX5FX7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (SEQ ID NO:66) wherein X2 is A, K, or Aib; X3 is D, K, or E; X5 is T, K, or S; X7 is K or I; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S, K, or N, X 12 is K or T, X 13 is A, Aib, K, or I; X 14 is L or K, X 15 is K, D, or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T, K, or omitted, X 33 is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of SEQ ID NO:66; The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor). It is an embodiment to provide a peptide dual agonist comprising or consisting of said sequence.

[0042] array HX2X3GX5FX7X8X9X 10 X11 X 12 X 13 X 14 X 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (sequence number 68) wherein X2 is Aib, X3 is D, K, or E; X5 is T, K, or S; X7 is K or I; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S, K, or N, X 12 is K or T, X 13 is A, Aib, K, or I; X 14 is L or K, X 15 is K, D, or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T, K, or omitted, X 33 is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); the peptide is modified by attachment of at least one fatty acid molecule to the N-terminus of SEQ ID NO:68 and / or to one or more lysine residues at any one of positions 1-15; The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor). It is an embodiment to provide a peptide dual agonist comprising or consisting of said sequence.

[0043] In one embodiment, the peptide dual agonist of the present disclosure comprises: HX2X3GX5FIX8X9X 10 X 11 X 12 X 13 LX 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (SEQ ID NO: 69), During the ceremony, X2 is Aib, X3 is D or E; X5 is T, K, or S; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S or K, X 12 is K or T, X 13 is Aib or I, X 15 is D or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T or omitted, X 33 is K, G, D or omitted.

[0044] The numbering in SEQ ID NOs: 66, 67, 68, and 69 corresponds to the numbering of the amino acid residues in the sequences. For example, H is the 1st residue in SEQ ID NOs: 66 and 67, X2 is the 2nd residue, X3 is the 3rd residue, G is the 4th residue, X5 is the 5th residue, F is the 6th residue, X7 is the 7th residue, X8 is the 8th residue, X9 is the 9th residue, and X 10 is the 10th residue, and X 11 is the residue at position 11, and X 12 is the residue at position 12, and X 13 is the residue at position 13, and X 14 is the 14th residue, and X 15 is the 15th residue, and X 16 is the residue at position 16, L is the residue at position 17, A is the residue at position 18, A is the residue at position 19, and X 20 is the residue at position 20, D is the residue at position 21, F is the residue at position 22, I is the residue at position 23, and X 24 is the residue at position 24, W is the residue at position 25, L is the residue at position 26, I is the residue at position 27, and X 28 is the residue at position 28, T is the residue at position 29, K is the residue at position 30, and X 31 is the 31st residue, and X 32 is the residue at position 32, and X 33 is the residue at position 33.

[0045] Similarly, Z is a peptide numbered as the sequence of residues 1 to 33, and thus one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58) are numbered, for example, such that N is at position 34, D is at position 35, W is at position 36, K is at position 37, H is at position 38, N is at position 39, I is at position 40, T is at position 41, and Q is at position 42.

[0046] However, in one embodiment, Z may consist of only one amino acid residue, in which case the amino acid residue is at position 34, even if the amino acid residue is not, for example, N. For example, in one embodiment, Z consists of only one K, in which case the K is at position 34.

[0047] In one embodiment, the disclosure relates to a peptide dual agonist of GIPR and GLP-2R comprising the amino acid sequence SEQ ID NO: 66, 67, 68, or 69, or a functional variant or functional fragment thereof.

[0048] SEQ ID NO:66 also H(A / K / Aib)(D / K / E)G(T / K / S)F(K / I)(K / S)(D / K)(Y / K)(S / K / N)(K / T)(A / Aib / I / K)(L / K)(K / D / E)(E / L / Aib / K / A / N)LAA(R / K)DFI(N / E)WLI(Q / E / A)TK(I / G / omitted)(T / G / omitted)(K / G / D / omitted)-Z, or may be a functional variant thereof, or a functional fragment thereof.

[0049] The peptide dual agonist is an agonist of GIPR and an agonist of GLP-2R, meaning that the peptide dual agonist is an agonist of GIPR and an agonist of GLP-2R. This does not exclude that the peptide dual agonist can bind to and / or activate additional receptors. However, the peptide dual agonist of the present disclosure is designed to selectively activate GIPR and GLP-2R, in particular to activate GLP-1R little or not at all.

[0050] Indeed, the inventors have found that attachment of a fatty acid to the N-terminal region of a peptide dual agonist of the present disclosure, e.g., any of amino acid residues 1-15 of peptides of SEQ ID NO:66, 67, 68, or 69, results in the peptide having little or no ability to bind to and / or activate GLP-1R.

[0051] As used throughout this specification references to GIPR, GLP-2R, and GLP-1R may be replaced with hGIPR, hGLP-2R, and hGLP-1R.

[0052] In one embodiment, the peptide dual agonist comprises: a Amino acids derived from hGLP-2 (SEQ ID NO: 57) and / or hGIP (SEQ ID NO: 56) at the N-terminus; b. A central / N-terminal stretch of amino acids derived primarily from hGIP (SEQ ID NO:56); c. a central / C-terminal stretch of amino acids derived primarily from hGLP-2 (SEQ ID NO:57), and d. Optionally, amino acids primarily derived from hGIP (SEQ ID NO:56) at the C-terminus.

[0053] In one embodiment, amino acids 12-20 or 12-30 are derived primarily from hGLP-2 (SEQ ID NO:57).

[0054] In one embodiment, amino acids 5-11 or 7-11 are predominantly derived from hGIP (SEQ ID NO:56).

[0055] In one embodiment, when an amino acid is defined as "predominantly derived from", this means that at least 50% of the amino acids are derived from the peptide, such as at least 55%, such as at least 60%, such as at least 65%, such as 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 100% are derived from the peptide (i.e. from hGIP or from hGLP-2).

[0056] In one embodiment, when an amino acid is defined as "predominantly derived from", this means that 50-55% of the amino acids are derived from the peptide, for example, 55-60%, for example, 60-65%, for example, 65-70%, for example, 70-75%, for example, 75-80%, for example, 80-85%, for example, 85-90%, for example, 90-95%, for example, 95-100% are derived from the peptide (i.e., derived from hGIP or hGLP-2).

[0057] When an amino acid is derived from hGIP or hGLP-2, this means that the amino acid at a certain position of the peptide dual agonist corresponds to the amino acid at the same position of hGIP or hGLP-2.For example, when the amino acid at position 1 is derived from GIP, this means that the amino acid is "Y".When the amino acid at position 1 is derived from GLP-2, this means that the amino acid is "H".

[0058] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of 20-43 contiguous amino acids, such as 20-22 amino acids, for example, 22-24 amino acids, for example, 24-26 amino acids, for example, 26-28 amino acids, for example, 28-30 amino acids, for example, 30-32 amino acids, for example, 32-34 amino acids, for example, 34-36 amino acids, for example, 36-38 amino acids, for example, 38-40 amino acids, for example, 40-42, for example, 38-43 contiguous amino acids as defined herein.

[0059] In one embodiment, a peptide dual agonist of the disclosure comprises or consists of 20 to 43 contiguous amino acids, e.g., 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, or 43 contiguous amino acids.

[0060] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of 20-33 consecutive amino acids, such as 20-21, for example 21-22, such as 22-23, for example 23-24, such as 24-25, for example 25-26, such as 26-27, for example 27-28, such as 28-29, for example 29-30, such as 30-31, for example 31-32, such as 32-33, for example 33-34, such as 34-35, for example 35-36, such as 36-37, for example 37-38, such as 38-39, for example 39-40, such as 40-41, for example 41-42, such as 42-43 consecutive amino acids.

[0061] In one embodiment, a peptide dual agonist of the present disclosure comprises or consists of 30 contiguous amino acids.

[0062] In one embodiment, a peptide dual agonist of the present disclosure comprises or consists of 32 contiguous amino acids.

[0063] In one embodiment, a peptide dual agonist of the present disclosure comprises or consists of 33 contiguous amino acids.

[0064] Preferably, in one embodiment, the peptide dual agonists of the present disclosure comprise or consist of at least 33 contiguous amino acids, although shorter peptide sequences may also be used.

[0065] In one embodiment, a peptide dual agonist of the present disclosure comprises or consists of 42 contiguous amino acids.

[0066] In one embodiment, a peptide dual agonist of the present disclosure comprises or consists of 43 contiguous amino acids.

[0067] In one embodiment, a peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule to any one of positions 2-15 of SEQ ID NO:66, 67, 68, or 69.

[0068] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO:66, wherein: X2 is K or Aib; X3 is D or E; X5 is T or K; X7 is I, X 11 is S or K, X 13 is Aib or I, X 15 is D or E, X 16 are E, L, Aib, K, A, and N; X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32is T or omitted.

[0069] It is also an embodiment to provide a peptide dual agonist comprising or consisting of the following sequence: HX2X3GX5FIX8X9X 10 X 11 X 12 X 13 LX 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (SEQ ID NO: 67), During the ceremony, X2 is K or Aib; X3 is D or E; X5 is T, K, or S; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S or K, X 12 is K or T, X 13 is Aib or I, X 15 is D or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T or omitted, X 33 is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of SEQ ID NO:67; The peptide is an agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of the GLP-2R (glucagon-like peptide-2 receptor).

[0070] Thus, in one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence SEQ ID NO:67, which also comprises H(K / Aib)(D / E)G(T / K / S)FI(K / S)(D / K)(Y / K)(S / K)(K / T)(Aib / I)L(D / E)(E / L / Aib / K / A / N)LAA(R / K)DFI(N / E)WLI(Q / E / A)TK(I / G / omitted)(T / omitted)(K / G / D / omitted)-Z, or may be a functional variant thereof, or a functional fragment thereof.

[0071] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence SEQ ID NO:66, 67, 68, or 69, wherein: X3 is D, X7 is I, X 15 is D, X 31 is I, X 32 is T.

[0072] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence SEQ ID NO: 66, 67, 68, or 69, where X2 is 2-aminoisobutyric acid (Aib). Thus, in one embodiment, the alanine at position 2 of hGIP, hGLP-2, or hGLP-1 is replaced with 2-aminoisobutyric acid. The presence of Aib at position 2 protects the dual agonist peptide from DPP-IV cleavage. Furthermore, the presence of Aib at position 2 may also improve potency.

[0073] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, 13 is Aib). Thus, in one embodiment, the alanine at position 13 of hGIP or the isoleucine at position 13 of hGLP-2 is substituted with 2-aminoisobutyric acid. The presence of Aib at position 13 increases potency for at least one of the GIPR and GLP-2R.

[0074] In general, the presence of one or more Aib residues renders the 3D structure of the peptide dual agonists of the disclosure more rigid, which may improve potency and selectivity for GIPR and / or GLP-2R.

[0075] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, 16 is A, Aib, L, E). Thus, in one embodiment, asparagine (N) at position 16 of GLP-2 is substituted with either A, Aib, L or E. Substitution of N with either A, Aib, L or E has been found to improve the physical stability of the peptide dual agonists of the present disclosure.

[0076] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69,20 is K).

[0077] In one embodiment, a peptide dual agonist of the disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, in which one or more asparagine (N) and / or glutamine (Q) residues of hGIP and / or hGLP-2 are substituted, e.g., any one of residues N16 of hGLP-2, N24 of hGIP and hGLP-2, and Q28 of GLP-2 are substituted. These residues may be substituted, e.g., with A, Aib, L, E or K, e.g., E, A or K, e.g., E or A.

[0078] Thus, in one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where X2 is Aib and X 13 is Aib).

[0079] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where X2 is Aib and X 11 is K).

[0080] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where X2 is Aib, X5 is K, and X 13 is Aib).

[0081] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where X2 is Aib and X 11 is K and X 13 is Aib).

[0082] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where X2 is Aib and X 11 is K and X 24 is E).

[0083] In one embodiment, X 31 X 32 X 33 is selected from the group consisting of ITD, GKK, GTD, IKD, and ITK. 31 X 32 X 33 is an ITD. In one embodiment, X 31 X 32 X 33 is GKK.

[0084] In one embodiment, a peptide dual agonist of the disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where Z is selected from the group consisting of ND, NDW, KDW, NDW, NDK, NDWK, NDWKH, NDWKHN, NDWKHNI, NDWKHNIT, NDWKHNITQ, and AEWKHAITQ or a variant containing one amino acid substitution.

[0085] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69 (wherein Z is a short amino acid sequence, e.g., Z is K).

[0086] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence of SEQ ID NO: 66, 67, 68, or 69, where Z is a long amino acid sequence, e.g., Z is AEWKHAITQ (SEQ ID NO: 65) and NDWKHNITQ (SEQ ID NO: 64).

[0087] In one embodiment, the peptide dual agonist of the present disclosure comprises: Compound No. 9, SEQ ID NO: 8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, Compound No. 10, SEQ ID NO: 9 H-Aib-DGTFKSDYSTILDNLAARDFINWLIQTKITK, Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTILKNLAARDFINWLIQTKITK, Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKGKKNDWKHNITQ, Compound No. 24, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 25, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 26, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, Compound No. 27, SEQ ID NO: 22 H-Aib-EGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 28, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITD, Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK, Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDYKTILDNLAARDFINWLIETKITK, Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDYKTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, Compound No. 1, SEQ ID NO: 1 HADGTFISDYSTILDNLAARDFINWLIQTKITD, Compound No. 2, SEQ ID NO: 2 HADGTFISDYSTILDNLAARDFINWLIQTKIT, Compound number 45, SEQ ID NO: 38 HADGTFISDYSTILDNLAAKDFINWLIQTKITK, Compound No. 3, SEQ ID NO: 3 HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ, Compound No. 46, SEQ ID NO: 39 HADGTFISDYSTILDNLAARDFINWLLAQKITK, Compound No. 4, SEQ ID NO: 1 HADGTFISDYSTILDNLAARDFINWLIQTKITD, Compound No. 5, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 6, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, Compound No. 7, SEQ ID NO: 6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, Compound No. 8, SEQ ID NO: 7 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, Compound No. 15, SEQ ID NO: 14 HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 48, SEQ ID NO: 41 HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ, Compound No. 49, SEQ ID NO: 42 HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ, Compound No. 50, SEQ ID NO: 43 HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ, Compound No. 51, SEQ ID NO: 44 HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ, Compound No. 52, SEQ ID NO: 45 HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ, Compound No. 53, SEQ ID NO: 33 HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 16, SEQ ID NO: 15 HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 17, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 19, SEQ ID NO: 16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 20, SEQ ID NO: 17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, Compound No. 21, SEQ ID NO: 18 H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, Compound No. 22, SEQ ID NO: 19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, Compound No. 23, SEQ ID NO: 20 H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, Compound No. 39, SEQ ID NO: 33 HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 40, SEQ ID NO: 34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 41, SEQ ID NO: 35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, Compound No. 42, SEQ ID NO: 36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, Compound No. 43, SEQ ID NO: 37 H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and Compound No. 44, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, or a functional variant thereof, or a functional fragment thereof, for example, the functional variant comprises one, two or three individual amino acid substitutions compared to any one of the above amino acid sequences.

[0088] In one embodiment, the peptide dual agonist of the present disclosure comprises: SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, SEQ ID NO:10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, SEQ ID NO:13 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, SEQ ID NO:21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:31 H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:44 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, and SEQ ID NO:26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK, or a functional variant thereof, or a functional fragment thereof, for example, the functional variant comprises one, two or three individual amino acid substitutions compared to any one of the above amino acid sequences.

[0089] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: SEQ ID NO:8 H-Aib-DG-KFISDYSTILDNLAARDFINWLIQTKITK, SEQ ID NO:9 H-Aib-DGTF-KSDYSTILDNLAARDFINWLIQTKITK, SEQ ID NO:10 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, SEQ ID NO:12 H-Aib-DGTFISDYSTILKNLAARDFINWLIQTKITK, SEQ ID NO:13 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:21 H-Aib-DG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:22 H-Aib-EG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:23 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:25 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITD, SEQ ID NO:26 H-Aib-DGTFISDY-KTILDKLAARDFIEWLIATKITK, SEQ ID NO:27 H-Aib-DGTFISDY-KTILDNLAARDFINWLIETKITK, SEQ ID NO:28 H-Aib-DGTFISDY-KT-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:24 Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:29 H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, SEQ ID NO:30 Ac-H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, SEQ ID NO:31 H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:32 Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:46 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, SEQ ID NO:7 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, SEQ ID NO:44 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:18 H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, SEQ ID NO:20 H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:37 H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK or a functional variant thereof, wherein the functional variant comprises one to three individual amino acid substitutions, with the proviso that the amino acid residue at position 2 of the functional variant is Aib; the amino acid residue at position 6 of the functional variant is phenylalanine (F); the amino acid residue at position 22 of the functional variant is phenylalanine (F); the amino acid residue at position 25 of the functional variant is tryptophan (W); the amino acid residue at position 26 of the functional variant is leucine (L); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of any one of the above sequences, The peptide is an agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of the GLP-2R (glucagon-like peptide-2 receptor).

[0090] In one aspect, the present disclosure provides a method for producing a method for manufacturing a semiconductor device comprising: SEQ ID NO:1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD SEQ ID NO:2 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKIT SEQ ID NO:38 (C16)HADGTFISDYSTILDNLAAKDFINWLIQTKITK SEQ ID NO:3 (C10)HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ SEQ ID NO:39 (C16)HADGTFISDYSTILDNLAARDFINWLLAQKITK SEQ ID NO:1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD SEQ ID NO:4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH SEQ ID NO:6 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK-OH SEQ ID NO:7 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT-OH SEQ ID NO:14 (C16)HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ SEQ ID NO:41 (C16)HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ SEQ ID NO:42 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ SEQ ID NO:43 (C16)HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ SEQ ID NO:44 (C16)HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ SEQ ID NO:45 (C16)HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ SEQ ID NO:33 (C16)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ SEQ ID NO:15 (C16)HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ SEQ ID NO:4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH SEQ ID NO:4 (C10-Diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH SEQ ID NO:16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH SEQ ID NO:17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH SEQ ID NO:18 (C16-Diacid)H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK-OH SEQ ID NO:19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH SEQ ID NO:20 (C16-DIACID)H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK-OH SEQ ID NO:33 (C16-diacid)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ SEQ ID NO:34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH SEQ ID NO:35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH SEQ ID NO:36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH SEQ ID NO:37 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, and SEQ ID NO:4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, or a functional variant thereof, wherein the functional variant comprises one to three individual amino acid substitutions, with the proviso that the amino acid residue at position 2 of the functional variant is Aib; the amino acid residue at position 6 of the functional variant is phenylalanine (F); the amino acid residue at position 22 of the functional variant is phenylalanine (F); the amino acid residue at position 25 of the functional variant is tryptophan (W); the amino acid residue at position 26 of the functional variant is leucine (L); The peptide is modified by attaching at least one fatty acid molecule to position 1 of any one of the described amino acid sequences, The peptide is an agonist of the GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of the GLP-2R (glucagon-like peptide-2 receptor).

[0091] In one embodiment, the peptide dual agonists of the present disclosure are C-terminally amidated (-NH2).

[0092] In one embodiment of the peptide dual agonists of the present disclosure, the C-terminus of the peptide is a carboxylic acid.

[0093] In one embodiment, the peptide dual agonists of the present disclosure are N-terminally acetylated (COCH3).

[0094] In one embodiment, the peptide dual agonist of the present disclosure is compound number 24 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH (SEQ ID NO: 21), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0095] In one embodiment, the peptide dual agonist of the present disclosure is compound number 25 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH (SEQ ID NO: 21), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0096] In one embodiment, the peptide dual agonist of the present disclosure is compound number 31 H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH (SEQ ID NO: 26), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0097] In one embodiment, the peptide dual agonist of the present disclosure is compound number 33 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH (SEQ ID NO: 28), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0098] In one embodiment, the peptide dual agonist of the present disclosure is compound number 37 H-Aib-DGTFISDY-K(γGlu-16)-T-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH (SEQ ID NO: 31), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0099] In one embodiment, the peptide dual agonist of the present disclosure is Compound No. 40 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH (SEQ ID NO: 34), or a functional variant or fragment thereof, which is particularly potent and selective for GIPR and GLP-1R.

[0100] A peptide comprising or consisting of a sequence means that the peptide may comprise, consist of, or at least contain the complete sequence. A peptide comprising a peptide sequence, such as the sequence H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ (SEQ ID NO: 34), means that the peptide contains all of the peptide sequence H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ (SEQ ID NO: 34). However, this does not exclude the presence of additional components or amino acids.

[0101] In one embodiment, a functional variant of a peptide dual agonist has at least 60% sequence identity, such as at least 70% sequence identity, such as at least 75% sequence identity, for example, at least 80% sequence identity, such as at least 85% sequence identity, for example, at least 90% sequence identity, such as at least 95% sequence identity, for example, at least 97% sequence identity to the peptide dual agonist.

[0102] In one embodiment, a functional variant of a peptide dual agonist has 60-65% sequence identity, such as 65-70% sequence identity, such as 70-75% sequence identity, such as 75-80% sequence identity, such as 80-85% sequence identity, such as 85-90% sequence identity, such as 90-95% sequence identity, such as 95-99% sequence identity, such as 99-100% sequence identity, to the peptide dual agonist. "Identity" and "sequence identity" may be used interchangeably herein.

[0103] In one embodiment, the functional variant comprises one or more amino acid substitutions, for example, 1 to 8 amino acid substitutions, for example, 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, or 7 to 8 amino acid substitutions.

[0104] In one embodiment, the functional variant comprises one amino acid substitution, two amino acid substitutions, three amino acid substitutions, four amino acid substitutions, or five amino acid substitutions.

[0105] In one embodiment, the amino acid substitutions are conservative amino acid substitutions. In one embodiment, the functional variant comprises one or more conservative amino acid substitutions.

[0106] Conservative substitutions (or synonymous substitutions) are substitutions of amino acids whose side chains have similar biochemical properties and therefore do not affect the function of the peptide.

[0107] Identity between amino acid sequences can be calculated using well-known algorithms such as BLOSUM 30, BLOSUM 40, BLOSUM 45, BLOSUM 50, BLOSUM 55, BLOSUM 60, BLOSUM 62, BLOSUM 65, BLOSUM 70, BLOSUM 75, BLOSUM 80, BLOSUM 85, or BLOSUM 90, or by simple comparison of specific amino acids present in corresponding positions of the two peptide sequences being compared. Homology can be used as a synonym for identity / sequence identity.

[0108] Conservative substitutions can be introduced at any one or more positions of a peptide according to the present disclosure so long as the variant remains functional. However, it may also be desirable to introduce non-conservative substitutions (non-synonymous substitutions) at one or more positions.

[0109] Any amino acid defined herein may be in the L or D configuration. If nothing is specified, reference to the L isomeric form is preferably meant.

[0110] The standard and / or non-standard amino acids can be linked by peptide bonds (to form a linear peptide chain) or by non-peptide bonds (e.g., via the variable side chains of the amino acids). Preferably, the amino acids of the present disclosure are linked by peptide bonds.

[0111] The terms "peptide" and "isolated peptide" may be used interchangeably herein. The terms "variant" and "functional variant" may be used interchangeably herein. The terms "fragment" and "functional fragment" may be used interchangeably herein. When referring to a "peptide" herein, this term includes reference to both the peptide itself and to the peptide for use as defined herein.

[0112] In one embodiment, the peptide is non-naturally occurring.

[0113] In one embodiment, the peptide is synthetic.

[0114] In one embodiment, the peptide is an isolated peptide.

[0115] In one embodiment, the peptide is a labeled peptide, such as a radioactively or fluorescently labeled peptide.

[0116] In another embodiment, variants as defined herein include sequences in which an alkyl amino acid is substituted with an alkyl amino acid, an aromatic amino acid is substituted with an aromatic amino acid, a sulfur-containing amino acid is substituted with a sulfur amino acid, a hydroxy-containing amino acid is substituted with a hydroxy-containing amino acid, an acidic amino acid is substituted with an acidic amino acid, a basic amino acid is substituted with a basic amino acid, and / or a dibasic monocarboxylic acid amino acid is substituted with a dibasic monocarboxylic acid amino acid.

[0117] The term peptide also encompasses post-translational modifications introduced by chemical or enzymatically catalyzed reactions, as is well known in the art, including acetylation, phosphorylation, methylation, glucosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation and sulfation of one or more amino acid residues, as well as proteolytic modifications by lysosomal cathepsins and known proteinases, including calpains, secretases, and matrix metalloproteinases.

[0118] Functional equivalents of peptides may also include chemical modifications such as ubiquitination, labeling (e.g., radionuclides, various enzymes, etc.), pegylation (derivatization with polyethylene glycol), or the insertion (or substitution by chemical synthesis) of an amino acid that does not normally occur in human proteins (non-proteinogenic), such as ornithine.

[0119] Stereo-analogous compounds can be constructed to mimic key portions of peptide structures. This can be accomplished by modeling and chemical design techniques known to those skilled in the art. For example, esterification and other alkylation can be used to modify, for example, the amino terminus of a di-arginine peptide backbone to mimic a tetrapeptide structure. It will be understood that all such sterically similar constructs fall within the scope of the present invention. Peptides with N- and C-terminal alkylation and esterification are also encompassed by the present invention.

[0120] A contiguous or contiguous peptide sequence is a sequence of consecutive amino acids that are linearly linked by peptide bonds. Contiguous amino acid sequence and contiguous amino acid sequence are used interchangeably herein.

[0121] At least one fatty acid molecule attached The peptide dual agonists of the present disclosure are characterized in that they are modified by the attachment of at least one fatty acid molecule at an amino acid residue at any one of positions 1-15 of the disclosed amino acid sequence. Indeed, attachment of a fatty acid at the N-terminal region of the disclosed amino acid sequence, e.g., at any one of positions 1-15 of the disclosed sequence, results in dual peptide agonists of hGIPR and hGLP-2R that have reduced or no ability to activate hGLP-1R and are thus referred to as "selective peptide dual agonists of hGIPR and hGLP-2R."

[0122] In one embodiment, the peptide dual agonists of the present disclosure are modified by attaching at least one fatty acid molecule at position 1 or the N-terminus of the disclosed amino acid sequence.

[0123] In one embodiment, a peptide dual agonist according to the present disclosure comprises or consists of SEQ ID NO:66, 67, 68, or 69, where X7 is I, and the peptide is modified by attaching one fatty acid molecule at position 1 of SEQ ID NO:66, 67, 68 or 69, e.g., at the N-terminus of SEQ ID NO:66, 67, 68 or 69.

[0124] In one embodiment, a fatty acid molecule according to the present disclosure is attached via a linker or spacer to the alpha-amino group of an amino acid residue, wherein the amino acid residue is the N-terminal amino acid residue.

[0125] The peptide dual agonists of the present disclosure are characterized in that they are modified by the attachment of at least one fatty acid molecule at an amino acid residue at any one of positions 2-15 of the disclosed amino acid sequence.

[0126] The peptide dual agonists of the present disclosure are characterized in that they are modified by the attachment of at least one fatty acid molecule at an amino acid residue at any one of positions 2-14 of the disclosed amino acid sequence.

[0127] In one embodiment, a peptide dual agonist of the present disclosure is modified at any one of lysine (K) positions 2-15 of SEQ ID NO:66, 67, 68, or 69 by attachment of at least one fatty acid molecule.

[0128] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 66, 67, 68, or 69, or a variant thereof, as disclosed herein.

[0129] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of SEQ ID NO: 66, 67, 68, or 69, or a variant thereof, as disclosed herein.

[0130] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule at position 2, 3, 4, 5, 6, 7, 8, 9, 10 or 11 of SEQ ID NO: 66, 67, 68, or 69, or a variant thereof, as disclosed herein.

[0131] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule at position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 66, 67, 68, or 69, or a variant thereof, as disclosed herein.

[0132] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule at position 5, 6, 7, 8, 9, 10, 11, or 12 of SEQ ID NO: 66, 67, 68, or 69, or a variant thereof, as disclosed herein.

[0133] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule to any one of positions 5, 7, 8, 11, 12, 15 of SEQ ID NO: 66, 67, 68, or 69, or variants thereof, disclosed herein.

[0134] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule to any one of positions 5, 7, 8, 11 of SEQ ID NO: 66, 67, 68, or 69, or variants thereof, disclosed herein.

[0135] In one embodiment, the peptide dual agonist of the present disclosure is modified by attaching at least one fatty acid molecule to any one of positions 5, 11, 12 of SEQ ID NO: 66, 67, 68, or 69, or variants thereof, disclosed herein.

[0136] It has been found that attachment of fatty acids to the N-terminal region of the disclosed peptides, e.g., at positions 1-15, e.g., the N-terminus, or at positions 5, 11 and / or 12, reduces activation of GLP-1R. Alternatively, attachment of fatty acids to the C-terminal region, e.g., positions 16-43, of peptide dual agonists of GIPR and GLP-2R may result in retention of GLP-1R agonist activity and may also increase potency at GLP-1R.

[0137] In one embodiment, the peptide dual agonist of the present disclosure comprises or consists of the amino acid sequence SEQ ID NO: 66, 67, 68, or 69, wherein X 13 is Aib, and the peptide is modified by attaching at least one fatty acid molecule at any one of positions 5 or 11 of SEQ ID NOs: 66, 67, 68, or 69.

[0138] In one embodiment of the present disclosure, the fatty acid molecule is a straight chain fatty acid.

[0139] In one embodiment of the present disclosure, the fatty acid molecule is a branched fatty acid.

[0140] In one embodiment of the present disclosure, the fatty acid molecule is a monoacyl fatty acid molecule containing one fatty acid.

[0141] In one embodiment of the present disclosure, the fatty acid molecule is a diacyl fatty acid molecule.

[0142] In one embodiment of the disclosure, the fatty acid molecule is CH3(CH2)8CO-(capryl, C10), CH3(CH2) 10 CO-(Lauryl, C12), CH3(CH2) 12CO-(myristoyl, C14), CH3(CH2) 14 CO-(Palmitoyl, C16), CH3(CH2) 16 CO-(Stearyl, C18) and CH3(CH2) 18 CO-(arachidyl, C20).

[0143] In one embodiment of the present disclosure, the fatty acid molecule is HOOC-CH3(CH2)8CO-(decanoyl, C10), 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) 18 CO-(eicosanoyl, C20), and HOOC-CH3(CH2) 19 It contains two acyl groups individually selected from the group consisting of CO-(19-carboxy-nonadecanoyl, C21).

[0144] In one embodiment, the fatty acid molecule is C16 (palmitoyl).

[0145] In one embodiment, the fatty acid molecule is COOH(CH2)8CO-(C10 diacid), COOH(CH2) 10 CO-(C12 diacid), COOH(CH2) 12 CO-(C14 diacid), 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).

[0146] In one embodiment of the disclosure, the fatty acid molecule is attached directly to the amino acid residue, eg, without the presence of a spacer or linker.

[0147] In one embodiment of the present disclosure, the fatty acid molecule is attached to the amino acid residue via a spacer or linker.

[0148] In one embodiment, the spacer is a hydrophilic linker. In one embodiment, the spacer is a non-natural amino acid hydrophilic linker.

[0149] In one embodiment, the spacers are repeats of an individual spacer moiety. In one embodiment, the spacers are repeats of the same spacer moiety. In one embodiment, the spacers are repeats of different spacer moieties.

[0150] In one embodiment, the fatty acid molecule is attached to the amino acid residue via a spacer in such a manner that a carboxyl group of the spacer forms an amide bond with an amino group of the fatty acid molecule.

[0151] In one embodiment, the spacer is one or more amino acids selected from the group consisting of succinic acid, Lys, Glu, and Asp; 4-Abu, y-aminobutyric acid, one or more of γ-aminobutanoyl (γ-aminobutyric acid), γ-glutamyl (γ-glutamic acid), β-asparagyl, β-alanyl, and glycyl, and [γ-Glutamic acid-8-amino-3,6-dioxaoctanoic acid] n (γGlu-AEEAc n ) (wherein n is an integer of 1 to 50, for example, an integer of 1 to 2, 2 to 3, 3 to 4, 4 to 5, 5 to 6, 6 to 7, 7 to 8, 8 to 9, 9 to 10, 10 to 11, 11 to 12, 12 to 13, 13 to 14, 14 to 15, 15 to 20, 20 to 25, 25 to 30, 30 to 35, 35 to 40, 40 to 45, or 45 to 50). The compound comprises one or more moieties individually selected from the group consisting of:

[0152] In one embodiment of the present disclosure, the spacer or linker comprises yGlu.

[0153] In one embodiment of the disclosure, the spacer comprises or consists of yGlu or yGlu-yGlu.

[0154] In some embodiments of the present disclosure, the peptide dual agonists disclosed herein are acylated, which in some embodiments makes them peptide dual selective agonists of GIPR and GLP-2R, but not GLP-1R, and increases half-life and in vivo stability in addition to retaining their agonist potency.

[0155] In one embodiment, the peptide dual agonist of the present disclosure comprises: Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-K(γGlu-C16)-SDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTIL-K(γGlu-C16)-NLAARDFINWLIQTKITK-OH Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2 Compound No. 24, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 25, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 26, SEQ ID NO:8 H-Aib-DG-K(γGlu-γGlu-C10)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 27, SEQ ID NO: 22 H-Aib-EG-K(γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 28, SEQ ID NO: 21 H-Aib-DG-K(γGlu-γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDY-K(γGlu-C10)-T-Aib-LDNLAARDFINWLIQTKITD-OH Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIETKITK-OH Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDY-K(γglu-C10)-T-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ-OH Compound No. 1, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 2, SEQ ID NO: 2 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKIT Compound No. 45, SEQ ID NO: 38 (C16)HADGTFISDYSTILDNLAAKDFINWLIQTKITK Compound No. 3, SEQ ID NO: 3 (C10)HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ Compound No. 46, SEQ ID NO: 39 (C16)HADGTFISDYSTILDNLAARDFINWLLAQKITK Compound No. 4, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 5, SEQ ID NO: 4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 6, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH Compound No. 7, SEQ ID NO: 6 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK-OH Compound No. 8, SEQ ID NO: 7 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT-OH Compound No. 15, SEQ ID NO: 14 (C16)HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ Compound No. 48, SEQ ID NO: 41 (C16)HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ Compound No. 49, SEQ ID NO: 42 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ Compound No. 50, SEQ ID NO: 43 (C16)HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ Compound No. 51, SEQ ID NO: 44 (C16)HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ Compound No. 52, SEQ ID NO: 45 (C16)HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ Compound No. 53, SEQ ID NO: 33 (C16)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 16, SEQ ID NO: 15 (C16)HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ Compound No. 17, SEQ ID NO: 4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 18, SEQ ID NO: 4 (C10-Diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 19, SEQ ID NO: 16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 20, SEQ ID NO: 17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 21, SEQ ID NO: 18 (C16-Diacid)H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK-OH Compound No. 22, SEQ ID NO: 19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH Compound No. 23, SEQ ID NO: 20 (C16-DIACID)H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK-OH Compound No. 39, SEQ ID NO: 33 (C16-diacid)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 40, SEQ ID NO: 34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 41, SEQ ID NO: 35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 42, SEQ ID NO: 36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 43, SEQ ID NO: 37 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 44, SEQ ID NO: 4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, or a variant thereof, wherein said variant comprises one or two individual amino acid substitutions.

[0156] In one embodiment, the peptide dual agonist is SEQ ID NO:4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH, Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH, SEQ ID NO: 10, Compound No. 10 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:11 H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:13 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2, SEQ ID NO:4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:28 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:31 H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, and SEQ ID NO:26 H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH, or a variant thereof, wherein said variant comprises one or two individual amino acid substitutions.

[0157] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 5, SEQ ID NO:4, (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH.

[0158] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 6, SEQ ID NO:5, (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH.

[0159] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 9, SEQ ID NO:8, H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH.

[0160] In one embodiment, the peptide dual agonist comprises or consists of the sequence, SEQ ID NO:10, compound number 11, H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH.

[0161] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound No. 12, SEQ ID NO:11, H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH.

[0162] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound No. 14, SEQ ID NO:13, H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2.

[0163] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound No. 17, SEQ ID NO: 4, (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH.

[0164] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound No. 19, SEQ ID NO:16, (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH.

[0165] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 20, SEQ ID NO:17, (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH.

[0166] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 22, SEQ ID NO:19, (C16-Diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH.

[0167] In one embodiment, the peptide dual agonist comprises or consists of the sequence Compound No. 24, SEQ ID NO:21, H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH. This peptide dual agonist has both good potency and good physical stability.

[0168] In one embodiment, the peptide dual agonist comprises or consists of the sequence Compound No. 25, SEQ ID NO:21, H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH. This peptide dual agonist has both good potency and good physical stability.

[0169] In one embodiment, the peptide dual agonist comprises or consists of the sequence, SEQ ID NO:25, compound number 21, H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH.

[0170] In one embodiment, the peptide dual agonist comprises or consists of the sequence Compound No. 33, SEQ ID NO: 28, H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH. This peptide dual agonist has both good potency and good physical stability.

[0171] In one embodiment, the peptide comprises or consists of the sequence, Compound Number 35, SEQ ID NO:29, H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH.

[0172] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 37, SEQ ID NO:31, H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH.

[0173] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 40, SEQ ID NO:34, (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH.

[0174] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 41, SEQ ID NO:35, (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH.

[0175] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 42, SEQ ID NO:36, (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH.

[0176] In one embodiment, the peptide dual agonist comprises or consists of the sequence, Compound Number 44, SEQ ID NO:4, (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH.

[0177] In one embodiment, the peptide dual agonist comprises or consists of the sequence Compound No. 31, SEQ ID NO: 26, H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH. This peptide dual agonist has both good potency and good physical stability.

[0178] Activity of peptide dual agonists In one embodiment, a functional variant or fragment retains the same biological activity or capability as the native peptide or peptide from which it is derived.

[0179] In one embodiment, peptide dual agonists, including functional variants or fragments thereof, can be one or more of the following: a. binding to GIPR and GLP-2R, and / or b. Activation of GIPR and GLP-2R, and / or c. stimulation of GIPR and GLP-2R activation, such as GIPR and GLP-2R mediated cAMP production, and / or d. inhibiting bone resorption, and / or e. Stimulating bone formation.

[0180] In one embodiment, peptide dual agonists, including functional variants or fragments thereof, are capable of: f. reducing the recruitment of beta-arrestin 2 to the GIPR compared to native hGIP; g. Reducing GIPR internalization compared to native hGIP.

[0181] These effects may be desirable because they may result in sustained pharmacological effects over long-term treatment (weeks, months, years) and may not result in desensitization of the GIPR, as discussed in Sameer et al. Mol Cell Biol. 2014 Oct 1;34(19):3618-29. doi:10.1128 / MCB.00256-14.

[0182] In one embodiment, the peptide dual agonists and functional variants or fragments thereof are full agonists of GIPR and GLP-2R.

[0183] In one embodiment, the peptide dual agonist can bind to and activate GIPR. In some embodiments, the GIPR is human GIPR (Uniprot Accession No. P48546). In one embodiment, the peptide dual agonist can bind to and activate GLP-2R. In some embodiments, the GLP-2R is human GLP-2R (Uniprot Accession No. O95838).

[0184] The activity of the peptide dual agonists of the present disclosure can be experimentally evaluated by a cAMP assay as described in the "Examples" section of this specification. Using such a cAMP assay, EC 50 and E max , as well as other relevant parameters, can be determined.

[0185] In one embodiment, the peptide dual agonists provided herein are capable of: a. At least 65% of the effectiveness of native human GIP in activating human GIPR, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% effectiveness of native human GIP in activating human GIPR (E max Activating the human GIPR at a specific concentration (value); b. at least 65% as effective as native human GLP-2 to activate human GLP-2R, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% as effective as native human GLP-2 to activate human GLP-2R (E max Activates human GLP-2R at 1000 ng / L (value).

[0186] In one embodiment, the peptide dual agonists provided herein are capable of: -activating the GIPR with the same or increased potency as native GIP activates the GIPR; and - Activate the GLP-2R with the same or increased potency as native GLP-2 activates the GLP-2R.

[0187] In one embodiment, the peptide dual agonists provided herein have an efficacy (E) that is up to 80% of the efficacy of native human GLP-1 in activating the human GLP-1R. maxThe GLP-1R is capable of activating the human GLP-1R with an efficacy (E value) that is, for example, up to 70% of the efficacy with which native human GLP-1 activates the human GLP-1R. max The GLP-1R is capable of activating the human GLP-1R with an efficacy (E value) that is, for example, up to 60% of the efficacy with which native human GLP-1 activates the human GLP-1R. max It is possible to activate human GLP-1R at a concentration of 1000 mM NaCl.

[0188] In one embodiment, the peptide dual agonists provided herein include a. An EC for human GIPR of 10 nM or less, such as 8 nM or less, for example 7 nM or less, such as 6 nM or less, for example 5 nM or less, such as 4 nM or less, for example 3 nM or less, such as 2 nM or less, for example 1 nM or less 50 having b. EC for human GLP-2R of 50 nM, such as 40 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 50 has.

[0189] In one embodiment, the peptide dual agonists provided herein have an EC for human GLP-1R of 10 nM or more, such as 12 nM or more, such as 15 nM or more. 50 has.

[0190] In one embodiment, the peptide dual agonists provided herein have a lower EC50 / E2 receptor binding capacity for the human GIPR than for the human GLP-1R. 50 at least 10-fold lower than its EC 50 at least 12-fold lower than its EC 50 At least 15 times lower than EC 50 has.

[0191] In one embodiment, the peptide dual agonists provided herein have a lower EC50 / E2 receptor binding capacity for the human GLP-2R than for the human GLP-1R. 50at least 10-fold lower than its EC 50 at least 12-fold lower than its EC 50 At least 15 times lower than EC 50 has.

[0192] Pharmaceutical / medical uses It is an aspect of the present disclosure to provide peptide dual agonists, nucleic acid constructs encoding peptide dual agonists, delivery vehicles comprising nucleic acid constructs encoding peptide dual agonists, and compositions comprising peptide dual agonists, as defined elsewhere herein, for use as pharmaceuticals.

[0193] It is therefore an aspect of the present disclosure to provide a peptide dual agonist as defined herein for use in a method of inhibiting bone resorption and / or stimulating bone formation.

[0194] It is also an aspect of the disclosure to provide a peptide dual agonist as defined herein for use in a method of inhibiting bone resorption and / or a method of stimulating bone formation.

[0195] There is also provided the use of a peptide dual agonist as defined herein for the manufacture of a medicament for inhibiting bone resorption and / or stimulating bone formation.

[0196] Also provided is a method of inhibiting bone resorption and / or stimulating bone formation, the method comprising administering to an individual in need thereof a therapeutically effective amount of a peptide dual agonist as defined herein.

[0197] It is a further aspect of the present disclosure to provide a peptide dual agonist as defined herein for use in a method for treating a bone disorder. In one embodiment, the bone disorder is a disorder associated with increased bone resorption and / or decreased bone formation. In one embodiment, the bone disorder is associated with low or reduced bone density.

[0198] Also provided is a peptide dual agonist as defined herein for use in a method of treating, including treating, preventing, and alleviating a bone disorder.

[0199] Also disclosed is a peptide dual agonist as disclosed herein for use in a method of treating a bone disorder.

[0200] Bone mineral density or bone mineral density (BMD) is the amount of bone mineral in bone tissue. The concept is the mass of mineral per volume of bone (related to density in the physical sense), but clinically it is measured by proxy, the optical density per square centimeter of bone surface during imaging. Bone mineral density measurements are used in clinical medicine as an indirect indicator of osteoporosis / osteopenia and fracture risk. It is measured by a procedure called densitometry. There is a statistical association between reduced bone mineral density and a higher probability of fracture. Bone mineral density measurements are used to screen people for risk of osteoporosis and to identify those who may benefit from measures to improve bone strength.

[0201] The T-score is a relevant measure in screening for osteoporosis. It is the bone mineral density (BMD) at a site compared to the normal reference mean for young people. The World Health Organization criteria are: Normal is a T score of -1.0 or greater Osteopenia is defined as a range between -1.0 and -2.5 Osteoporosis is defined as a bone mineral density below -2.5, or 2.5 standard deviations below the mean of the normal reference for youth.

[0202] In one embodiment, the bone disorder is associated with a T-score of -1.0 or less, such as between -1.0 and -2.5, such as -2.5 or less.

[0203] In one embodiment, there is provided a use of a peptide dual agonist as defined herein for the manufacture of a medicament for the treatment of a bone disorder.

[0204] Also provided is a method for treating a bone disorder, comprising administering to an individual in need thereof a therapeutically effective amount of a peptide dual agonist as defined herein.

[0205] The individual in need referred to herein is an individual who may benefit from the administration of dual agonist peptide. Such an individual may suffer from or be at risk of suffering from bone disorder. An individual may be any human being, male or female, infant, middle-aged or elderly. The disorder that is treated or prevented in an individual is related to the age of the individual, the general health of the individual, the drug used to treat the individual, and whether the individual has a history of suffering from a disease or disorder that may have or have led to bone density disorder.

[0206] In one embodiment, the bone disorder is selected from the group consisting of osteopenia, osteoporosis, severe osteoporosis, postmenopausal osteoporosis, iodiopathic osteoporosis, osteomalacia, rickets, osteitis cystica (OFC), and Paget's disease of bone.

[0207] In one embodiment, the bone disorder is osteopenia.

[0208] In one embodiment, the bone disorder is osteoporosis.

[0209] In one embodiment, the bone disorder is postmenopausal osteoporosis.

[0210] In one embodiment, the bone disorder is iodiopathic osteoporosis, for example juvenile iodopathic osteoporosis.

[0211] It is a further aspect of the present disclosure to provide a peptide dual agonist as defined herein for use in a method of treating osteoporosis, e.g., idiopathic osteoporosis, in an individual suffering from Duchenne muscular dystrophy (DMD) or cerebral palsy.

[0212] In one embodiment, the bone disorder is a secondary disorder, for example, a secondary disorder in an individual suffering from Duchenne muscular dystrophy (DMD) or cerebral palsy.

[0213] In one embodiment, the bone disorder is a secondary disorder, for example a secondary disorder in individuals receiving steroids, such as glucocorticoid treatment, and / or affected by immobility.

[0214] Idiopathic osteoporosis refers to the development of osteopenia and fractures with minimal or no trauma in otherwise young, healthy individuals who are not postmenopausal or have other identifiable secondary causes of osteoporosis.

[0215] Also disclosed is a peptide dual agonist selected from the group consisting of SEQ ID NOs: 66 and 67, or a functional variant or functional fragment thereof, for use in a method of treating a bone disorder selected from the group consisting of osteopenia, osteoporosis, severe osteoporosis, postmenopausal osteoporosis, idiopathic osteoporosis, osteomalacia, rickets, osteitis fibrosa cystic (OFC) and Paget's disease of bone.

[0216] In one embodiment there is provided a peptide dual agonist selected from the group consisting of SEQ ID NOs: 66 and 67, or a functional variant or functional fragment thereof, for use in a method of treating osteopenia.

[0217] In one embodiment there is provided a peptide dual agonist selected from the group consisting of SEQ ID NOs: 66 and 67, or a functional variant or functional fragment thereof, for use in a method of treating osteoporosis.

[0218] In one embodiment there is provided a peptide dual agonist selected from the group consisting of SEQ ID NOs: 66 and 67, or a functional variant or functional fragment thereof, for use in a method of treating osteoporosis in an individual afflicted with Duchenne muscular dystrophy (DMD) or cerebral palsy.

[0219] Combination therapy It is also an aspect to provide a peptide dual agonist as defined herein for use in combination with a further active pharmaceutical ingredient, which in one embodiment is useful for treating a bone disorder, such as a bone disorder associated with reduced bone density.

[0220] In one embodiment, the further active pharmaceutical ingredient is selected from the group consisting of bisphosphonates, e.g. alendronate (Fosamax), risedronate (Actonel, Atelvia, Benet), ibandronate (Boniva), zoledronic acid (Reclast, Aclasta, Zometa), etidronic acid (Didronel), pamidronic acid (Aredia / Pamimed), tiludronic acid (Skelid); estrogen replacement therapy; hormone therapy; hormone-like drugs such as raloxifene (Evista); calcitonin (Fortical and Miacalcin), denosumab (Prolia); teriparatide (Forteo); vitamin D (alphacalcidol or calcitriol); calcium or phosphorus supplementation.

[0221] In one embodiment, the further active pharmaceutical ingredient extends the half-life of the peptide dual agonist. In one embodiment, the further active pharmaceutical ingredient is an inhibitor of dipeptidyl peptidase 4 (DPP-4 / DDP-IV inhibitor) or a gliptin. Examples include sitagliptin, vildagliptin, saxagliptin, linagliptin, gemigliptin, anagliptin, teneligliptin, alogliptin, trelagliptin, dutogliptin, and omarigliptin (MK-3102).

[0222] Nucleic acid constructs encoding dual agonist peptides In one embodiment, there is provided a nucleic acid construct that encodes the dual agonist peptide defined herein.In one embodiment, said nucleic acid construct can continuously express said peptide for a long period of time, for example, at least 1 month, for example, at least 2 months, for example, at least 3 months, for example, at least 4 months, for example, at least 5 months, for example, at least 6 months, for example, at least 7 months, for example, at least 8 months, for example, at least 9 months, for example, at least 12 months.

[0223] Thus, it is an aspect to provide a nucleic acid construct encoding a peptide dual agonist as defined herein.

[0224] In one embodiment, a nucleic acid construct is provided that encodes a peptide dual agonist of SEQ ID NO: 66 or 67, or a functional variant, or a functional fragment thereof, or any peptide dual agonist disclosed herein.

[0225] It is also an aspect to provide a nucleic acid construct encoding a dual agonist peptide as defined herein for use in a method of treating a bone disorder.

[0226] By nucleic acid construct is understood a genetically engineered nucleic acid. The nucleic acid construct can be a non-replicating and linear nucleic acid, a circular expression vector, or a self-replicating plasmid. The nucleic acid construct can include several elements, such as, but not limited to, a gene or fragment thereof, a promoter, an enhancer, a terminator, a polyA tail, a linker, a polylinker, an operative linker, a multiple cloning site (MCS), a marker, a stop codon, an internal ribosome entry site (IRES), and a host homologous sequence for integration or other defined elements. It is understood that the nucleic acid construct according to the present invention can include all or a subset of any combination of the above elements.

[0227] Methods for engineering nucleic acid constructs are well known in the art (see, e.g., Molecular Cloning: A Laboratory Manual, Sambrook et al., eds., Cold Spring Harbor Laboratory, 2nd Edition, Cold Spring Harbor, NY, 1989). Furthermore, the nucleic acid constructs according to the present invention may be synthesized without a template or obtained from various commercial suppliers (e.g., Genscript Corporation).

[0228] In one embodiment, the nucleic acid construct is a naked DNA construct comprising a sequence encoding the dual agonist peptide.

[0229] Delivery Vehicle It is also an embodiment to provide the nucleic acid construct described herein above contained in a delivery vehicle.A delivery vehicle is an entity capable of transferring a nucleotide sequence or a polypeptide, or both, from at least one medium to another.Delivery vehicles are generally used for the expression of the sequence encoded in the nucleic acid construct and / or for the intracellular delivery of the construct or the polypeptide encoded therein.

[0230] In one embodiment, there is provided a delivery vehicle comprising a nucleic acid construct as defined herein. The delivery vehicle may be selected from the group consisting of RNA-based vehicles, DNA-based vehicles / vectors, lipid-based vehicles (such as liposomes), polymer-based vehicles (such as cationic polymer DNA carriers), colloidal gold particles (coatings) and virus-derived DNA or RNA vehicles or vectors.

[0231] Non-viral delivery methods include physical approaches (carrier-free delivery) and chemical approaches (synthetic vector-based delivery).

[0232] Physical approaches, including needle injection, gene gun, jet injection, electroporation, ultrasound, and hydrodynamic delivery, use physical forces that can be electrical or mechanical to penetrate cell membranes and facilitate intracellular gene transfer.

[0233] Examples of chemical delivery vehicles include, but are not limited to, biodegradable polymeric microspheres, lipid-based formulations such as liposomal carriers, liposomes, cationically charged molecules such as calcium salts or dendrimers, lipopolysaccharides, polypeptides, and polysaccharides.

[0234] Another embodiment comprises a vector, herein referred to as a viral vector (i.e., not a virus), as a delivery vehicle.The viral vector according to the present invention is made of modified viral genome, i.e., the actual DNA or RNA that forms the viral genome, and is introduced in naked form.Therefore, any coat structure surrounding the viral genome, made from viral or non-viral proteins, is not part of the viral vector.

[0235] The virus from which the viral vector is derived may be selected from the non-exhaustive group of adenovirus, retrovirus, lentivirus, adeno-associated virus, herpes virus, vaccinia virus, foamy virus, cytomegalovirus, Semliki Forest virus, pox virus, RNA viral vectors and DNA viral vectors. Such viral vectors are well known in the art.

[0236] In one embodiment, the viral vector can be selected from the group consisting of adenovirus, lentivirus, adeno-associated virus (AAV), and recombinant adeno-associated virus (rAAV). In one preferred embodiment, the viral vector is a therapeutic rAAV vector, such as a therapeutic rAAV vector.

[0237] Adenovirus is a group of viruses that contain double-stranded DNA. Adenovirus can be genetically modified to be replication-incompetent or conditionally replication-incompetent. In this form, as adenovirus construct or adenovector, adenovirus can be used as a gene delivery vehicle for vaccination or gene therapy.

[0238] Recombinant cells Another aspect relates to cells comprising the nucleic acid constructs defined herein. Such recombinant cells can be used as a delivery vehicle for nucleic acid constructs or as part of gene therapy programs, tools for in vitro research. Nucleic acid constructs can be introduced into cells by techniques well known in the art, including microinjection of DNA into the nucleus of cells, transfection, electroporation, lipofection / liposome fusion, and particle bombardment. Suitable cells include autologous and non-autologous cells, and can include xenogeneic cells.

[0239] Preparation method (peptide) The dual agonist peptides defined herein may be prepared by any method known in the art, for example by standard peptide preparation techniques including solution synthesis or Merrifield-type solid phase synthesis.

[0240] In one embodiment, the peptides according to the invention are synthetically made or produced. Methods for synthetic production of peptides are well known in the art. Detailed explanations and practical advice for the production of synthetic peptides can be found in Synthetic Peptides: A User's Guide (Advances in Molecular Biology), Grant GA ed., Oxford University Press, 2002, or in: Pharmaceutical Formulation: Development of Peptides and Proteins, Frokjaer and Hovgaard eds., Taylor and Francis, 1999.

[0241] In one embodiment, the peptide or peptide sequence of the invention is produced synthetically, in particular by the sequence-assisted peptide synthesis (SAPS) method, by solution synthesis, by solid phase peptide synthesis (SPPS), such as Merrifield-type solid phase synthesis, by recombinant techniques (production by a host cell comprising a first nucleic acid sequence encoding the peptide operably associated with a second nucleic acid capable of directing its expression in said host cell) or by enzymatic synthesis, which are well known to those skilled in the art.

[0242] Peptides can be synthesized either batchwise on a fully automated peptide synthesizer using the Na-amino protecting group and 9-fluorenylmethyloxycarbonyl (Fmoc) or tert-butyloxycarbonyl (Boc) as the preferred general protecting groups for side chain functionalities.

[0243] After purification, such as by reverse phase HPLC, the peptides can be further processed to obtain, for example, C-terminally or N-terminally modified isoforms. Methods for terminal modifications are well known in the art.

[0244] For example, the following method for conjugation of fatty acids can be used: After the final N-terminal N-Fmoc is removed, the N-terminal amino group is acylated by treatment with 3 equivalents of 1,16-hexadecanedioic acid in the presence of 3 equivalents of HATU and 6 equivalents of DIPEA. Alternatively, lysine with a Dde-protected side chain is used in solid-phase peptide synthesis at the acylation position. After assembly of the peptide chain, the N-terminal amino group is capped with 3 equivalents of Boc2O in the presence of 6 equivalents of DIPEA. The protecting group Dde is then removed by treatment with 2% hydrazine / DMF (v / v). Alternatively, 3 equivalents of palmitoyl chloride can be used for palmitoylation in the presence of 6 equivalents of DIPEA. Alternatively, 3 equivalents of 1,16-hexadecanedioic acid can be activated by HATU / DIPEA and then conjugated to the side chain of lysine. As a further alternative, Fmoc-γ-Glu(tBu)-OH or Fmoc-4-Abu-OH or Fmoc-β-Ala-OH or Fmoc-AEEAc-OH are conjugated to the side chain of Lys using standard DIC / HOBT protocols. The N-terminal amino group of the unnatural amino acid is then palmitoylated by treatment with 3 equivalents of palmitoyl chloride in the presence of 6 equivalents of DIPEA.

[0245] Pharmaceutical Compositions and Formulations While it is possible for the dual agonist peptides defined herein to be administered as raw chemicals (peptides), it may be preferable to present them in the form of a pharmaceutical formulation, which may be referred to as a pharmaceutical composition, a pharma- ceutically acceptable composition, or a pharma- ceutically safe composition.

[0246] Thus, there is also provided a pharmaceutical formulation comprising a dual agonist peptide as defined herein, or a pharma- ceutically acceptable salt or ester thereof, and a pharma- ceutically acceptable carrier, excipient and / or diluent. The pharmaceutical formulation may be prepared by conventional techniques, for example as described in Remington: The Science and Practice of Pharmacy 2005, Lippincott, Williams & Wilkins.

[0247] Pharmaceutically acceptable salts of the peptide compounds, where they can be prepared, are also intended to be covered. These salts are acceptable for pharmaceutical application, meaning that the salts retain the biological activity of the parent compound and that the salts do not impart undesirable or deleterious effects in their application and use in the treatment of disease.

[0248] Pharmaceutically acceptable salts are prepared by standard methods. 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.

[0249] The peptide compounds may be administered in effective amounts in the form of their alkali metal or alkaline earth metal salts, concomitantly, simultaneously or together with pharma- ceutically acceptable carriers or diluents, particularly and preferably in the form of pharmaceutical compositions thereof, whether by oral, rectal or parenteral (including subcutaneous) route.

[0250] Examples of pharma- ceutically acceptable acid addition salts include inorganic acids, such as hydrochloric acid, hydrobromic acid, phosphoric acid, metaphosphoric acid, nitric acid, and sulfuric acid, and organic acids, such as tartaric acid, acetic acid, citric acid, malic acid, lactic acid, fumaric acid, benzoic acid, glycolic acid, gluconic acid, succinic acid, p-toluenesulfonic acid, and arylsulfonic acids.

[0251] The pharma- ceutically acceptable salts of the peptides of the invention are preferably in a solution having a physiologically acceptable pH, ie, a solution containing the peptide salt preferably has a pH that is acceptable for clinical use.

[0252] Provided herein are compositions comprising a peptide dual agonist as defined herein, or multimeric compounds comprising said peptide dual agonists, or nucleic acid constructs comprising / encoding said peptide dual agonists.

[0253] Administration and Dosage In one embodiment of the present disclosure, the peptide as defined herein or the nucleic acid construct encoding the peptide, or the composition comprising the peptide, is administered to an individual in need of treatment in a medicamentously effective dose or therapeutically effective amount. The dosage requirements vary depending on the specific drug composition used, the route of administration, and the specific subject being treated, and depend on the severity and type of disorder, as well as the subject's weight and general condition. Those skilled in the art will also recognize that the optimal amount and interval of individual doses will be determined by the nature and extent of the condition being treated, the form, route and site of administration, and the specific patient being treated, and that such optimal values ​​can be determined by conventional techniques. Those skilled in the art will also understand that the optimal course of treatment, i.e., the number of doses of compound given per day for a defined number of days, can be ascertained using conventional course-of-treatment determination tests.

[0254] In one embodiment the peptide or composition 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.

[0255] Doses may also be administered at intermittent intervals, or at intervals where the doses are not administered every day, rather, one or more doses may be administered every 2, 3, 4, 5, 6 days, every week, every 2, 3, 4, 5, 6 weeks, or any interval within those ranges (e.g., every 2-4 weeks or every 4-6 weeks).

[0256] In one embodiment, the peptide or composition is administered once daily.

[0257] In one embodiment, the peptide or composition is administered once daily, such as overnight, when bone resorption is highest.

[0258] In one embodiment, the peptide or composition is administered once a week.

[0259] Those skilled in the art know that if the number of daily administrations is increased, the dose to be administered in each administration may be decreased accordingly.Similarly, if the duration of each administration is decreased, the dosage may be increased accordingly.

[0260] Route of administration It will be understood that the preferred route of administration will depend on the general condition and age of the subject being treated, the nature of the condition being treated, the location of the tissue being treated within the body, and the active ingredient selected.

[0261] whole body treatment For systemic treatment, the route of administration can introduce the peptide, a nucleic acid construct encoding the peptide, or a composition containing the peptide into the bloodstream for ultimate targeting to the desired site of action.

[0262] Such routes of administration may be any suitable route, such as enteral routes (including oral, rectal, nasal, pulmonary, buccal, sublingual, transdermal, intravesical and intraperitoneal administration), and / or parenteral routes (including subcutaneous, intramuscular, intrathecal, intracerebral, intravenous and intradermal administration).

[0263] Parenteral Administration Parenteral administration is any administration route other than the oral / enteral route by which the drug avoids first-pass degradation in the liver. Thus, parenteral administration includes any injection and infusion, for example, bolus injection or continuous infusion, such as intravenous, intramuscular, or subcutaneous administration. In addition, parenteral administration includes inhalation and topical administration.

[0264] Thus, the compounds are administered topically across any mucous membrane of the animal to which the biologically active agent is administered, for example, mucous membranes in the nose, vagina, eye, mouth, reproductive tract, lungs, gastrointestinal tract, or rectum, preferably the nasal or oral mucosa, and thus parenteral administration can also include buccal, sublingual, nasal, rectal, vaginal and intraperitoneal administration, as well as pulmonary and bronchial administration by inhalation or implantation. Agents may also be administered topically across the skin.

[0265] Local treatment The peptides defined herein, or the nucleic acid constructs encoding the peptides, or the compositions comprising the peptides, may in one embodiment be used as a local treatment, i.e. directly introduced into the site(s) of action. Thus, the peptides may be applied directly to the skin or mucous membranes, or the peptides may be injected into the site of action, for example into the diseased tissue or into a terminal artery that leads directly to the diseased tissue.

[0266] Parts Kit The present invention also relates to a kit of parts comprising one or more of the above mentioned agents (peptides, nucleic acid constructs or compositions) and at least one additional or further component.

[0267] The kit of parts in one embodiment comprises one or more of the agents defined herein for the treatment, prevention or alleviation of bone disorders, osteoporosis and osteopenia. The kit defined herein allows for simultaneous, sequential or separate administration of the active agent according to the invention and / or one or more second active ingredients as described elsewhere herein. EXAMPLES

[0268] Example 1. Dual peptide agonists of GIPR and GLP-2R Materials and Methods material All applied peptides were synthesized by WuXi AppTec, Shanghai, China, with purity of at least 95% as determined by HPLC analysis, and the exact molecular weight was confirmed using mass spectrometry. Human GIPR, GLP-2R, and GLP-1R applied in in vitro experiments can be purchased from Origene, Rockville, USA. Human N-terminal SNAP-tagged GIPR was custom manufactured at Cisbio, Codolet, France.

[0269] C10, C12 or C16 or C16-diacid acyl groups were added at positions 1, 5, 7, 11, 12, 15 as shown in Table 1 to improve the selectivity of the dual agonists.

[0270] result: The peptide dual agonists listed in Table 1 were obtained.

[0271] [Table 1] TIFF2024547006000003.tif245165TIFF2024547006000004.tif244165TIFF2024547006000005.tif121165

[0272] Example 2 method COS-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) 1885 supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, 180 units / ml penicillin, and 45 g / ml streptomycin at 10% CO and 37°C. Prior to the experiments, transient transfection of COS-7 cells was performed using the calcium phosphate precipitation method as previously described ( van der Velden et al., 2021 ).

[0273] Transiently transfected COS-7 cells expressing either human GIPR, GLP-2R, or GLP-1R were seeded at a density of 35.000 cells / well in white 96-well plates the day after transfection. The following day, the assay was initiated by washing with HEPES-buffered saline (HBS), followed by an incubation step with assay buffer (HBS supplemented with 1 mM isobutyl-1-methylxanthine (IBMX)) for 30 min at 37°C. Ligand was then added and incubated for another 30 min at 37°C. After ligand incubation, the HitHunter® cAMP assay (Eurofins DiscoverX, Fremont, 150 USA) was performed according to the manufacturer's instructions. Luminescence was measured by a PerkinElmer™ EnVision 2014 multilabel reader (PerkinElmer, Waltham, MA). Potency (EC 50 Efficacy (E value) was determined by nonlinear regression using GraphPad Prism 9 (San Diego, California, USA). Sigmoidal curves were fitted logistically. max Values) were determined by normalizing to the highest applied concentration of endogenous ligand for each receptor.

[0274] result From Tables 2 and 3, it can be seen that attaching a fatty acid molecule to an amino acid at the N-terminal region (residues 1-15 of the peptides according to the present disclosure), for example at positions 5, 7, 8, 11, 12, 15, or at the N-terminus, results in a potent dual GIPR / GLP-2R agonist that targets only or primarily GIPR and GLP-2R and not GLP-1R by decreasing its potency and / or efficacy at GLP-1R. For comparison, see the compounds in Table 4, especially compound numbers 63, 65, 64, 62, 60 and 61, which have a fatty acid attached to the C-terminal amino acid residue or residue at position 16 and can activate hGLP-1R in addition to hGIP and hGLP-2R.

[0275] Aibs at positions 2 and / or 13 may increase potency at the GIPR and / or GLP-2R. Aibs at positions 2 and / or 13 may also induce additional selectivity for the GLP-1R.

[0276] An Ala at position 2 appears to result in a dual agonist peptide with disproportionate potency and / or efficacy towards the GIPR but not the GLP-2R.

[0277] Increasing the length of the fatty acid (e.g., C16 versus C10) may induce greater selectivity, presumably because steric hindrance is better tolerated by GIPR and GLP-2R than by GLP-1R at certain positions.

[0278] The yGlu (gamma-glutamic acid) linker may also induce higher selectivity, presumably because steric hindrance is better tolerated by GIPR and GLP-2R than by GLP-1R at certain positions.

[0279] Amino acids in the N-terminal region, such as isoleucine at position 7 in combination with positions 5, 7, 8, 11, 12, 15 or the attachment of a fatty acid molecule to the N-terminus, reduce potency and / or efficacy at GLP-1R.

[0280] [Table 2] TIFF2024547006000007.tif232165TIFF2024547006000008.tif240165TIFF2024547006000009.tif167165

[0281] [Table 3] TIFF2024547006000011.tif240165TIFF2024547006000012.tif111165

[0282] [Table 4]

[0283] [Table 5]

[0284] [Table 6]

[0285] Example 3 method HEK293 cells were cultured in DMEM-GlutaMAX™-I supplemented with 10% FBS, 180 units / mL penicillin, and 45 μg / mL streptomycin at 10% CO2 and 37°C. These cells were transfected with PEI for beta-arrestin recruitment assays as described in detail in van der Velden et al., 2021.

[0286] HEK293 cells were transiently transfected with human GIPR, donor Rluc8-arrestin-3-Sp1 (beta-arrestin2 recruitment), acceptor mem-linker-citrine-SH3, and GPCR kinase 2 (GRK2). Two days after transfection, cells were washed with PBS and resuspended in PBS containing 5 mM glucose. Then, 85 μL of cell suspension was added to each well of a white 96-well plate, followed by PBS containing 5 μM coelenterazine-h. After 10 min incubation, increasing concentrations of ligand were added and incubated for an additional 30 min. Luminescence was measured on a Berthold Technologies Mithras Multilabel reader (Rluc8 at 485 ± 40 nm and YFP at 530 ± 25 nm). Potency (EC 50 Efficacy (E value) was determined by nonlinear regression using GraphPad Prism 9 (San Diego, California, USA). Sigmoidal curves were fitted logistically.max The AUC values ​​were determined by normalization to the highest applied concentration of the endogenous ligand for GIPR (GIP). AUC values ​​for the sigmoidal curve up to a concentration of 100 nM were calculated similarly.

[0287] result All of the dual agonists tested recruited less beta-arrestin2 to the human GIPR than native GIP, and some of them did not recruit beta-arrestin2 at all.

[0288] [Table 7]

[0289] Example 4 method HEK293A cells were cultured in DMEM-GlutaMAX™-I supplemented with 10% FBS, 180 units / mL penicillin, and 45 μg / mL streptomycin at 5% CO2 and 37° C. For receptor internalization assays, the cells were transfected using Lipofectamine 2000 from Thermo Fischer Scientific, Massachusetts, USA, according to the manufacturer's instructions.

[0290] HEK293A cells transiently expressing human SNAP-GIPR were seeded at a density of 15.000 cells / well in white 384-well plates on the day of transfection. The next day, the medium was removed and new fresh culture medium was added. The assay was performed on the third day. First, cells were labeled with 100 nM Tag-Lite SNAP-Lumi4-Tb (donor) in OptiMEM for 60 min at 37 °C. Next, cells were washed four times with internalization buffer (HBBS supplemented with 1 mM CaCl2, 1 mM MgCl2, and 20 mM HEPES) followed by the addition of 100 μM pre-warmed fluorescein-O'-acetate (acceptor). Before ligand stimulation, plates were placed in a 37 °C incubator for 5 min to allow temperature regulation before reading the plates. The cells were then stimulated with ligand solutions pre-warmed to 37° C., and internalization was measured every 3 min in a PerkinElmer™ EnVision 2014 Multilabel reader (PerkinElmer, Waltham, Mass.) for 60 min at 37° C. AUC values ​​for sigmoidal curves up to a concentration of 1 μM were calculated similarly.

[0291] result All dual agonists tested induced less GIPR internalization than native GIP. Compounds that did not recruit beta-arrestin2 to the GIPR at all also did not induce GIPR internalization.

[0292] [Table 8]

[0293] Example 5 method COS-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) 1885 supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, 180 units / ml penicillin, and 45 g / ml streptomycin at 10% CO and 37°C. Prior to the experiments, transient transfection of COS-7 cells was performed using the calcium phosphate precipitation method as previously described ( van der Velden et al., 2021 ).

[0294] Transiently transfected COS-7 cells expressing human GIPR were seeded into clear 96-well plates at a density of 7,500 cells / well the day after transfection. The number of cells added per well was determined by the radioligand, 125 The cells were then washed twice in binding buffer (HEPES + 0.1% casein) and then incubated with 15–40 pM of I-GIP(1-42) (NEX402010UC, PerkinElmer, Waltham, MA) for 90 min. The next day, the medium of the cells was changed to DMEM supplemented with 2% FBS and pre-incubated for 90 min with or without 10 nM of ligand. The cells were then washed twice in binding buffer (HEPES + 0.1% casein) and then incubated with 15–40 pM of I-GIP(1-42) (NEX402010UC, PerkinElmer, Waltham, MA). 125 I-GIP(1-42) was used for incubation at 4°C for 3 hours. After incubation, cells were washed twice with 100 μl ice-cold binding buffer per well and lysed for 30 minutes using 175 μl per well of 200 mM NaOH containing 1% SDS. Samples were analyzed by Wizard Gamme counter (PerkinElmer, Waltham, MA). Data were analyzed by comparing counts measured from ligand-preincubated and non-preincubated cells.

[0295] result As shown in Figure 3, preincubation with GIP results in a downregulation of GIPR from the cell surface that is not observed with either of the two peptide dual agonists tested.

[0296] Example 6 method: Sprague Dawley female rats, 10 weeks old (Janvier Labs, France), n=4, were fasted from 06:00 until after the last blood sample. Baseline blood samples were taken at 10:00 just before subcutaneous administration of compounds. Compounds were dissolved in 50 mM phosphate buffer (pH 7.5 + 0.1% Haemaccel). Dose: Compound No. 11 4248.5 μg / kg.

[0297] Blood samples were collected at 10:00, 14:00, 18:00 and 22:00. Plasma was obtained within 20 min after blood collection and stored at -20°C.

[0298] CTX and P1NP were measured using RatLaps (CTX-I) EIA and rat / mouse P1NP EIA (Immunidiagnosticsystems, UK) according to the protocol.

[0299] Data are presented as % of baseline, mean + / - SEM and analyzed by 2-way Anova with Sidaks multiple comparison test or by unpaired t-test using GraphPad Prism V9.3.0.

[0300] result: Administration of compound #11 showed a reduction (ns) in the increase of the resorption marker CTX (time point 14:00, p-value=0.08). See FIG. 2A. The AUC calculated from the lowest measurement point (70%) above showed a trend towards a reduction in CTX AUC (p-value=0.10). See FIG. 2C. For the formation marker P1NP, administration of compound #11 showed an increase at 14:00 and 18:00 (FIG. 2B).

[0301] Example 7 method Sprague Dawley male or female rats, weighing 200-300g, n=3 were used for PK studies. Compounds were dissolved in 80% DMSO and further diluted / or dissolved directly in 50mM phosphate buffer (pH 7.5 + 0.1% Haemaccel or casein). The dose given was 100nmol / kg for all SC administrations and 20nmol / kg or 100nmol / kg for IV administrations. Blood samples were collected in the time window of 0-72 hours after compound administration. Plasma was obtained and stored at -20°C until evaluation by LC-MS or LC-MS / MS.

[0302] result [Table 9]

[0303] Example 8 method COS-7 cells were cultured in Dulbecco's modified Eagle's medium (DMEM) 1885 supplemented with 10% fetal bovine serum (FBS), 2 mM glutamine, 180 units / ml penicillin, and 45 g / ml streptomycin at 10% CO and 37°C. Prior to the experiments, transient transfection of COS-7 cells was performed using the calcium phosphate precipitation method as previously described ( van der Velden et al., 2021 ).

[0304] Transiently transfected COS-7 cells expressing either rat GIPR or GLP-2R or macaque GIPR or GLP-2R were seeded at a density of 35.000 cells / well in white 96-well plates the day after transfection. The assay was started the next day by washing with HEPES-buffered saline (HBS), followed by an incubation step with assay buffer (HBS supplemented with 1 mM isobutyl-1-methylxanthine (IBMX)) for 30 min at 37°C. Ligand was then added and incubated for another 30 min at 37°C. After ligand incubation, the HitHunter® cAMP assay (Eurofins DiscoverX, Fremont, 150 USA) was performed according to the manufacturer's instructions. Luminescence was measured by a PerkinElmer™ EnVision 2014 multilabel reader (PerkinElmer, Waltham, MA). Potency (EC 50 Efficacy (E value) was determined by nonlinear regression using GraphPad Prism 9 (San Diego, California, USA). Sigmoidal curves were fitted logistically. max Values) were determined by normalizing to the highest applied concentration of endogenous ligand for each receptor.

[0305] result The results in Tables 5 and 6 below show that the tested peptide dual agonists, although developed based on human receptors and peptide ligands, also have good efficacy against GIPR and GLP-2R in rats and macaques, and therefore their efficacy in medical treatment can be tested in animal models.

[0306] [Table 10]

[0307] [Table 11]

[0308] Example 9. Sequence overview of dual agonists of the present disclosure K(γGlu-C16) provided herein should be read as fatty acid C16 being attached to the side chain amino group of lysine via the yGlu linker. Thus, the yGlu linker is directly attached to the amino group on the side chain of lysine, and the fatty acid is directly attached to yGlu. The same applies to other fatty acids and linkers listed in parentheses herein below.

[0309] Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-K(γGlu-C16)-SDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTIL-K(γGlu-C16)-NLAARDFINWLIQTKITK-OH Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2 Compound No. 24, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 25, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 26, SEQ ID NO: 8B H-Aib-DG-K(γGlu-γGlu-C10)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 27, SEQ ID NO: 22 H-Aib-EG-K(γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 28, SEQ ID NO: 21 H-Aib-DG-K(γGlu-γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDY-K(γGlu-C10)-T-Aib-LDNLAARDFINWLIQTKITD-OH Compound No. 31, SEQ ID NO: 26B H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIETKITK-OH Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDY-K(γglu-C10)-T-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ-OH Compound No. 1, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 2, SEQ ID NO: 2 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKIT Compound No. 45, SEQ ID NO: 38 (C16)HADGTFISDYSTILDNLAAKDFINWLIQTKITK Compound No. 3, SEQ ID NO: 3 (C10)HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ Compound No. 46, SEQ ID NO: 39 (C16)HADGTFISDYSTILDNLAARDFINWLLAQKITK Compound No. 4, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 5, SEQ ID NO: 4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 6, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH Compound No. 7, SEQ ID NO: 6 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK-OH Compound No. 8, SEQ ID NO: 7 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT-OH Compound No. 15, SEQ ID NO: 14 (C16)HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ Compound No. 48, SEQ ID NO: 41 (C16)HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ Compound No. 49, SEQ ID NO: 42 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ Compound No. 50, SEQ ID NO: 43 (C16)HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ Compound No. 51, SEQ ID NO: 44 (C16)HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ Compound No. 52, SEQ ID NO: 45 (C16)HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ Compound No. 53, SEQ ID NO: 33 (C16)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 16, SEQ ID NO: 15 (C16)HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ Compound No. 17, SEQ ID NO: 4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 18, SEQ ID NO: 4 (C10-Diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 19, SEQ ID NO: 16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 20, SEQ ID NO: 17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 21, SEQ ID NO: 18 (C16-Diacid)H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK-OH Compound No. 22, SEQ ID NO: 19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH Compound No. 23, SEQ ID NO: 20 (C16-DIACID)H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK-OH Compound No. 39, SEQ ID NO: 33 (C16-diacid)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 40, SEQ ID NO: 34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 41, SEQ ID NO: 35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 42, SEQ ID NO: 36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 43, SEQ ID NO: 37 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 44, SEQ ID NO: 4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 56, SEQ ID NO: 47 HADGTFISDYSTILDKLAAK(C16)DFINWLIQTKITK Compound No. 57, SEQ ID NO: 48 HADGTFISDYSTILDKLAARDFINWLIQTK(C16)ITK Compound No. 58, SEQ ID NO: 48 HADGTFISDYSTILDKLAARDFINWLIQTKITK(C16) Compound No. 60, SEQ ID NO: 49 HADGTFISDYSTILDNLAARDFINWLIQTKGKK (yGlu-C18-diacid) Compound No. 61, SEQ ID NO: 50 HADGTFISDYSTAibLDNLAARDFINWLIQTKGKKK (yGlu-C18-diacid) Compound No. 62, SEQ ID NO: 51 HADGTFISDYSTAibLDK(yGlu-C18-diacid)LAARDFINWLIQTKGKK Compound No. 63, SEQ ID NO: 52 H-Aib-DGTFISDYSTILDNLAARDFINWLIQTKITK(C10)-OH Compound No. 64, SEQ ID NO: 53 HADGTFISDYSTILDK(yGlu-C18-diacid)LAARDFINWLIQTKGKK Compound No. 65, SEQ ID NO: 54 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK(C10)-NH2 Compound No. 66, SEQ ID NO: 55 HGEGSFGSDMSIALDKLAARDFVNWLLQTKITD

[0310] References Van der Velden et al. 2021. GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats Sameer et al. Mol Cell Biol. 2014 Oct 1;34(19):3618-29. doi: 10.1128 / MCB.00256-14.

[0311] item 1. Sequence: HX2X3GX5FX7X8X9X 10 X 11 X 12 X 13 X 14 X 15 X 16 LAAX 20 DFIX 24 WLIX 28 TKX 31 X 32 X 33 -Z (SEQ ID NO:66) wherein X2 is A, K, or Aib; X3 is D, K, or E; X5 is T, K, or S; X7 is K or I; X8 is K or S; X9 is D or K; X 10 is Y or K, X 11 is S, K, or N, X12 is K or T, X 13 is A, Aib, K, or I; X 14 is L or K, X 15 is K, D, or E, X 16 are E, L, Aib, K, A, and N; X 20 is R or K, X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T, K, or omitted, X 33 is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of SEQ ID NO: 66; The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor); A peptide dual agonist comprising or consisting of the sequence.

[0312] 2. The peptide dual agonist of item 1, wherein the peptide is modified by attaching at least one fatty acid molecule to any one of positions 2 to 15 of SEQ ID NO:66.

[0313] 3. A peptide dual agonist according to any one of items 1 or 2, X2 is K or Aib; X3 is D or E; X5 is T or K; X7 is I, X 11 is S or K, X 13 is Aib or I, X 15 is D or E, X 16 are E, L, Aib, K, A, and N; X 24 is N or E, X 28 is Q, E, or A, X 31 is I, G, or omitted, X 32 is T or omitted, The peptide dual agonists.

[0314] 4. The peptide dual agonist according to item 1, X3 is D, X7 is I, X 15 is D, X 31 is I, X 32 is T, The peptide dual agonists.

[0315] 5. A peptide dual agonist according to any one of the preceding paragraphs, comprising: The peptide dual agonist, wherein X2 is Aib.

[0316] 6. X 13 The peptide dual agonist of any one of the preceding claims, wherein is Aib.

[0317] 7. X 16 The peptide dual agonist of any one of the preceding claims, wherein is A, Aib, L, E.

[0318] 8. X2 is Aib and X 13The peptide dual agonist of any one of the preceding claims, wherein is Aib.

[0319] 9. X2 is Aib and X 11 The peptide dual agonist of any one of the preceding claims, wherein

[0320] 10. X2 is Aib, X5 is K, and X 13 The peptide dual agonist of any one of the preceding claims, wherein is Aib.

[0321] 11. X2 is Aib and X 11 is K and X 13 The peptide dual agonist of any one of the preceding claims, wherein is Aib.

[0322] 12. X2 is Aib and X 11 is K and X 24 The peptide dual agonist of any one of the preceding claims, wherein

[0323] 13. Z: 8. The peptide dual agonist of any one of the preceding claims, selected from the group consisting of ND, NDW, KDW, NDW, NDK, NDWK, NDWKH, NDWKHN, NDWKHNI, NDWKHNIT, NDWKHNITQ, and AEWKHAITQ or a variant containing one amino acid substitution.

[0324] 14. Z: AEWKHAITQ (sequence number) and NDWKHNITQ (SEQ ID NO: 1).

[0325] 15. The peptide dual agonist of item 1, wherein the peptide is modified at the N-terminal amino acid residue of SEQ ID NO:66, for example at amino acid residue 1 of SEQ ID NO:66, by attaching at least one fatty acid molecule.

[0326] 16. The peptide dual agonist of any one of the preceding items, wherein X7 is I, and the peptide is modified by attaching one fatty acid molecule to position 1 of SEQ ID NO:66, such as to the N-terminus of SEQ ID NO:66.

[0327] 17. The peptide dual agonist of any one of the preceding claims, wherein the peptide is selected from the group consisting of: Compound No. 9, SEQ ID NO: 8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, Compound No. 10, SEQ ID NO: 9 H-Aib-DGTFKSDYSTILDNLAARDFINWLIQTKITK, Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTILKNLAARDFINWLIQTKITK, Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKGKKNDWKHNITQ, Compound No. 24, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 25, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 26, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, Compound No. 27, SEQ ID NO: 22 H-Aib-EGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 28, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITD, Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK, Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDYKTILDNLAARDFINWLIETKITK, Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDYKTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, Compound No. 1, SEQ ID NO: 1 HADGTFISDYSTILDNLAARDFINWLIQTKITD, Compound No. 2, SEQ ID NO: 2 HADGTFISDYSTILDNLAARDFINWLIQTKIT, Compound No. 45, SEQ ID NO: 38 HADGTFISDYSTILDNLAAKDFINWLIQTKITK, Compound No. 3, SEQ ID NO: 3 HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ, Compound No. 46, SEQ ID NO: 39 HADGTFISDYSTILDNLAARDFINWLLAQKITK, Compound No. 4, SEQ ID NO: 1 HADGTFISDYSTILDNLAARDFINWLIQTKITD, Compound No. 5, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 6, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, Compound No. 7, SEQ ID NO: 6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, Compound No. 8, SEQ ID NO: 7 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, Compound No. 15, SEQ ID NO: 14 HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 48, SEQ ID NO: 41 HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ, Compound No. 49, SEQ ID NO: 42 HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ, Compound No. 50, SEQ ID NO: 43 HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ, Compound No. 51, SEQ ID NO: 44 HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ, Compound No. 52, SEQ ID NO: 45 HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ, Compound No. 53, SEQ ID NO: 33 HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 16, SEQ ID NO: 15 HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 17, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 19, SEQ ID NO: 16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 20, SEQ ID NO: 17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, Compound No. 21, SEQ ID NO: 18 H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, Compound No. 22, SEQ ID NO: 19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, Compound No. 23, SEQ ID NO: 20 H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, Compound No. 39, SEQ ID NO: 33 HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 40, SEQ ID NO: 34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 41, SEQ ID NO: 35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, Compound No. 42, SEQ ID NO: 36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, Compound No. 43, SEQ ID NO: 37 H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and Compound No. 44, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK.

[0328] 18. The peptide dual agonist of any one of the preceding claims, wherein the peptide is selected from the group consisting of: SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAARDFINWLIQTKITK, SEQ ID NO:10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, SEQ ID NO:13 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, SEQ ID NO:21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:31 H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, and SEQ ID NO:26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK.

[0329] 19. The following: Compound No. 9, SEQ ID NO: 8 H-Aib-DG-KFISDYSTILDNLAARDFINWLIQTKITK, Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-KSDYSTILDNLAARDFINWLIQTKITK, Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYS-KILDNLAARDFINWLIQTKITK, SEQ ID NO:12 H-Aib-DGTFISDYSTIL-KNLAARDFINWLIQTKITK, SEQ ID NO:13 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:21 H-Aib-DG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:22 H-Aib-EG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:23 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:25 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITD, SEQ ID NO:26 H-Aib-DGTFISDY-KTILDKLAARDFIEWLIATKITK, SEQ ID NO:27 H-Aib-DGTFISDY-KTILDNLAARDFINWLIETKITK, SEQ ID NO:28 H-Aib-DGTFISDY-KT-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:24 Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:29 H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, SEQ ID NO:30 Ac-H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, SEQ ID NO:31 H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:32 Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:46 H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, SEQ ID NO:7 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:18 H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, SEQ ID NO:20 H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:37 H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, or a functional variant thereof, wherein said functional variant comprises one to three individual amino acid substitutions, with the proviso that the amino acid residue at position 2 of said functional variant is Aib; the amino acid residue at position 6 of the functional variant is phenylalanine (F); the amino acid residue at position 22 of the functional variant is phenylalanine (F); the amino acid residue at position 25 of said functional variant is tryptophan (W); the amino acid residue at position 26 of said functional variant is leucine (L); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of the above sequence, The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor); The peptide dual agonists.

[0330] 20. The peptide dual agonist of any one of the preceding claims, wherein the peptide is amidated (-NH2) at the C-terminus or the C-terminus is a carboxylic acid.

[0331] 21. The peptide dual agonist of any one of the preceding paragraphs, wherein the peptide is modified by attaching at least one fatty acid molecule to a lysine (K) at any one of positions 2-15 of SEQ ID NO: 66 or 67.

[0332] 22. The peptide dual agonist of any one of the preceding paragraphs, wherein the peptide is modified by attachment of at least one fatty acid molecule to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 66 or 67.

[0333] 23. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified by attaching at least one fatty acid molecule at position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, or 12 of SEQ ID NO: 66 or 67.

[0334] 24. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified by attaching at least one fatty acid molecule at position 2, 3, 4, 5, 6, 7, 8, 9, 10, or 11 of SEQ ID NO: 66 or 67.

[0335] 25. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified by attaching at least one fatty acid molecule at position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 66 or 67.

[0336] 26. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified by attaching at least one fatty acid molecule at position 5, 6, 7, 8, 9, 10, 11 or 12 of SEQ ID NO: 66 or 67.

[0337] 27. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at any one of positions 5, 7, 8, 11, 12, 15 of SEQ ID NO: 66 or 67 by attaching at least one fatty acid molecule.

[0338] 28. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at any one of positions 5, 7, 8, 11 of SEQ ID NO: 66 or 67 by attaching at least one fatty acid molecule.

[0339] 29. X 13 is Aib, and the peptide is modified at any one of positions 5 or 11 of SEQ ID NO: 66 or 67 by attaching at least one fatty acid molecule.

[0340] 30. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a straight chain fatty acid.

[0341] 31. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a branched fatty acid.

[0342] 32. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a monoacyl fatty acid molecule containing one fatty acid.

[0343] 33. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a diacyl fatty acid molecule.

[0344] 34. The fatty acid molecule is CH3(CH2)8CO-(capryl, C10), CH3(CH2) 10 CO-(Lauryl, C12), CH3(CH2) 12 CO-(myristoyl, C14), CH3(CH2) 14 CO-(Palmitoyl, C16), CH3(CH2) 16 CO-(Stearyl, C18) and CH3(CH2) 18 The peptide dual agonist of any one of the preceding claims, comprising an acyl group selected from the group consisting of CO-(arachidyl, C20).

[0345] 35. The fatty acid molecule is HOOC-CH3(CH2)8CO-(decanoyl, C10), 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) 18 CO-(eicosanoyl, C20), and HOOC-CH3(CH2) 19 The peptide dual agonist of any one of the preceding claims, comprising two acyl groups individually selected from the group consisting of: CO-(19-carboxy-nonadecanoyl, C21).

[0346] 36. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is attached to the amino acid residue via a spacer.

[0347] 37. The peptide dual agonist of any one of the preceding claims, wherein the spacer comprises yGlu.

[0348] 38. The peptide dual agonist of any one of the preceding claims, wherein the spacer comprises or consists of yGlu or yGlu-yGlu.

[0349] 39. The peptide, a. At least 65% of the effectiveness of native human GIP in activating human GIPR, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% effectiveness of native human GIP in activating human GIPR (E max Activate human GIPR with b. at least 65% as effective as native human GLP-2 to activate human GLP-2R, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% as effective as native human GLP-2 to activate human GLP-2R (E max activates human GLP-2R at The peptide dual agonist of any one of the preceding paragraphs.

[0350] 40. The peptide has an efficacy (E) of up to 80% of the efficacy of native human GLP-1 in activating human GLP-1R. max value) that is up to 70% of the efficacy with which native human GLP-1 activates the human GLP-1R. max value) that is up to 60% of the efficacy with which native human GLP-1 activates the human GLP-1R. max2. The peptide dual agonist of any one of the preceding claims, which activates human GLP-1R with a mAb value.

[0351] 41. The peptide, a. EC for human GIPR of 10 nM or less 50 having b. EC for human GLP-2R ≤ 50 nM 50 having The peptide dual agonist of any one of the preceding paragraphs.

[0352] 42. The peptide has an EC50 activity against human GLP-1R of 10 nM or more. 50 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

[0353] 43. The peptide has an EC 50 EC50 for human GIPR at least 10-fold lower than that 50 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

[0354] 44. The peptide has an EC 50 EC50 for human GLP-2R at least 10-fold lower than 50 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

[0355] 45. The peptide dual agonist of any one of the preceding items, wherein the peptide is selected from the group consisting of: Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-K(γGlu-C16)-SDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTIL-K(γGlu-C16)-NLAARDFINWLIQTKITK-OH Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2 Compound No. 24, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 25, SEQ ID NO: 21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 26, SEQ ID NO:8 H-Aib-DG-K(γGlu-γGlu-C10)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 27, SEQ ID NO: 22 H-Aib-EG-K(γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 28, SEQ ID NO: 21 H-Aib-DG-K(γGlu-γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDY-K(γGlu-C10)-T-Aib-LDNLAARDFINWLIQTKITD-OH Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIETKITK-OH Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYS-K(γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDY-K(γglu-C10)-T-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ-OH Compound No. 1, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 2, SEQ ID NO: 2 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKIT Compound No. 45, SEQ ID NO: 38 (C16)HADGTFISDYSTILDNLAAKDFINWLIQTKITK Compound No. 3, SEQ ID NO: 3 (C10)HADGTFISDYSTILDNLAAKDFINWLIQTKITKNDWKHNITQ Compound No. 46, SEQ ID NO: 39 (C16)HADGTFISDYSTILDNLAARDFINWLLAQKITK Compound No. 4, SEQ ID NO: 1 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITD Compound No. 5, SEQ ID NO: 4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 6, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH Compound No. 7, SEQ ID NO: 6 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK-OH Compound No. 8, SEQ ID NO: 7 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT-OH Compound No. 15, SEQ ID NO: 14 (C16)HADGTFISDYSTILELLAARDFINWLIQTKITKNDWKHNITQ Compound No. 48, SEQ ID NO: 41 (C16)HADGTFISDYSTILDELAARDFINWLIQTKITKNDWKHNITQ Compound No. 49, SEQ ID NO: 42 (C16)HADGTFISDYSTILDNLAARDFINWLIQTKITKAEWKHAITQ Compound No. 50, SEQ ID NO: 43 (C16)HADGTFISDYSTILDNLAARDFIEWLIQTKITKNDWKHNITQ Compound No. 51, SEQ ID NO: 44 (C16)HADGTFISDYSTILDNLAARDFINWLIETKITKNDWKHNITQ Compound No. 52, SEQ ID NO: 45 (C16)HADGTFISDYSTILDNLAARDFINWLIATKITKNDWKHNITQ Compound No. 53, SEQ ID NO: 33 (C16)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 16, SEQ ID NO: 15 (C16)HADGTFISDYSTILDAibLAARDFINWLIQTKITKNDWKHNITQ Compound No. 17, SEQ ID NO: 4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 18, SEQ ID NO: 4 (C10-Diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 19, SEQ ID NO: 16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 20, SEQ ID NO: 17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 21, SEQ ID NO: 18 (C16-Diacid)H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK-OH Compound No. 22, SEQ ID NO: 19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH Compound No. 23, SEQ ID NO: 20 (C16-DIACID)H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK-OH Compound No. 39, SEQ ID NO: 33 (C16-diacid)HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ Compound No. 40, SEQ ID NO: 34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 41, SEQ ID NO: 35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 42, SEQ ID NO: 36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 43, SEQ ID NO: 37 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, and Compound No. 44, SEQ ID NO: 4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH.

[0356] 46. ​​The peptide dual agonist of any one of the preceding claims, wherein the peptide is selected from the group consisting of: SEQ ID NO:4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH, Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K(γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH, SEQ ID NO: 10, Compound No. 10 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:11 H-Aib-DGTFISDYS-K(γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:13 H-Aib-DGTFISDY-K(γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2, SEQ ID NO:4 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:16 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:17 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:19 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K(γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:23 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:28 H-Aib-DGTFISDY-K(γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:31 H-Aib-DGTFISDY-K(γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:34 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:35 (C16-diacid)H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:36 (C16-diacid)H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:4 (C10)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, and SEQ ID NO:26 H-Aib-DGTFISDY-K(γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH.

[0357] 47. A peptide dual agonist according to any one of the preceding paragraphs for use as a medicament.

[0358] 48. A peptide dual agonist according to any one of the preceding paragraphs for use in a method of inhibiting bone resorption and / or stimulating bone formation.

[0359] 49. A peptide dual agonist according to any one of the preceding paragraphs for use in a method for treating a bone disorder.

[0360] 50. A peptide dual agonist for use according to any one of the preceding claims, wherein the bone disorder is selected from the group consisting of osteopenia, osteoporosis, severe osteoporosis, postmenopausal osteoporosis, idiopathic osteoporosis, osteomalacia, rickets, osteitis cystica (OFC) and Paget's disease of bone.

[0361] 51. A peptide dual agonist according to any one of the preceding paragraphs for use in a method for treating osteoporosis in an individual suffering from Duchenne muscular dystrophy (DMD) or cerebral palsy.

Claims

1. array: HX ２ X ３ GX ５ FX ７ X ８ X ９ X １０ X １１ X １２ X １３ X １４ X １５ X １６ LAAX ２０ DFIX ２４ WLIX ２８ TKX ３１ X ３２ X ３３ -Z (SEQ ID NO: 68) wherein X ２ is Aib, X ３ is D, K, or E; X ５ is T, K, or S; X ７ is K or I, X ８ is K or S, X ９ is D or K, X １０ is Y or K, X １１ is S, K, or N; X １２ is K or T, X １３ is A, Aib, K, or I; X １４ is L or K, X １５ is K, D, or E; X １６ are E, L, A, K, A, and N; X ２０ is R or K, X ２４ is N or E, X ２８ is Q, E, or A; X ３１ is I, G, or omitted, X ３２ is T, K, or omitted, X ３３ is K, G, D or omitted, wherein Z is a peptide comprising one or more amino acid residues of GIP(34-42) (NDWKHNITQ, SEQ ID NO:58); the peptide is modified by attachment of at least one fatty acid molecule to the N-terminus of SEQ ID NO:68 and / or to one or more lysine residues at any one of positions 1-15; The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor); A peptide dual agonist comprising or consisting of the sequence.

2. The peptide has the sequence HX ２ X ３ GX ５ FIX ８ X ９ X １０ X １１ X １２ X １３ LX １５ X １６ LAAX ２０ DFIX ２４ WLIX ２８ TKX ３１ X ３２ X ３３ -Z (SEQ ID NO: 69), wherein X ２ is Aib, X ３ is D or E, X ５ is T, K, or S; X ８ is K or S, X ９ is D or K, X １０ is Y or K, X １１ is S or K, X １２ is K or T, X １３ is Aib or I, X １５ is D or E, X １６ are E, L, A, K, A, and N; X ２０ is R or K, X ２４ is N or E, X ２８ is Q, E, or A; X ３１ is I, G, or omitted, X ３２ is T or omitted, X ３３ is K, G, D or omitted, 2. The peptide dual agonist of claim 1, comprising or consisting of said sequence.

3. 10. A peptide dual agonist according to any one of the preceding claims, wherein the peptide is modified at any one of positions 2-15 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

4. 13. A peptide dual agonist according to any one of the preceding claims, comprising: X ２ is Aib, X ３ is D or E, X ５ is T or K, X ７ is I, X １１ is S or K, X １３ is Aib or I, X １５ is D or E, X １６ are E, L, A, K, A, and N; X ２４ is N or E, X ２８ is Q, E, or A; X ３１ is I, G, or omitted, X ３２ is T or omitted, The peptide dual agonists.

5. 13. A peptide dual agonist according to any one of the preceding claims, comprising: X ３ is D, X ７ is I, X １５ is D, X ３１ is I, X ３２ is T, The peptide dual agonists.

6. X １３ 4. The peptide dual agonist of any one of the preceding claims, wherein is Aib.

7. X １６ 4. The peptide dual agonist of any one of the preceding claims, wherein is A, Aib, L, E.

8. X ２ is Aib, and X １３ 4. The peptide dual agonist of any one of the preceding claims, wherein is Aib.

9. X ２ is Aib, and X １１ 4. The peptide dual agonist of any one of the preceding claims, wherein

10. X ２ is Aib, and X ５ is K and X １３ 4. The peptide dual agonist of any one of the preceding claims, wherein is Aib.

11. X ２ is Aib, and X １１ is K and X １３ 4. The peptide dual agonist of any one of the preceding claims, wherein is Aib.

12. X ２ is Aib, and X １１ is K and X ２４ 4. The peptide dual agonist of any one of the preceding claims, wherein

13. Z is:

10. The peptide dual agonist of any one of the preceding claims, selected from the group consisting of ND, NDW, KDW, NDW, NDK, NDWK, NDWKH, NDWKHN, NDWKHNI, NDWKHNIT, NDWKHNITQ, and AEWKHAITQ or a variant containing one amino acid substitution.

14. Z is: AEWKHAITQ (SEQ ID NO:65) and NDWKHNITQ (SEQ ID NO:64) 2. The peptide dual agonist of any one of the preceding claims, selected from the group consisting of:

15. A peptide dual agonist according to any one of claims 1 and 2, wherein the peptide is modified at the N-terminal amino acid residue of SEQ ID NO:68, for example at the amino acid residue at position 1 of SEQ ID NO:68, by attaching at least one fatty acid molecule.

16. X ７ is I, and the peptide is modified by attaching one fatty acid molecule to position 1 of SEQ ID NO:68, such as to the N-terminus of SEQ ID NO:

68.

17. The peptide Compound No. 9, SEQ ID NO: 8 H-Aib-DGKFISDYSTILDNLAAARDFINWLIQTKITK, Compound No. 10, SEQ ID NO: 9 H-Aib-DGTFKSDYSTILDNLAARDFINWLIQTKITK, Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTILKNLAARDFINWLIQTKITK, Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKGKKNDWKHNITQ, Compound No. 24, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 25, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 26, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAAARDFINWLIQTKITK, Compound No. 27, SEQ ID NO: 22 H-Aib-EGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 28, SEQ ID NO: 21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITD, Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK, Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDYKTILDNLAARDFINWLIETKITK, Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYSKAib-LDNLAARDFINWLIQTKITK, Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDYKTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, Compound No. 5, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 6, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, Compound No. 7, SEQ ID NO: 6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, Compound No. 8, SEQ ID NO: 7 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, Compound No. 17, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 19, SEQ ID NO: 16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Compound No. 20, SEQ ID NO: 17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, Compound No. 21, SEQ ID NO: 18 H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, Compound No. 22, SEQ ID NO: 19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, Compound No. 23, SEQ ID NO: 20 H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, Compound No. 39, SEQ ID NO: 33 HADGTFISDYSTAibLDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 40, SEQ ID NO: 34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Compound No. 41, SEQ ID NO: 35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, Compound No. 42, SEQ ID NO: 36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, Compound No. 43, SEQ ID NO: 37 H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and Compound No. 44, SEQ ID NO: 4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, or a functional variant thereof, wherein the functional variant is selected from the group consisting of the functional variants comprising one or two individual amino acid substitutions.

10. A peptide dual agonist according to any one of the preceding claims.

18. The peptide is SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:8 H-Aib-DGKFISDYSTILDNLAAARDFINWLIQTKITK, SEQ ID NO:10 H-Aib-DGTFISDYKTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYSKILDNLAARDFINWLIQTKITK, SEQ ID NO:13 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:16 H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:17 H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, SEQ ID NO:21 H-Aib-DGKFISDYST-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:23 H-Aib-DGTFISDYKT-Aib-LDNLAARDFINWLIQTKITK, SEQ ID NO:28 H-Aib-DGTFISDYKT-Aib-LDALAARDFIEWLIQTKITK, SEQ ID NO:31 H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:35 H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:36 H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, and SEQ ID NO:26 H-Aib-DGTFISDYKTILDKLAARDFIEWLIATKITK, or a functional variant thereof, wherein the functional variant is selected from the group consisting of the functional variants comprising one or two individual amino acid substitutions.

10. A peptide dual agonist according to any one of the preceding claims.

19. below: Compound No. 9, SEQ ID NO: 8 H-Aib-DG-KFISDYSTILDNLAAARDFINWLIQTKITK, Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-KSDYSTILDNLAARDFINWLIQTKITK, Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKITK, SEQ ID NO:11 H-Aib-DGTFISDYS-KILDNLAARDFINWLIQTKITK, SEQ ID NO:12 H-Aib-DGTFISDYSTIL-KNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDY-KTILDNLAARDFINWLIQTKGKKNDWKHNITQ, SEQ ID NO:21 H-Aib-DG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DG-KFISDYSTILDNLAAARDFINWLIQTKITK, Sequence number H-Aib-EG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DG-KFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITD, Sequence number H-Aib-DGTFISDY-KTILDKLAARDFIEWLIATKITK, Sequence number H-Aib-DGTFISDY-KTILDNLAARDFINWLIETKITK, Sequence number H-Aib-DGTFISDY-KT-Aib-LDALAARDFIEWLIQTKITK, Sequence number Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, Sequence number Ac-H-Aib-DGTFISDYS-KAib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDY-KTAib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Sequence number Ac-H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Sequence number H-Aib-DGTFISDY-KT-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ, SEQ ID NO:5 H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK, SEQ ID NO:6 H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK, Sequence number H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT, SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, Sequence number H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK, Sequence number H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK, SEQ ID NO:19 H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK, Sequence number H-Aib-DGTFISDYST-Aib-LDKLAARDFINWLIETKITK, SEQ ID NO:34 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ, Sequence number H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ, Sequence number H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, Sequence number H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ, and SEQ ID NO:4 H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK, or a functional variant thereof, wherein said functional variant comprises one to three individual amino acid substitutions, with the proviso that the amino acid residue at position 2 of said functional variant is Aib; the amino acid residue at position 6 of the functional variant is phenylalanine (F); the amino acid residue at position 22 of the functional variant is phenylalanine (F); the amino acid residue at position 25 of the functional variant is tryptophan (W); the amino acid residue at position 26 of said functional variant is leucine (L); the peptide is modified by attaching at least one fatty acid molecule to one or more amino acid residues at any one of positions 1 to 15 of the above sequence; The peptide is an agonist of GIPR (glucose-dependent insulinotropic polypeptide receptor) and an agonist of GLP-2R (glucagon-like peptide-2 receptor); The peptide dual agonists.

20. The peptide is amidated at the C-terminus (-NH ２ 2. The peptide dual agonist of any one of the preceding claims, wherein the C-terminus is either 1 or 2;

21. 2. A peptide dual agonist according to any one of the preceding claims, wherein the peptide is modified by attaching at least one fatty acid molecule to the lysine (K) at any one of positions 2-15 of SEQ ID NO: 68 or 69.

22. 20. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified by attachment of at least one fatty acid molecule to position 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 68 or 69.

23. 2. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at position 3, 4, 5, 6, 7, 8, 9, 10, 11 or 12 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

24. 2. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at position 3, 4, 5, 6, 7, 8, 9, 10, or 11 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

25. 2. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at position 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, or 15 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

26. 2. The peptide dual agonist of any one of the preceding claims, wherein the peptide is modified at position 5, 6, 7, 8, 9, 10, 11 or 12 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

27. 2. A peptide dual agonist according to any one of the preceding claims, wherein the peptide is modified at any one of positions 5, 7, 8, 11, 12, 15 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

28. 2. A peptide dual agonist according to any one of the preceding claims, wherein the peptide is modified at any one of positions 5, 7, 8, 11, 12 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

29. X １３ is Aib, and the peptide is modified at any one of positions 5 or 11 of SEQ ID NO: 68 or 69 by attaching at least one fatty acid molecule.

30. 2. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a straight chain fatty acid.

31. 2. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a branched fatty acid.

32. 10. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a monoacyl fatty acid molecule containing one fatty acid.

33. 2. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is a diacyl fatty acid molecule.

34. The fatty acid molecule is CH ３ (CH ２ ) ８ CO- (Capryl, C10), CH ３ (CH ２ ) １０ CO-(Lauryl, C12), CH ３ (CH ２ ) １２ CO-(myristoyl, C14), CH ３ (CH ２ ) １４ CO-(palmitoyl, C16), CH ３ (CH ２ ) １６ CO-(stearyl, C18) and CH ３ (CH ２ ) １８ 2. The peptide dual agonist of any one of the preceding claims, comprising an acyl group selected from the group consisting of: CO-(arachidyl, C20).

35. The fatty acid molecule is HOOC-CH ３ (CH ２ ) ８ CO-(decanoyl, C10), HOOC-CH ３ (CH ２ ) １０ CO-(dodecanoyl, C12), HOOC-CH ３ (CH ２ ) １２ CO-(1-tetradecanoyl, C14), HOOC-CH ３ (CH ２ ) １４ CO-(hexadecanoyl, C16), HOOC-CH ３ (CH ２ ) １５ CO-(15-carboxy-pentadecanoyl, C17), HOOC-CH ３ (CH ２ ) １６ CO-(octadecanoyl, C18), HOOC-CH ３ (CH ２ ) １７ CO-(17-carboxy-heptadecanoyl, C19), HOOC-CH ３ (CH ２ ) １８ CO- (eicosanoyl, C20), and HOOC-CH ３ (CH ２ ) １９ 2. A peptide dual agonist according to any one of the preceding claims, comprising two acyl groups individually selected from the group consisting of: CO-(19-carboxy-nonadecanoyl, C21).

36. 2. The peptide dual agonist of any one of the preceding claims, wherein the fatty acid molecule is attached to the amino acid residue via a spacer.

37. 2. The peptide dual agonist of any one of the preceding claims, wherein the spacer comprises yGlu.

38. 10. A peptide dual agonist according to any one of the preceding claims, wherein the spacer comprises or consists of yGlu or yGlu-yGlu.

39. The peptide is a. at least 65% as effective as native human GIP in activating human GIPR, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% as effective as native human GIP in activating human GIPR (E ｍａｘ Activating human GIPR with b. at least 65% as effective as native human GLP-2 to activate human GLP-2R, e.g., at least 70%, e.g., at least 75%, e.g., at least 80%, e.g., at least 85%, e.g., at least 90%, e.g., at least 95% as effective as native human GLP-2 to activate human GLP-2R (E ｍａｘ Activating human GLP-2R with 10. A peptide dual agonist according to any one of the preceding claims.

40. The peptide has an efficacy (E) that is up to 80% of the efficacy of native human GLP-1 in activating the human GLP-1R. ｍａｘ value) that is up to 70% of the efficacy with which native human GLP-1 activates human GLP-1R. ｍａｘ value) that is up to 60% of the efficacy with which native human GLP-1 activates human GLP-1R. ｍａｘ 2. A peptide dual agonist according to any one of the preceding claims which activates human GLP-1R with a GLP-1R concentration of 0.1 to 0.25 mM.

41. The peptide is a. EC50 for human GIPR of 10 nM or less ５０ having b. EC50 for human GLP-2R of 50 nM or less ５０ having 10. A peptide dual agonist according to any one of the preceding claims.

42. The peptide has an EC ５０ 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

43. The peptide has an EC ５０ EC50 for human GIPR at least 10-fold lower than ５０ 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

44. The peptide has an EC ５０ EC50 for human GLP-2R is at least 10-fold lower than ５０ 2. The peptide dual agonist of any one of the preceding claims, having the following structure:

45. The peptide comprising: Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K (γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 10, SEQ ID NO: 9 H-Aib-DGTF-K (γGlu-C16)-SDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 11, SEQ ID NO: 10 H-Aib-DGTFISDY-K (γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH Compound No. 12, SEQ ID NO: 11 H-Aib-DGTFISDYS-K (γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH Compound No. 13, SEQ ID NO: 12 H-Aib-DGTFISDYSTIL-K (γGlu-C16)-NLAARDFINWLIQTKITK-OH Compound No. 14, SEQ ID NO: 13 H-Aib-DGTFISDY-K (γGlu-C16)-TILDNLAARDFINWLIQTKGKKNDWKHNITQ-NH2 Compound No. 24, SEQ ID NO: 21 H-Aib-DG-K (γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 25, SEQ ID NO: 21 H-Aib-DG-K (γGlu-C16 diacid)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 26, SEQ ID NO:8 H-Aib-DG-K (γGlu-γGlu-C10)-FISDYSTILDNLAARDFINWLIQTKITK-OH Compound No. 27, SEQ ID NO: 22 H-Aib-EG-K (γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 28, SEQ ID NO: 21 H-Aib-DG-K (γGlu-γGlu-C16)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 29, SEQ ID NO: 23 H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 30, SEQ ID NO: 25 H-Aib-DGTFISDY-K (γGlu-C10)-T-Aib-LDNLAARDFINWLIQTKITD-OH Compound No. 31, SEQ ID NO: 26 H-Aib-DGTFISDY-K (γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH Compound No. 32, SEQ ID NO: 27 H-Aib-DGTFISDY-K (γGlu-C16)-TILDNLAARDFINWLIETKITK-OH Compound No. 33, SEQ ID NO: 28 H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 34, SEQ ID NO: 24 Ac-H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 35, SEQ ID NO: 29 H-Aib-DGTFISDYS-K (γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 36, SEQ ID NO: 30 Ac-H-Aib-DGTFISDYS-K (γGlu-C16)-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 37, SEQ ID NO: 31 H-Aib-DGTFISDY-K (γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 38, SEQ ID NO: 32 Ac-H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 54, SEQ ID NO: 46 H-Aib-DGTFISDY-K (γglu-C10)-T-Aib-LDNLAARDFINWLIQTKITGNDWKHNITQ-OH Compound No. 5, SEQ ID NO: 4 (C16)H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 6, SEQ ID NO:5 (C16)H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH Compound No. 7, SEQ ID NO: 6 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKITK-OH Compound No. 8, SEQ ID NO: 7 (C16)H-Aib-DGTFISDYSTILDNLAARDFIEWLIQTKIT-OH Compound No. 17, SEQ ID NO: 4 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 18, SEQ ID NO: 4 (C10-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 19, SEQ ID NO: 16 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH Compound No. 20, SEQ ID NO: 17 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH Compound No. 21, SEQ ID NO: 18 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDKLAARDFINWLIQTKITK-OH Compound No. 22, SEQ ID NO: 19 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH Compound No. 23, SEQ ID NO: 20 Compound No. 40, SEQ ID NO: 34 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 41, SEQ ID NO: 35 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH Compound No. 42, SEQ ID NO: 36 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH Compound No. 43, SEQ ID NO: 37 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, and Compound No. 44, SEQ ID NO: 4 (C10) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, or a functional variant thereof, wherein the functional variant is selected from the group consisting of the functional variants comprising one or two individual amino acid substitutions.

10. A peptide dual agonist according to any one of the preceding claims.

46. The peptide SEQ ID NO:4 (C16) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:5 (C16) H-Aib-DGTFISDYSTILD-Aib-LAARDFINWLIQTKITK-OH, Compound No. 9, SEQ ID NO: 8 H-Aib-DG-K (γGlu-C16)-FISDYSTILDNLAARDFINWLIQTKITK-OH, SEQ ID NO: 10, Compound No. 10 H-Aib-DGTFISDY-K (γGlu-C16)-TILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:11 H-Aib-DGTFISDYS-K (γGlu-C16)-ILDNLAARDFINWLIQTKITK-OH, SEQ ID NO:13 <h2 style=";text-align:left;direction:ltr">I am sorry, I did not find this information.<h2 style=";text-align:left;direction:ltr"> ２ <h2 style=";text-align:left;direction:ltr"> 、 SEQ ID NO:4 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:16 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:17 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:19 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDKLAARDFIEWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K (γGlu-C10)-FISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DG-K(γGlu-C16 diacid)-FISDYST-Aib-LDNL AARDFINWLIQTKITK-OH, SEQ ID NO:21 H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDNLAARDFINWLIQTKITK-OH, SEQ ID NO:28 H-Aib-DGTFISDY-K (γGlu-C16)-T-Aib-LDALAARDFIEWLIQTKITK-OH, SEQ ID NO:31 H-Aib-DGTFISDY-K (γGlu-C16)-TAib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:34 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:35 (C16-diacid) H-Aib-EGTFISDYST-Aib-LDALAARDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:36 (C16-diacid) H-Aib-DGTFISDYST-Aib-LDNLAAKDFINWLIQTKITKNDWKHNITQ-OH, SEQ ID NO:4 (C10) H-Aib-DGTFISDYST-Aib-LDNLAARDFINWLIQTKITK-OH, and SEQ ID NO:26 H-Aib-DGTFISDY-K (γGlu-C10)-TILDKLAARDFIEWLIATKITK-OH, or a functional variant thereof, wherein the functional variant is selected from the group consisting of the functional variants comprising one or two individual amino acid substitutions.

10. A peptide dual agonist according to any one of the preceding claims.

47. 13. A peptide dual agonist according to any one of the preceding claims for use as a medicament.

48. 13. A peptide dual agonist according to any one of the preceding claims for use in a method for inhibiting bone resorption and / or stimulating bone formation.

49. 13. A peptide dual agonist according to any one of the preceding claims for use in a method for treating a bone disorder.

50. 2. The peptide dual agonist for use according to any one of the preceding claims, wherein the bone disorder is selected from the group consisting of osteopenia, osteoporosis, severe osteoporosis, postmenopausal osteoporosis, idiopathic osteoporosis, osteomalacia, rickets, osteitis cystica (OFC) and Paget's disease of bone.

51. 10. A peptide dual agonist according to any one of the preceding claims for use in a method for treating osteoporosis in an individual suffering from Duchenne muscular dystrophy (DMD) or cerebral palsy.

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