WO2020115048A1 - Modified gip peptide analogues - Google Patents

Modified gip peptide analogues Download PDF

Info

Publication number
WO2020115048A1
WO2020115048A1 PCT/EP2019/083506 EP2019083506W WO2020115048A1 WO 2020115048 A1 WO2020115048 A1 WO 2020115048A1 EP 2019083506 W EP2019083506 W EP 2019083506W WO 2020115048 A1 WO2020115048 A1 WO 2020115048A1
Authority
WO
WIPO (PCT)
Prior art keywords
gip
seq
amino acid
diacid
cex
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Ceased
Application number
PCT/EP2019/083506
Other languages
English (en)
French (fr)
Inventor
Alexander Hovard SPARRE-ULRICH
Bjørn Behrens SIVERTSEN
Ditte Riber
Mette Marie ROSENKILDE
Current Assignee (The listed assignees may be inaccurate. Google has not performed a legal analysis and makes no representation or warranty as to the accuracy of the list.)
Antag Therapeutics Aps
Original Assignee
Antag Therapeutics Aps
Priority date (The priority date is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the date listed.)
Filing date
Publication date
Application filed by Antag Therapeutics Aps filed Critical Antag Therapeutics Aps
Priority to CA3121043A priority Critical patent/CA3121043A1/en
Priority to AU2019391300A priority patent/AU2019391300B2/en
Priority to EP19812788.8A priority patent/EP3891173A1/en
Priority to JP2021552785A priority patent/JP7605747B2/ja
Priority to KR1020217019677A priority patent/KR102906485B1/ko
Priority to MX2021006505A priority patent/MX2021006505A/es
Priority to US17/298,512 priority patent/US12297250B2/en
Priority to BR112021010447-0A priority patent/BR112021010447A2/pt
Priority to SG11202105586YA priority patent/SG11202105586YA/en
Priority to CN201980090373.3A priority patent/CN113366014B/zh
Publication of WO2020115048A1 publication Critical patent/WO2020115048A1/en
Priority to MX2022006737A priority patent/MX2022006737A/es
Priority to CA3157387A priority patent/CA3157387A1/en
Priority to JP2022532697A priority patent/JP7788376B2/ja
Priority to US17/776,976 priority patent/US20250346647A2/en
Priority to PCT/EP2020/084487 priority patent/WO2021110845A1/en
Priority to CN202080083881.1A priority patent/CN114761420A/zh
Priority to KR1020227018518A priority patent/KR20220108064A/ko
Priority to IL293249A priority patent/IL293249A/en
Priority to AU2020398675A priority patent/AU2020398675A1/en
Priority to EP20815874.1A priority patent/EP4069719A1/en
Priority to IL283385A priority patent/IL283385A/en
Anticipated expiration legal-status Critical
Priority to US19/096,393 priority patent/US20250376499A1/en
Priority to JP2025141835A priority patent/JP2025172864A/ja
Priority to AU2025237957A priority patent/AU2025237957A1/en
Ceased legal-status Critical Current

Links

Classifications

    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/605—Glucagons
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides
    • A61K38/16—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • A61K38/17—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • A61K38/22—Hormones
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P3/00—Drugs for disorders of the metabolism
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
    • C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
    • C07K14/575—Hormones
    • C07K14/645—Secretins
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • the present invention relates to glucose-dependent insulinotropic peptide (GIP) - derived peptide analogues which are antagonists of the GIP receptor.
  • GIP glucose-dependent insulinotropic peptide
  • These GIP peptide analogues are modified by comprising one or more individual amino acid substitutions and are fatty acid conjugated with/without a linker, so to have improved antagonistic activity and improved pharmacokinetic profile.
  • GLP-1 compounds A range of different approaches have been used for modifying the structure of GLP-1 compounds in order to provide a longer duration of action in vivo. These include introduction of a lipophilic substituent to an amino acid residue (WO 96/29342 and WO 98/08871 ) and acylated GLP-1 analogues (WO 00/34331 ).
  • WO 02/46227 discloses GLP-1 and exendin-4 analogues fused to human serum albumin in order to extend in vivo half-life.
  • GIP peptides such as peptides comprising one or more of GIP(31-42) residues or peptides comprising one or more residues of Exendin-4 attached to the C-terminus of any one of GIP3-30, GIP5-30 and GIP6-30, and which are acylated, retain or even show improved GIPR antagonistic properties and/or extraordinarily long in vivo half-life’s and/or increased selectivity. This makes them potentially useful in a range of therapeutic applications.
  • GIP(3-30)/GIP(5-30)/GIP(6- 30) and analogues thereof are extended with amino acid residues from the C-terminal part of Exendin-4 or GIP(1-42), such as e.g. GPSSGAPPPS, PSSGAPPPS or
  • drug and “medicament” as used herein include biologically, physiologically, or pharmacologically active substances that act locally or systemically in the human or animal body.
  • the term "palliation”, and variations thereof, as used herein, means that the extent and/or undesirable manifestations of a physiological condition or symptom are lessened and/or time course of the progression is slowed or lengthened, as compared to not administering compositions of the present invention.
  • a treatment according to the invention can be prophylactic, ameliorating and/or curative.
  • bioactive agent in the present context refers to a GIP peptide analogue as disclosed herein.
  • GPS GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,
  • GPSSGAPPPS, PSSGAPPPS, GKKNDW, or fragments thereof, and lipidation in specific positions may result in both improved antagonistic effect and at the same time improved half-life to a surprisingly large extent of more than 5 or 10 hours or even more than 15 or 20 hours compared to the corresponding sequence without C-terminal extension.
  • said peptide is C-terminally carboxylated (-COOH).
  • a free C-terminal carboxylic acid may be able to assist in an increased binding to albumin and thus unexpectedly extend in vivo half-life further.
  • Exendin-4 is a GLP-1 agonist, thus improving GIP antagonistic effects by extending of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5- 30), SEQ ID NO: GIP(6-30) analogues with amino acid residues from the C-terminal part of Exendin-4 is very unexpected.
  • amino acid at position 21 is selected from D and E;
  • amino acid at position 24 is selected from N, K, Q and E;
  • amino acid at position 29 is selected from Q and G; and/or
  • GIP peptide analogue or a functional variant thereof as disclosed herein, wherein said GIP peptide analogue consists of amino acid sequence SEQ ID NO: XX, and wherein Xi and X2 are omitted.
  • a GIP peptide analogue or a functional variant thereof as disclosed herein wherein said functional variant has 1 to 2 individual amino acid substitutions, such as 2 to 3 individual amino acid substitutions, such as 3 to 4 individual amino acid substitutions, such as 4 to 5 individual amino acid substitutions, such as 5 to 6 individual amino acid substitutions, such as 6 to 7 individual amino acid substitutions, such as 7 to 8 individual amino acid substitutions at any one of amino acid residues 3, 4, 7, 8, 9, 11 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 24, 28, 29 and 30 of SEQ ID NO: XX.
  • a GIP peptide analogue or a functional variant thereof as disclosed herein wherein said functional variant has1 to 2 individual amino acid substitutions at any one of amino acid residues 4 to 10 of SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6- 30).
  • a GIP peptide analogue or a functional variant thereof as disclosed herein wherein the E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:), such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3- 30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30) is substituted with a pyroE (pyroglutamate).
  • E (Glu) at position 3 of (hGIP3-30, SEQ ID NO:) such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3- 30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30) is substituted with a pyroE (pyroglutamate).
  • GIP(3-30)XI-X 2 SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30),
  • GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a functional variant thereof, is substituted with an amino acid residue selected from the group consisting of L, Norleucine (Nle) and K.
  • the amino acid at position 14 is L or Nle. Since, M is prone to oxidation it may be an advantage to substitute it with another amino acid such as L, Nle or K, for example L or Nle.
  • a GIP peptide analogue or a functional variant thereof wherein the D at position 9 and/or at position 15 of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30) or a functional variant thereof, is substituted with E.
  • GIP(3-30)XI-X 2 SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or of the functional variant thereof, is substituted with a conservative amino acid.
  • GIP(3-30)XI-X 2 SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or of a functional variant thereof, is substituted with a K or a Orn.
  • GIP(3-30)XI-X 2 SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or of the functional variant thereof, is substituted with K or Orn.
  • a GIP peptide analogue or a functional variant thereof wherein the amino acid residues at positions 9, 15, 21 , and 24 are all individually an alfa-helix stabilizing amino acid residue selected from the group consisting of A, L, E and K.
  • GIP peptide analogue SEQ ID NO: XX
  • a functional variant thereof wherein
  • amino acid at position 10 is Y;
  • amino acid at position 22 is F
  • amino acid at position 23 is V;
  • a GIP peptide analogue (SEQ ID NO: XX) or a functional variant thereof, wherein the amino acid at position 6 is F.
  • a GIP peptide analogue (SEQ ID NO: XX) or a functional variant thereof, wherein the amino acid at position 7 is I.
  • GIP peptide analogue SEQ ID NO: XX
  • a functional variant thereof wherein the amino acid at position 10 is Y.
  • GIP peptide analogue SEQ ID NO: XX
  • a functional variant thereof wherein the amino acid at position 23 is V.
  • a GIP peptide analogue (SEQ ID NO: XX) or a functional variant thereof, wherein the amino acid at position 27 is L.
  • GIP peptide analogue (SEQ ID NO: XX) wherein the amino acid residue at position 3 is E or glutaric acid or absent,
  • amino acid residue at position 4 is G or absent
  • amino acid residue at position 5 is T
  • amino acid residue at position 7 is I
  • amino acid residue at position 1 1 is K or S
  • amino acid residue at position 19 is Q
  • amino acid residue at position 21 is D or E
  • amino acid residue at position 24 is N, A, Q or E,
  • amino acid residue at position 28 is A, E or K,
  • GIP peptide analogue (SEQ ID NO: XX) wherein the amino acid at position 3 is E or glutaric acid or absent;
  • amino acid at position 4 is Gly or absent
  • amino acid at position 16 is selected from K and R;
  • amino acid at position 24 is selected from N, Q and E;
  • amino acid at position 29 is selected from Q and G; and/or
  • amino acid at position 26 is L;
  • the present disclosure provides a GIP peptide analogue consisting of SEQ ID NO: (GIP3-30): 18 19 20 21 22 23 24 25 26 27 28 29 30
  • Z consists of one or more consecutive amino acid residues of GIP(31-42) (SEQ ID NO: Z).
  • Z consists of one or more amino consecutive acid residues of the C-terminus of Exendin-4(30-39) (PSSGAPPPS; SEQ ID NO: CE30-39).
  • Z comprises at least one G or one P.
  • Z comprises a G or P, such as e.g. in position 31 and/or 32, the half-life of the GIP peptide analogue increases, which may be due to decreased degradation from the C-terminus, which increases the in vivo stability of the GIP peptide analogue.
  • Z comprises at least two P.
  • Z is a peptide selected from the group consisting of
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GKKKDW, GKKNDK GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any one of the amino acid residues, or
  • a fatty acid molecule is not attached at the N-terminal amino group of the amino acid residue at position 3 of SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi or SEQ ID NO: GIP(3-30).
  • a fatty acid molecule is not attached at the N-terminal amino group of the amino acid residue at position 5 of SEQ ID NO: GIP(5-30).
  • a fatty acid molecule is not attached to an amino acid residue of Z.
  • a fatty acid molecule is attached to an amino acid residue at any one of positions 7 to 29 of said GIP peptide analogue, such as of SEQ ID NO: XX.
  • a fatty acid molecule is attached to an amino acid residue at any one of positions 7 to 29 of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a variant thereof.
  • a fatty acid molecule is attached to an amino acid residue at position 5, position 6, position 7, position 8, position 9, position 10, position 1 1 , position 12, position 13, position 14, position 15, position 16, position 17, position 18, position 19, position 20, position 21 , position 22, position 23, position 24, position 25, position 26, position 27, position 28 or position 29 of said GIP peptide analogue, such as of SEQ ID NO: XX, or a functional variant thereof.
  • a fatty acid molecule is attached to one or more amino acid residues in the mid-region of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)X I -X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6- 30), or a functional variant thereof.
  • a fatty acid molecule is attached to one or more amino acid residues at any one of positions 1 1 , 12, 17 and 18 of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5- 30), SEQ ID NO: GIP(6-30), or a functional variant thereof. Attachment of a fatty acid at any one of these positions may result in a GIP peptide analogue with particularly long half-life and having a particularly high antagonistic potency.
  • a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 16 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a functional variant thereof.
  • a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 18 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ I D NO: GI P(3-30)X 2 , SEQ I D NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a variant thereof, wherein H at position 18 has been substituted with K or Orn in said GIP peptide analogue. Attachment of a fatty acid to the side chain amino group of the amino acid residue at position 18 may result in a GIP peptide analogue with particularly long half- life and having a particularly high antagonistic potency.
  • a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 1 1 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a variant thereof, wherein S at position 1 1 has been substituted with K or Orn in said GIP peptide analogue.
  • a fatty acid molecule is attached to the side chain amino group of the amino acid residue at position 12 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a variant thereof, wherein I at position 12 has been substituted with K or Orn in said GIP peptide analogue.
  • At least one fatty acid molecule is attached at the amino acid residue at positions 1 1 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3- 30)Xi, SEQ ID NO: GIP(3-30), SEQ ID NO: GIP(4-30)X 2 , SEQ ID NO: GIP(4-30), SEQ ID NO: GIP(5-30), SEQ ID NO: GIP(6-30), or a functional variant thereof.
  • At least one fatty acid molecule is attached at a Lysine at position 18 of said GIP peptide analogue, such as of any one of SEQ ID NO: XX, SEQ ID NO: GIP(3-30)XI-X 2, SEQ ID NO: GIP(3-30)X 2 , SEQ ID NO: GIP(3-30)Xi, SEQ ID NO:
  • GIP(3-30) [D9T;S1 1 K; M14L;N24E], EGTFISDYSIAibMDKIKQQDFVEWLLAQK - Z; SEQ ID NO; GIP(3-30)
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 4 to 29 of any one of any one of the above sequences, and wherein said peptide may be C-terminal carboxylated.
  • GIP GIP peptide analogue or functional variant thereof, said peptide being an analogue of hGIP5-30 (SEQ ID NO: GIP(5-30)), and having a sequence selected from the group consisting of:
  • TFISDYSIAMDKIHQKDFVNWLLAQK - Z SEQ ID NO: ; GIP(5-30) [Q20K], and TFISDYSIAMDKIHQQDFVKWLLAQK - Z; SEQ ID NO: ; GIP(5-30) [N24K], wherein said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 4 to 29 of any one of any one of the above sequences, and wherein said peptide may be C-terminal carboxylated.
  • GIP GIP peptide analogue or functional variant thereof, said peptide being an analogue of hGIP6-30 (SEQ ID NO: GIP(6-30)), and having a sequence selected from the group consisting of:
  • the GIP peptide analogue of the present disclosure is C-terminally amidated (-NH 2 ).
  • a conservative substitution is the substitution of amino acids whose side chains have similar biochemical properties and thus do not affect the function of the peptide.
  • amino acid substitutions as disclosed herein are K to R, A, G; E to D, S, P,
  • a functional variant as defined herein includes sequences wherein an alkyl amino acid is substituted for an alkyl amino acid, wherein an aromatic amino acid is substituted for an aromatic amino acid, wherein a sulfur-containing amino acid is substituted for a sulfur-containing amino acid, wherein a hydroxy-containing amino acid is substituted for a hydroxy-containing amino acid, wherein an acidic amino acid is substituted for an acidic amino acid, wherein a basic amino acid is substituted for a basic amino acid, and/or wherein a dibasic monocarboxylic amino acid is substituted for a dibasic monocarboxylic amino acid.
  • substantially in polarity for example a residue with a non-polar side chain (Ala, Leu, Pro, Trp, Val, lie, Leu, Phe or Met) substituted for a residue with a polar side chain such as Gly, Ser, Thr, Cys, Tyr, Asn, or Gin or a charged amino acid such as Asp, Glu, Arg, or Lys, or substituting a charged or a polar residue for a non-polar one; and/or ii) differ substantially in its effect on peptide backbone orientation such as substitution of or for Pro or Gly by another residue; and/or iii) differ substantially in electric charge, for example substitution of a negatively charged residue such as Glu or Asp for a positively charged residue such as Lys, His or Arg (and vice versa); and/or iv) differ substantially in steric bulk, for example substitution of a bulky residue such as His, Trp, Phe or Tyr for one having a minor side chain, e.g. Ala, Gly
  • the GIP peptide analogues or their functional variant counterparts as defined herein comprise proteinogenic or natural amino acids, i.e. the 22 amino acids naturally incorporated into polypeptides. Of these, 20 are encoded by the universal genetic code and the remaining 2; selenocysteine (Sec, U) and pyrrolysine (Pyl, O), are incorporated into proteins by unique synthetic mechanisms.
  • a GIP peptide analogue as defined herein in one embodiment comprises one or more non-naturally occurring amino acid residues (unnatural, non-proteinogenic or non standard amino acids) or amino acid mimetics, such as glutaric acid.
  • Non-naturally occurring amino acids include e.g., without limitation, beta-2-naphthyl-alanine, trans-3- methylproline, 2,4-methanoproline, cis-4-hydroxyproline, ornithine (Orn), trans-4- hydroxyproline, N-methylglycine, allo-threonine, methylthreonine, hydroxyethylcysteine, hydroxyethylhomocysteine, nitroglutamnine, homoglutamine, pipecolic acid, thiazolidine carboxylic acid, dehydroproline, 3- and 4-methylproline, 3,3- dimethylproline, tert-leucine, norleucine (Nle), methoxinine (Mox
  • amino acid Met is substituted with an oxidation resistant amino acid analogue, for example, norleucine (Nle) or Leu which preserves the length of the amino acid side chain important for hydrophobic interactions but not its hydrogen bonding properties; or methoxinine (Mox), a non-canonical amino acid that resembles more closely the electronic properties of Met in comparison to Nle; or Lys.
  • an oxidation resistant amino acid analogue for example, norleucine (Nle) or Leu which preserves the length of the amino acid side chain important for hydrophobic interactions but not its hydrogen bonding properties; or methoxinine (Mox), a non-canonical amino acid that resembles more closely the electronic properties of Met in comparison to Nle; or Lys.
  • the standard and/or non-standard amino acids may be linked by peptide bonds (to form a linear peptide chain), or by non-peptide bonds (e.g. via the variable side-chains of the amino acids).
  • the amino acids of the peptides defined herein are linked by peptide bonds.
  • peptide also embraces post-translational modifications introduced by chemical or enzyme-catalyzed reactions, as are known in the art. These include acetylation, phosphorylation, methylation, glucosylation, glycation, amidation, hydroxylation, deimination, deamidation, carbamylation and sulfation of one or more amino acid residues, and also proteolytic modification by known proteinases including lysosomal kathepsins, and also calpains, secretases and matrix-metalloproteinases.
  • Sterically similar compounds may be formulated to mimic the key portions of the peptide structure. This may be achieved by techniques of modelling and chemical designing known to those of skill in the art. For example, esterification and other alkylations may be employed to modify the amino terminus of e.g. a di-arginine peptide backbone, to mimic a tetra peptide structure. It will be understood that all such sterically similar constructs fall within the scope of the present invention. Peptides with N-terminal and C-terminal alkylations and esterifications are also encompassed within the present invention. For example, glutaric acid is a sterically similar compound that mimics Glutamic acid.
  • the N-terminal amino acid of the GIP peptide analogues of the present disclosure does not have any chemical modifications. It may be advantageous that the amino group at the N-terminus of the GIP peptide analogue is free, i.e. not substituted, since substitution may lead to agonistic effects at the GIPR.
  • a fatty acid molecule is attached to one or more amino acid residues having a side-chain amino-alkyl group (-C n H2 n NH2).
  • a fatty acid molecule is attached to one or more amino acid residues having a side-chain amino group (NH2).
  • a fatty acid molecule is attached to an amino group (NH2) of an amino acid residue.
  • a fatty acid molecule is attached to the side-chain amino group of an amino acid residue.
  • a fatty acid molecule is attached to the d (delta) side-chain amino group of an ornithine residue (Orn).
  • Orn ornithine residue
  • the amino acid residue having a fatty acid molecule attached is selected from the group consisting of Lys and Orn.
  • amino acid residue having a fatty acid molecule attached is Lys.
  • the fatty acid molecule is attached to the delta-amino group of a Orn residue of said GIP peptide analogue, such as of SEQ ID NO: XX, or a functional variant comprising an Orn amino acid residue.
  • the fatty acid molecule is attached to the epsilon-amino group of a K residue of said GIP peptide analogue, such as of SEQ ID NO: XX, or a functional variant thereof.
  • the fatty acid molecule according to the present disclosure is a straight-chain fatty acid.
  • a GIP peptide may be conjugated to a monoacyl fatty acid (such as Hexadecanoyl) via a linker, as depicted in Formula I:
  • a monoacyl fatty acid such as Hexadecanoyl
  • the fatty acid molecule according to the present disclosure is a diacyl fatty acid molecule.
  • a diacyl fatty acid molecule is a fatty acid molecule comprising two carboxyl groups. Preferably, one or both the carboxyl groups are located at one or each of the endings of the fatty acid molecule.
  • a GIP peptide may be conjugated to a diacyl fatty, acid also referred to as “diacid”, (such as 15-carboxy-pentadecanoyl) via a linker, as depicted in Formula II:
  • the fatty acid molecule according to the present disclosure comprises an acyl group of the formula CH (CH ) n CO-, wherein n is an integer from 4 to 24.
  • said fatty acid molecule comprises an acyl group selected from the group consisting of CH 3 (CH 2 ) 6 CO-, CH 3 (CH 2 ) 8 CO-, CH 3 (CH 2 )i 0 CO-, CH 3 (CH 2 ) I2 CO-, CH 3 (CH 2 )14CO-, CH 3 (CH 2 ) I 6 CO-, CH 3 (CH 2 ) I8 CO-, CH 3 (CH 2 ) 20 CO- and CH 3 (CH 2 ) 22 CO-.
  • said fatty acid molecule is a (mono)acyl fatty acid selected from the group consisting of CH 3 (CH 2 )I O CO- (lauryl, C12), CH 3 (CH 2 )I 2 CO- (myristoyl, C14), CH 3 (CH 2 )i4cO- (palmitoyl, C16), CH 3 (CH 2 )I 6 CO- (stearyl, C18), CH 3 (CH 2 )I 8 CO- (arachidyl, C20) and CH 3 (CH 2 ) 20 CO- (behenyl, C22).
  • a (mono)acyl fatty acid selected from the group consisting of CH 3 (CH 2 )I O CO- (lauryl, C12), CH 3 (CH 2 )I 2 CO- (myristoyl, C14), CH 3 (CH 2 )i4cO- (palmitoyl, C16), CH 3 (CH 2 )I 6 CO- (stearyl, C18), CH 3 (CH 2 )I
  • said fatty acid molecule is a (di)acyl fatty acid selected from the group consisting of HOOC-CH3(CH2) IO CO- (dodecanoyl, C12), HOOC-CH3(CH2)i2CO- (1-tetradecanoyl, C14), HOOC-CH3(CH2)i4CO- (hexadecanoyl, C16), HOOC- CH 3 (CH 2 ) I5 CO- (15-carboxy-pentadecanoyl, C17), HOOC-CH3(CH2)i6CO- (octadecanoyl, C18), HOOC-CH3(CH2)i7CO- (17-carboxy-heptadecanoyl, C19), HOOC- CH 3 (CH 2 ) I8 CO- (eicosanoyl, C20), HOOC-CH3(CH2)i9CO- (19-carboxy-nonadecanoyl, C21 )
  • said fatty acid molecule is selected from C12, C14, C16, C18, C20 and C22.
  • said fatty acid molecule is selected from C14 diacid, C16 diacid, C18 diacid, C20 diacid and C22 diacid.
  • said fatty acid molecule is 17-carboxy-heptadecanoyl.
  • said fatty acid molecule is arachidyl.
  • said fatty acid molecule is 19-carboxy-nonadecanoyl.
  • said fatty acid molecule is behenyl.
  • said fatty acid molecule is 1 ,22-Docosanoic acid / docosanoic acid.
  • said fatty acid molecule comprises or consists of COOH(CH2)i4CO- . In one embodiment said fatty acid molecule comprises or consists of
  • said fatty acid molecule comprises or consists of COOH(CH 2 ) I8 CO-.
  • a fatty acid molecule may be attached to an amino acid residue directly, in such a way that a carboxyl group of the fatty acid molecule forms an amide bond with an amino group of the amino acid residue.
  • Attachment of fatty acid molecules to a peptide herein can occur either directly in indirectly, i.e. via a linker or spacer.
  • the fatty acid molecule according to the present disclosure is attached to an amino acid residue directly.
  • the fatty acid molecule according to the present disclosure is directly attached to the alpha-amino group of an amino acid residue, wherein said amino acid residue is the N-terminal amino acid residue. In one embodiment the fatty acid molecule according to the present disclosure is directly attached to the epsilon-amino group of a Lys residue.
  • the fatty acid molecule according to the present disclosure is directly attached to the delta-amino group of an Orn residue.
  • the fatty acid molecule according to the present disclosure is attached to the epsilon-amino group of a Lys residue via linker or spacer.
  • the fatty acid molecule according to the present disclosure is attached to the delta-amino group of an Orn residue via linker or spacer.
  • a further linker may in some instances be inserted between the e-amino group of Lys and the fatty acid molecule.
  • a further linker is succinic acid which forms an amide bond with the e-amino group of Lys and with an amino group present in the fatty acid molecule.
  • Other linkers are Nc-(y-L-glutamyl), Nc-(3-L-asparagyl), Ne- glycyl, and Nc-(a-(y-aminobutanoyl)).
  • the linker comprises one or more moieties individually selected from the group consisting of:
  • y-aminobutanoyl y-aminobutyric acid
  • y-Glu y-glutamic acid
  • b-Asp b-asparagyl
  • b-Ala b-alanyl
  • n is an integer between 1 and 50, such as an integer between 1-4, 1-3 or 1-2.
  • the linker is a hydrophilic linker. In one embodiment the linker is a non-natural amino acid hydrophilic linker. In one embodiment the linker is selected from the group consisting of y-aminobutanoyl (g-aminobutyric acid), y-glutamyl (g-glutamic acid), b-asparagyl, b-alanyl and glycyl. In one embodiment the linker comprises one or more of g-aminobutanoyl (y-aminobutyric acid), g-glutamyl (g-glutamic acid), b-asparagyl, b-alanyl and glycyl. In one embodiment the linker is a repeat of individual linker moieties. In one embodiment the linker is a repeat of identical linker moieties. In one embodiment the linker is a repeat of different linker moieties.
  • the linker is g-glutamic acid.
  • the linker comprises one or more repeats of g-glutamic acid - 8- amino-3, 6-dioxaoctanoic acid (y-Glu)-(AEEAc n ).
  • the linker is [g-glutamic acid] - [8-amino-3,6-dioxaoctanoic acid] n (Y-Glu)-(AEEAc n ), wherein n is an integer selected from the group consisting of 1 , 2, 3, 4, 5, 6, 7, 8, 9, 10, 1 1 , 12, 13, 14, 15, 16, 17, 18, 19, 20, 21 , 22, 23, 24, 25, 26, 27, 28, 29, 30, 31 , 32, 33, 34, 35, 36, 37, 38, 39, 40, 41 , 42, 43, 44, 45, 46, 47, 48, 49 and 50.
  • the linker is [8-amino-3,6-dioxaoctanoic acid] n (AEEAc n ), wherein n is an integer between 1 and 50, such as an integer between 1 -2, 2-3, 3-4, 4-5, 5-6, 6-7, 7-8, 8-9, 9-10, 10-1 1 , 1 1 -12, 12-13, 13-14, 14-15, 15-20, 20-25, 25-30, 30-35, 35-40, 40-45, 45-50.
  • the linker is [8-amino-3,6-dioxaoctanoic acid] n AEEAc n ), wherein n is an integer selected from the group consisting of 1 , 2, 3.
  • the linker is [g-glutamic acid] - [8-amino-3,6-dioxaoctanoic acid] n (Y-Glu)-AEEAc n ), wherein n is an integer selected from the group consisting of 1 , 2, 3.
  • the linker is [g-glutamic acid] - [8-amino-3,6-dioxaoctanoic acid] (g- Glu)-AEEAc or [8-amino-3,6-dioxaoctanoic acid] - [g-glutamic acid] (AEEAc- g-Glu).
  • a GIP peptide may be conjugated to a fatty acid (for example C16 or palmitic acid/palmitoyl in Formula IV, but any other fatty acid may be used) via [g- glutamic acid] - [8-amino-3,6-dioxaoctanoic acid] as depicted in Formula IV:
  • Formula IV the formula does not depict the stereochemistry, usually, the natural L-form is used, unless otherwise specified.
  • a GIP peptide may be conjugated to a fatty acid (for example C16 or palmitic acid/palmitoyl in Formula IV, but any other fatty acid may be used) via [8- amino-3,6-dioxaoctanoic acid] - [g-glutamic acid] as depicted in Formula V:
  • a fatty acid for example C16 or palmitic acid/palmitoyl in Formula IV, but any other fatty acid may be used
  • Formula V the formula does not depict the stereochemistry, usually, the natural L-form is used, unless otherwise specified.
  • the linker is [g-glutamic acid] - [8-amino-3,6-dioxaoctanoic acid]2 (Y-GIU)-(AEEAC)2.
  • the linker may comprise or consist of yGlu-AEEAc- AEEAc- or AEEAc-yGlu-AEEAc- or AEEAc-AEEAc-yGlu-.
  • the linker is [g-glutamic acid] - [8-amino-3,6-dioxaoctanoic acid]3 (Y-GIU)-(AEEAC) 3 .
  • the linker may comprise or consist of yGlu-AEEAc- AEEAc- AEEAc- or AEEAc-yGlu-AEEAc- AEEAc- or AE E Ac-AE E Ac-y G I u-AE E Ac- or AEEAc-AEEAc- AEEAc-yGlu-.
  • the linker is an amino acid residue except Cys. In one embodiment the linker is 4-Abu. In one embodiment the linker is y-aminobuturic acid. In another embodiment the linker is a dipeptide, such as a dipeptide wherein the C- terminal amino acid residue is Lys, His or Trp, preferably Lys, and wherein the N- terminal amino acid residue is selected from the group comprising Ala, Arg, Asp, Asn, Gly, Glu, Gin, lie, Leu, Val, Phe and Pro. In one embodiment the dipeptide linker is Gly- Lys.
  • the linker comprises one or more moieties selected from the group consisting of y-aminobutanoyl (y-aminobutyric acid), y-glutamyl (y-glutamic acid), b- asparagyl, b-alanyl and glycyl.
  • the linker comprises one or more of g-aminobutanoyl (g-aminobutyric acid), g-glutamyl (g-glutamic acid), b-asparagyl, b- alanyl, glycyl, g-glutamic acid - 8-amino-3,6-dioxaoctanoic acid (y-Glu- AEEAc n , wherein n is an integer between 1 and 50), an amino acid residue except Cys, 4-Abu, y-aminobuturic acid and a dipeptide.
  • g-aminobutanoyl g-aminobutyric acid
  • g-glutamyl g-glutamic acid
  • b-asparagyl b- alanyl
  • glycyl g-glutamic acid - 8-amino-3,6-dioxaoctanoic acid
  • the GIP peptide analogue disclosed herein comprises a fatty acid, and the fatty acid molecule is attached to an amino acid residue via a linker so that the combination of linker and fatty acid is selected from the group consisting of:
  • EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSSGAP- C16-diacid/K18 SEQ ID NO: GIP(3-30)+Cex(Cex7) [H18K],
  • EGTFISDYSIAMDKIKQQDFVNWLLAQKGPSS- C16-diacid/K18 SEQ ID NO: GIP(3- 30)+Cex(Cex4) [H18K],
  • EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNI-C16-diacid/K18 SEQ ID NO: GIP(3-40) [H18K]
  • EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNIT-C16-diacid/K18 SEQ ID NO: GIP(3-41 ) [H18K]
  • EGTFISDYSIAMDKIKQQDFVNWLLAQKGKKNDWKHNITQ- C16-diacid/K18 SEQ ID NO: GIP(3-42) [H18K]
  • C16 is the fatty acid CH (CH )i CO- (palmitoyl) and C18 is the fatty acid CH 3 (CH 2 ) I6 CO- (stearyl).
  • the suffix“-diacid” means that the fatty acid molecule is a diacyl fatty acid molecule. No such suffix refers to a monoacyl fatty acid molecule.
  • C20 is the fatty acid CH (CH )i CO- (arachidyl).
  • the suffix“-diacid” means that the fatty acid molecule is a diacyl fatty acid molecule. No such suffix refers to a monoacyl fatty acid molecule.
  • the peptide according to the present disclosure is formulated as a multimer.
  • a multimer is a protein comprising or consisting of multiple peptide monomers.
  • a multimer is an aggregate of multiple molecules that is usually held together with non-covalent bonds. This definition distinguishes a multimer from a polymer, which is a series of monomers that are held together with covalent bonds.
  • a peptide sequence of the present disclosure is in one embodiment connected to another (identical or non-identical) peptide sequence of the present disclosure by a chemical bond or through a linker group.
  • a peptide of the disclosure is formulated as an oligomer or multimer of monomers, wherein each monomer is as a peptide sequence as defined according to the present disclosure.
  • a multimeric compound is in one embodiment a polymer comprising two or more peptide sequences of the disclosure, said peptide sequences being identical or non-identical, wherein at least one of the two or more peptide sequences is a peptide according to the present disclosure.
  • both peptide sequences are a peptide according to the present disclosure.
  • the multimeric compound is a dimer, comprising two peptides according to the present disclosure, said two peptides being identical or non-identical with respect to each other.
  • the multimeric compound is a trimer, comprising three peptides according to the present disclosure, said peptides being identical or non-identical with respect to each other.
  • the multimeric compound is a tetramer, comprising four peptides according to the present disclosure, said peptides being identical or non identical with respect to each other.
  • the multimeric compound is a dendrimer, such as a tetrameric or octameric dendrimer.
  • Dendrimers are repeatedly branched, roughly spherical large molecules, typically symmetric around the core, and often adopts a spherical three- dimensional morphology.
  • the multimeric compound comprises two identical amino acid sequences of the present invention (dimer) or the compound comprises four identical copies of an amino acid sequence of the present disclosure (tetrameric dendrimer).
  • the multimers according to the disclosure is in one embodiment made by linking two or more peptide monomers via a peptide bond or a linker group.
  • they are linked to a lysine backbone, such as a lysine residue (each peptide chain is linked to a single lysine residue), or coupled to a polymer carrier, for example a protein carrier.
  • Said linker group in one embodiment comprises a plurality of lysine residues, such as a core moiety having a plurality of lysine residues, such as seen in a lysine- based dendromeric structure containing three, seven, fifteen and more lysine residues
  • any other linking of peptide monomers known to the skilled person may be envisioned.
  • the linking in one embodiment occurs at the N-terminal and/or C-terminal end of the peptide monomers.
  • a multimeric compound consisting of:
  • GIP glucose-dependent insulinotropic peptide
  • Xi and x 2 are individually any amino acid or omitted; or a functional variant thereof, wherein said variant has 1 to 7, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX, wherein said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX, or said functional variant thereof,
  • Z is a peptide comprising one or more amino acid residues of GIP(31- 42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E); and
  • GIP glucose-dependent insulinotropic peptide
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 4 to 29 of any one of SEQ ID NO: and SEQ ID NO:, or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), with or without a linker,
  • GPS Global System for Mobile Communications
  • GPSSGAPPP and GPSSGAPPPS are GPSSGAPPP and GPSSGAPPPS
  • PS PS, PSS, PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and
  • PSSG, PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS or a variant thereof comprising 1 or 2 individual amino acid substitutions at any one of the amino acid residues;
  • a peptide is an antagonist of the GIPR
  • methods known in the art may be employed, for example by determining the IC50 of the peptide. This can be done by constructing a dose-response curve and examining the effect of different concentrations of the peptide on reversing agonist activity.
  • the agonist can be GIP1-42, for example hGIP-1-42 or hGIP1-30.
  • the GIPR can be hGIPR, rGIPR, mGIPR, dog GIPR, pig GIPR or the Macaca mulatta GIPR.
  • IC50 values can be calculated for a given antagonist by determining the concentration needed to inhibit half of the maximum biological response of the agonist.
  • a method for determining whether a peptide is an antagonist is described in example 4, but other methods known in the art may also be used. For example, Schild plot analysis may be performed on hGIP1- 42 cAMP dose-response curves with increasing concentrations of GIP-derived peptides. In this way, the type of antagonist activity may also be determined.
  • the GIP peptide analogues of the present disclosure are characterized by having antagonistic activity towards GIPR.
  • the GIP peptide analogues of the present disclosure are potent antagonists of GIPR, due to a large extent to the presence of a fatty acid in the core of the GIP peptide (residues 3 to 29 of GIP) as well as to the presence of an elongation at the C-terminus of the GIP peptide.
  • the GIP peptide analogue of the present disclosure is an antagonist of GIPR.
  • the GIP peptide analogue of the present disclosure inhibits, such as is capable of inhibiting, GIPR activity of at least 70%, such as of at least 75%, such as of at least 80%, such as of at least 85%, such as of at least 90%, such as of at least 95%, such as of about 100%, as measured via an assay that determines the decrease in intracellular cAMP, such as via a CisBio cAMP assay and/or via a DiscoveRx cAMP assay, which are described in’’Materials and methods”.
  • the GIP peptide analogue of the present disclosure inhibits GIPR activity of at least 80%, such as of at least 85%, such as of at least 90%, such as of at least 95%, such as of about 100%, wherein inhibition of GIPR activity is determined as a decrease in intracellular cAMP, for example via an assay that determines the decrease in intracellular cAMP, such as via a CisBio cAMP assay and/or via a
  • DiscoveRx cAMP assay which are described in’’Materials and methods”.
  • the % inhibition is a % of inhibition of Emax, which means that if a peptide inhibits Emax of 85%, there is 15% activity left of the GIPR.
  • the GIP peptide analogue of the present disclosure has a GIPR antagonistic activity corresponding to an IC50 of 50 nM or less, such as of 45 nM or less, such as of 40 nM or less, such as of 35 nM or less, such as of 30 nM or less, such as of 25 nM or less, such as of 20 nM or less, such as of 15 nM or less, such as of 10 nM or less, such as of 5 nM or less, such as of between 1 and 5 nM, wherein antagonistic activity (also referred to as“potency”) is measured via an assay that determines the decrease in intracellular cAMP, such as via a CisBio cAMP assay and/or via a DiscoveRx cAMP assay, which are described in’’Materials and methods”.
  • antagonistic activity also referred to as“potency”
  • the GIP peptide analogues of the present disclosure are also characterized by having low or no agonistic activity towards GIPR.
  • GIP peptide analogues having low or no agonistic activity towards GIPR such as an agonistic activity of 20% or less, preferably of 10% or less, ever more preferably of 5% or less, are also referred to as“silent antagonists”.
  • the GIP peptide analogue of the present disclosure is capable of stimulating GIPR activity of at most 30%, such as of at most 25%, such as of at the most 20%, such as of at the most 15%, such as of at the most 10%, such as of at the most 5%, in one embodiment the GIP peptide analogue of the present disclosure has no agonistic activity towards GIPR, that is it stimulates GIPR activity of about 0%.
  • Agonstic activity of a GIP peptide analogue towards GIPR can be determined in the same way as antagonistic activity, but an increase in intracellular cAMP is measured, instead of a decrease, as described in“Materials and methods”.
  • Xi and x 2 are individually any amino acid or omitted;
  • variant has 1 to 8, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,
  • Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E)for use as a medicament.
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 6 to 29 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6- 30), with or without a linker,
  • GPS GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN,
  • PSSG PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,
  • GIP glucose-dependent insulinotropic peptide
  • Xi and x 2 are individually any amino acid or omitted;
  • variant has 1 to 8, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,
  • Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E) for use in a method of inhibiting or reducing one or more of i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and/or fatty acid incorporation, vi) high or increased expression or activity of a GIPR, vii) post-prandial GIP release, viii) serum levels of free fatty acids and/or triglycerides, ix) GIP-induced appetite increases, x) GIP-induced reduction in energy expenditure, xi)
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 6 to 29 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6- 30), with or without a linker,
  • GPS GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN,
  • PSSG PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS, or a variant thereof comprising 1 or 2 individual amino acid substitutions at any one of the amino acid residues,
  • GIP-induced glucagon secretion for use in a method of inhibiting or reducing one or more of i) GIP-induced glucagon secretion, ii) GIP-induced insulin secretion, iii) GIP-induced somatostatin secretion, iv) GIP-induced glucose uptake, v) GIP-induced fatty acid synthesis and/or fatty acid incorporation, vi) high or increased expression or activity of a GIPR, vii) post-prandial GIP release, viii) serum levels of free fatty acids and/or triglycerides, ix) GIP-induced reduction of bone resorption.
  • GIP glucose-dependent insulinotropic peptide
  • Xi and x 2 are individually any amino acid or omitted;
  • variant has 1 to 8, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX, or said functional variant thereof,
  • Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use in a method of treating a condition selected from the group consisting of metabolic syndrome, obesity, pre-diabetes, type I diabetes, type 2 diabetes, insulin resistance, elevated fasting glucose, hyperglycemia, elevated fasting serum triglyceride levels, low levels of very low-density lipoprotein (VLDL), low high-density lipoprotein (HDL) levels, dyslipidemia, increased/decreased low-density lipoprotein (LDL), high cholesterol levels, abnormal deposition of lipids, a cardiovascular disease, elevated blood pressure and atherosclerosis.
  • a condition selected from the group consisting of metabolic syndrome, obesity, pre-diabetes, type
  • GIP analogue selected from the group consisting of: a peptide having an amino acid sequence consisting of SEQ ID NO: hGIP(3-30):
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 6 to 29 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6- 30), with or without a linker,
  • GPS GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,
  • PSSG PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,
  • a condition selected from the group consisting of metabolic syndrome, obesity, over-weight, an obesity-related disorder, pre
  • GIP glucose-dependent insulinotropic peptide
  • variant has 1 to 8, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX, or said functional variant thereof, wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use in a method of inducing weight-loss.
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 6 to 29 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6- 30), with or without a linker,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN, GKKNDWKHNI, GKKNDWKHNIT and GKKNDWKHNITQ,
  • PSSG PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,
  • Xi and x 2 are individually any amino acid or omitted;
  • variant has 1 to 8, such as 1 to 4 individual amino acid substitutions at any amino acid of SEQ ID NO: XX,
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 3 to 29 of SEQ ID NO XX, or said functional variant thereof, wherein Z is a peptide comprising one or more amino acid residues of GIP(31-42) (GKKNDWKHNITQ; SEQ ID NO: Z) or one or more amino acid residues of Exendin-4 (HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPPS; SEQ ID NO: E), for use in the manufacture of a medicament for
  • cancer including but not limited to colon cancer, a neuroendocrine cancer and adrenal adenoma.
  • said peptide is modified by attaching at least one fatty acid molecule at one or more amino acid residues at positions 6 to 29 of any one of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6-30), or a functional variant thereof comprising between 1 and 4 amino acid substitutions at any one of the amino acid residues of SEQ ID NO: hGIP(3-30), SEQ ID NO: hGIP(5-30) and SEQ ID NO: hGIP(6- 30), with or without a linker,
  • GPS GPS, GPSS, GPSSG, GPSSGA, GPSSGAP, GPSSGAPP, GPSSGAPPP and GPSSGAPPPS,
  • GPSSGA GPSSGAP, GPSSGAPP, GPSSGAPPP, GPSSGAPPPS, GKKNDW, GRKNDW, GKRNDW, GRRNDW, GKKNDWK, GKKNDWKH, GKKNDWKHN,
  • PSSG PSSGA, PSSGAP, PSSGAPP, PSSGAPPP and PSSGAPPPS,
  • cancer including but not limited to colon cancer, a neuroendocrine cancer and adrenal adenoma.
  • GIP peptide analogue as defined herein for use in a method of treating obesity.
  • a GIP peptide analogue as defined herein for use in a method of treating diabetes mellitus, including diabetes mellitus type I and type II.
  • a GIP peptide analogue as defined herein for use in a method of treating insulin resistance.
  • An obesity related disorders may be any one of: increased food-intake, increased appetite, binge eating, bulimia nervosa, obesity induced by administration of an antipsychotic or a steroid, reduced/increased gastric motility, delayed/increased gastric emptying, decreased physical mobility, osteoarthritis, dyslipidemia, increased/decreased low-density lipoprotein (LDL), high cholesterol levels, and abnormal deposition of lipids.
  • LDL low-density lipoprotein
  • dyslipidemia increased/decreased low-density lipoprotein (LDL), cholesterol, and abnormal deposition of lipids are referred to as fatty acid metabolism disorders.
  • LDL low-density lipoprotein
  • a diabetes related disorders may be any one of: impaired glucose tolerance (IGT), progression from IGT to type 2 diabetes, progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes, decreased beta-cell function, decreased beta-cell mass, increased beta-cell apoptosis, decreased glucose sensitivity to beta- cells.
  • IGT impaired glucose tolerance
  • progression from IGT to type 2 diabetes progression of non-insulin requiring type 2 diabetes to insulin requiring type 2 diabetes
  • beta-cell function decreased beta-cell mass
  • increased beta-cell apoptosis decreased glucose sensitivity to beta- cells.
  • the cancer is selected from the group consisting of colon cancer, a neuroendocrine cancer and adrenal adenoma. It is a further aspect to provide a GIP peptide analogue as defined herein for use in a method of treating a bone density disorder (or a bone volume disorder).
  • a GIP peptide analogue as defined herein for use in a method of inhibiting activity of bone cells In one embodiment there is provided a peptide as defined herein for use in a method of inhibiting (or antagonizing) GIP- induced postprandial reduction in bone resorption. In one embodiment there is provided a peptide as defined herein for use in a method of treating bone cancer.
  • the bone density (or volume) disorder is selected from the group consisting of osteoporosis, disorders characterized by low bone density and/or reduced bone volume, disorders characterized by high bone density and/or increased bone volume and osteoporosis.
  • a GIP peptide analogue as defined herein for use in a method of characterizing or examining aspects of a disorder, and/or characterizing or examining aspects of the human physiology associated with a disorder, wherein said disorder in one embodiment is selected from metabolic syndrome, obesity, diabetes mellitus, insulin resistance, obesity related disorders as defined herein or diabetes related disorders as defined herein.
  • the invention relates to methods of treating cancer, such as colon cancer or adrenal adenoma.
  • the invention relates to methods of treating a bone density disorder characterized by high bone density and/or increased bone volume or osteoporosis.
  • the invention relates to methods of treating atherosclerosis.

Landscapes

  • Health & Medical Sciences (AREA)
  • Chemical & Material Sciences (AREA)
  • Life Sciences & Earth Sciences (AREA)
  • Organic Chemistry (AREA)
  • General Health & Medical Sciences (AREA)
  • Medicinal Chemistry (AREA)
  • Proteomics, Peptides & Aminoacids (AREA)
  • Endocrinology (AREA)
  • Zoology (AREA)
  • Gastroenterology & Hepatology (AREA)
  • Molecular Biology (AREA)
  • Toxicology (AREA)
  • Genetics & Genomics (AREA)
  • Biophysics (AREA)
  • Biochemistry (AREA)
  • Bioinformatics & Cheminformatics (AREA)
  • Engineering & Computer Science (AREA)
  • Public Health (AREA)
  • Veterinary Medicine (AREA)
  • Animal Behavior & Ethology (AREA)
  • Pharmacology & Pharmacy (AREA)
  • Epidemiology (AREA)
  • Immunology (AREA)
  • Diabetes (AREA)
  • Hematology (AREA)
  • Obesity (AREA)
  • Chemical Kinetics & Catalysis (AREA)
  • General Chemical & Material Sciences (AREA)
  • Nuclear Medicine, Radiotherapy & Molecular Imaging (AREA)
  • Peptides Or Proteins (AREA)
  • Medicines That Contain Protein Lipid Enzymes And Other Medicines (AREA)
PCT/EP2019/083506 2018-12-03 2019-12-03 Modified gip peptide analogues Ceased WO2020115048A1 (en)

Priority Applications (24)

Application Number Priority Date Filing Date Title
CA3121043A CA3121043A1 (en) 2018-12-03 2019-12-03 Modified gip peptide analogues
AU2019391300A AU2019391300B2 (en) 2018-12-03 2019-12-03 Modified GIP peptide analogues
EP19812788.8A EP3891173A1 (en) 2018-12-03 2019-12-03 Modified gip peptide analogues
JP2021552785A JP7605747B2 (ja) 2018-12-03 2019-12-03 修飾されたｇｉｐペプチド類似体
KR1020217019677A KR102906485B1 (ko) 2018-12-03 2019-12-03 변형된 gip 펩티드 유사체
MX2021006505A MX2021006505A (es) 2018-12-03 2019-12-03 Analogos peptidicos del peptido insulinotropico dependiente de glucosa (gip) modificados.
US17/298,512 US12297250B2 (en) 2018-12-03 2019-12-03 Modified GIP peptide analogues
BR112021010447-0A BR112021010447A2 (pt) 2018-12-03 2019-12-03 Análogos de peptídeos gip modificados
SG11202105586YA SG11202105586YA (en) 2018-12-03 2019-12-03 Modified gip peptide analogues
CN201980090373.3A CN113366014B (zh) 2018-12-03 2019-12-03 经修饰的gip肽类似物
EP20815874.1A EP4069719A1 (en) 2019-12-03 2020-12-03 Optimized gip peptide analogues
JP2022532697A JP7788376B2 (ja) 2019-12-03 2020-12-03 最適化されたｇｉｐペプチド類縁体
IL293249A IL293249A (en) 2019-12-03 2020-12-03 Optimized gip peptide analogs
MX2022006737A MX2022006737A (es) 2019-12-03 2020-12-03 Analogos peptidicos del peptido insulinotropico dependiente de glucosa (gip) optimizados.
US17/776,976 US20250346647A2 (en) 2019-12-03 2020-12-03 Optimized GIP Peptide Analogues
PCT/EP2020/084487 WO2021110845A1 (en) 2019-12-03 2020-12-03 Optimized gip peptide analogues
CN202080083881.1A CN114761420A (zh) 2019-12-03 2020-12-03 优化的gip肽类似物
KR1020227018518A KR20220108064A (ko) 2019-12-03 2020-12-03 최적화된 gip 펩타이드 유사체
CA3157387A CA3157387A1 (en) 2019-12-03 2020-12-03 Optimized gip peptide analogues
AU2020398675A AU2020398675A1 (en) 2019-12-03 2020-12-03 Optimized GIP peptide analogues
IL283385A IL283385A (en) 2018-12-03 2021-05-24 Modified gip peptide analogues
US19/096,393 US20250376499A1 (en) 2018-12-03 2025-03-31 Modified gip peptide analogues
JP2025141835A JP2025172864A (ja) 2019-12-03 2025-08-28 最適化されたｇｉｐペプチド類縁体
AU2025237957A AU2025237957A1 (en) 2018-12-03 2025-09-24 Modified GIP peptide analogues

Applications Claiming Priority (4)

Application Number Priority Date Filing Date Title
EP18209896.2 2018-12-03
EP18209896 2018-12-03
EP19176739 2019-05-27
EP19176739.1 2019-05-27

Related Child Applications (2)

Application Number Title Priority Date Filing Date
US17/298,512 A-371-Of-International US12297250B2 (en) 2018-12-03 2019-12-03 Modified GIP peptide analogues
US19/096,393 Continuation US20250376499A1 (en) 2018-12-03 2025-03-31 Modified gip peptide analogues

Publications (1)

Publication Number Publication Date
WO2020115048A1 true WO2020115048A1 (en) 2020-06-11

Family

ID=68731999

Family Applications (2)

Application Number Title Priority Date Filing Date
PCT/EP2019/083509 Ceased WO2020115049A1 (en) 2018-12-03 2019-12-03 Modified gip peptide analogues
PCT/EP2019/083506 Ceased WO2020115048A1 (en) 2018-12-03 2019-12-03 Modified gip peptide analogues

Family Applications Before (1)

Application Number Title Priority Date Filing Date
PCT/EP2019/083509 Ceased WO2020115049A1 (en) 2018-12-03 2019-12-03 Modified gip peptide analogues

Country Status (11)

Country Link
US (3) US12187773B2 (enExample)
EP (2) EP3891173A1 (enExample)
JP (1) JP7605747B2 (enExample)
CN (1) CN113366014B (enExample)
AU (2) AU2019391300B2 (enExample)
BR (1) BR112021010447A2 (enExample)
CA (1) CA3121043A1 (enExample)
IL (1) IL283385A (enExample)
MX (1) MX2021006505A (enExample)
SG (1) SG11202105586YA (enExample)
WO (2) WO2020115049A1 (enExample)

Cited By (6)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007805A1 (zh) * 2020-07-06 2022-01-13 鸿绪生物医药科技（北京）有限公司 新型多肽及其治疗用途
WO2022007809A1 (zh) * 2020-07-06 2022-01-13 鸿绪生物医药科技（北京）有限公司 新型多肽制剂及其治疗用途
WO2022258805A1 (en) * 2021-06-10 2022-12-15 Antag Therapeutics Aps Treatment of obesity and obesity-related disorders
WO2023139106A2 (en) 2022-01-18 2023-07-27 Novo Nordisk A/S Long-acting gipr antagonists
WO2025154020A1 (en) * 2024-01-19 2025-07-24 Takeda Pharmaceutical Company Limited Improved gip receptor agonist peptide compounds and uses thereof
WO2025154021A1 (en) * 2024-01-19 2025-07-24 Takeda Pharmaceutical Company Limited Improved gip receptor agonist peptide compounds and uses thereof

Families Citing this family (9)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20250346647A2 (en) * 2019-12-03 2025-11-13 Antag Therapeutics Aps Optimized GIP Peptide Analogues
KR20240118914A (ko) 2021-01-20 2024-08-05 바이킹 테라퓨틱스 인코포레이티드 대사 및 간 질환 치료를 위한 조성물 및 방법
WO2023044290A1 (en) 2021-09-15 2023-03-23 Viking Therapeutics, Inc. Compositions and methods for the treatment of metabolic and liver disorders
CR20250051A (es) * 2022-07-13 2025-03-18 Hangzhou Zhongmeihuadong Pharmaceutical Co Ltd Agonista dual de glp-1/gip, método de preparación y uso del mismo
CN118255864A (zh) * 2022-12-26 2024-06-28 杭州中美华东制药有限公司 Gip受体激动剂及其用途
GB202302686D0 (en) * 2023-02-24 2023-04-12 Imperial College Innovations Ltd Novel compounds
WO2024209050A1 (en) * 2023-04-05 2024-10-10 Antag Therapeutics Aps Gip activity modulators and orthostatic intolerance
TW202529796A (zh) * 2023-11-22 2025-08-01 大陸商杭州中美華東製藥有限公司 Glp-1r/gipr雙標靶激動劑在製備動物藥的用途
WO2025176999A2 (en) * 2024-02-23 2025-08-28 Ip2Ipo Innovations Limited Novel compounds

Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029342A1 (en) 1995-03-17 1996-09-26 Novo Nordisk A/S Lipophilic peptide hormone derivatives
WO1998008871A1 (en) 1996-08-30 1998-03-05 Novo Nordisk A/S Glp-1 derivatives
WO1998024464A1 (en) 1996-12-03 1998-06-11 Trustees Of Boston University Specific antagonists for glucose-dependent insulinotropic polypeptide (gip)
WO2000034331A2 (en) 1998-12-07 2000-06-15 Societe De Conseils De Recherches Et D'applications Scientifiques Sas Analogues of glp-1
WO2002046227A2 (en) 2000-12-07 2002-06-13 Eli Lilly And Company Glp-1 fusion proteins
WO2004067548A2 (en) 2003-01-31 2004-08-12 Theratechnologies Inc. Chemically modified metabolites of regulatory peptides and methods of producing and using same
WO2006086769A2 (en) * 2005-02-11 2006-08-17 Amylin Pharmaceuticals, Inc. Gip analog and hybrid polypeptides with selectable properties
US20080312157A1 (en) * 2005-02-11 2008-12-18 Amylin Pharmaceuticals, Inc. Gip analog and hybrid polypeptides with selectable properties
US7875587B2 (en) 1999-03-29 2011-01-25 Uutech Limited Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
WO2012055770A1 (en) 2010-10-25 2012-05-03 F. Hoffmann-La Roche Ag Glucose-dependent insulinotropic peptide analogs
WO2016034186A1 (en) 2014-09-05 2016-03-10 University Of Copenhagen Gip peptide analogues
WO2018220123A1 (en) * 2017-05-31 2018-12-06 University Of Copenhagen Long-acting gip peptide analogues

Family Cites Families (30)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US5745335A (en) 1996-06-27 1998-04-28 Gennum Corporation Multi-layer film capacitor structures and method
US6458924B2 (en) 1996-08-30 2002-10-01 Novo Nordisk A/S Derivatives of GLP-1 analogs
US6268343B1 (en) 1996-08-30 2001-07-31 Novo Nordisk A/S Derivatives of GLP-1 analogs
DE69900026T2 (de) 1998-01-30 2001-05-10 Novo Nordisk As Eine injektionsspritze
JP2003522099A (ja) 1998-02-27 2003-07-22 ノボ ノルディスク アクティーゼルスカブ 遅延作用プロファイルを有するｇｌｐ−１のｇｌｐ−１誘導体及びエキセンジン
DE69918070T2 (de) 1998-03-13 2005-08-25 Novo Nordisk A/S Stabilisierte, wässrige Glukagonlösungen, enthaltend Detergenzien
JP2002526554A (ja) 1998-10-07 2002-08-20 メディカル カレッジ オブ ジョージア リサーチ インスティチュート，インコーポレイテッド 骨親和性ホルモンとして用いられるグルコース依存性インスリン親和性ペプチド
ATE272650T1 (de) 1999-03-29 2004-08-15 Uutech Ltd Analoge des magensaft inhibierenden peptides und ihre verwendung für die behandlung von diabetes
GB0404124D0 (en) 2004-02-25 2004-03-31 Univ Ulster Antagonists of GIP
DE60216629T2 (de) 2001-09-21 2007-10-11 Koninklijke Philips Electronics N.V. Gibt es kein spezifisches kontrollmodul? benutzen sie eines das weniger spezifisch ist
US20030232761A1 (en) 2002-03-28 2003-12-18 Hinke Simon A. Novel analogues of glucose-dependent insulinotropic polypeptide
TWI372629B (en) 2005-03-18 2012-09-21 Novo Nordisk As Acylated glp-1 compounds
WO2007109354A2 (en) 2006-03-21 2007-09-27 Amylin Pharmaceuticals, Inc. Peptide-peptidase inhibitor conjugates and methods of using same
EP2987805A3 (en) 2008-08-07 2016-04-13 Ipsen Pharma S.A.S. Analogues of glucose-dependent insulinotropic polypeptide
KR20110043688A (ko) 2008-08-07 2011-04-27 입센 파마 에스.에이.에스 포도당 의존적인 인슐린 분비 자극성 폴리펩타이드 유사체
PT2320923E (pt) 2008-08-07 2015-02-24 Ipsen Pharma Sas Análogos truncados de polipéptido insulinotrópico dependente de glucose
EA020091B1 (ru) 2008-08-07 2014-08-29 Ипсен Фарма С.А.С. Аналоги глюкозозависимого инсулинотропного полипептида (gip), модифицированные по n-концу
WO2010016936A1 (en) 2008-08-07 2010-02-11 Ipsen Pharma S.A.S. Pharmaceutical compositions of analogues of glucose-dependent insulinotropic polypeptide
AR084558A1 (es) 2010-12-22 2013-05-22 Marcadia Biotech Metodos para tratar trastornos metabolicos y obesidad con peptidos basados en glucagon activos para el receptor de peptido insulinotropico dependiente de glucosa (gip)/peptido-1 similar al glucagon (glp-1)
EP2718317B1 (en) * 2011-06-10 2018-11-14 Beijing Hanmi Pharmaceutical Co., Ltd. Glucose dependent insulinotropic polypeptide analogs, pharmaceutical compositions and use thereof
US9340600B2 (en) * 2012-06-21 2016-05-17 Indiana University Research And Technology Corporation Glucagon analogs exhibiting GIP receptor activity
TW201625668A (zh) * 2014-04-07 2016-07-16 賽諾菲公司 作為胜肽性雙重ｇｌｐ－１／昇糖素受體激動劑之艾塞那肽－４衍生物
TW201625669A (zh) * 2014-04-07 2016-07-16 賽諾菲公司 衍生自艾塞那肽－４（Ｅｘｅｎｄｉｎ－４）之肽類雙重ＧＬＰ－１／升糖素受體促效劑
EP3212218B1 (en) 2014-10-29 2021-06-30 Zealand Pharma A/S Gip agonist compounds and methods
CN107921098A (zh) 2015-06-17 2018-04-17 加州生物医学研究所 修饰的治疗剂及其组合物
US10774127B2 (en) 2016-10-12 2020-09-15 University Of Copenhagen Peptide dual agonists of GIPR and GLP2R
CN110312532A (zh) * 2016-12-19 2019-10-08 韩美药品株式会社 脑靶向长效蛋白质缀合物
US11319369B2 (en) 2016-12-26 2022-05-03 Kao Corporation Motor control function improving agent
JP7165496B2 (ja) 2016-12-26 2022-11-04 花王株式会社 認知機能改善剤
US20190330332A1 (en) 2016-12-26 2019-10-31 Kao Corporation Hypothermia Ameliorating Agent

Patent Citations (12)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO1996029342A1 (en) 1995-03-17 1996-09-26 Novo Nordisk A/S Lipophilic peptide hormone derivatives
WO1998008871A1 (en) 1996-08-30 1998-03-05 Novo Nordisk A/S Glp-1 derivatives
WO1998024464A1 (en) 1996-12-03 1998-06-11 Trustees Of Boston University Specific antagonists for glucose-dependent insulinotropic polypeptide (gip)
WO2000034331A2 (en) 1998-12-07 2000-06-15 Societe De Conseils De Recherches Et D'applications Scientifiques Sas Analogues of glp-1
US7875587B2 (en) 1999-03-29 2011-01-25 Uutech Limited Peptide analogues of GIP for treatment of diabetes, insulin resistance and obesity
WO2002046227A2 (en) 2000-12-07 2002-06-13 Eli Lilly And Company Glp-1 fusion proteins
WO2004067548A2 (en) 2003-01-31 2004-08-12 Theratechnologies Inc. Chemically modified metabolites of regulatory peptides and methods of producing and using same
WO2006086769A2 (en) * 2005-02-11 2006-08-17 Amylin Pharmaceuticals, Inc. Gip analog and hybrid polypeptides with selectable properties
US20080312157A1 (en) * 2005-02-11 2008-12-18 Amylin Pharmaceuticals, Inc. Gip analog and hybrid polypeptides with selectable properties
WO2012055770A1 (en) 2010-10-25 2012-05-03 F. Hoffmann-La Roche Ag Glucose-dependent insulinotropic peptide analogs
WO2016034186A1 (en) 2014-09-05 2016-03-10 University Of Copenhagen Gip peptide analogues
WO2018220123A1 (en) * 2017-05-31 2018-12-06 University Of Copenhagen Long-acting gip peptide analogues

Non-Patent Citations (53)

* Cited by examiner, † Cited by third party
Title
ADRIAN TEBLOOM SRHERMANSEN KIVERSEN J: "Pancreatic polypeptide, glucagon and insulin secretion from the isolated perfused canine pancreas", DIABETOLOGIA, vol. 14, no. 6, 1978, pages 413 - 417
AHLQVIST EOSMARK PKUULASMAA T ET AL.: "Link Between GIP and Osteopontin in Adipose Tissue and Insulin Resistance", DIABETES, vol. 62, no. 6, 2013, pages 2088 - 2094
ASMAR MSIMONSEN LMADSBAD SSTALLKNECHT BHOIST JJBOLOW J: "Glucose-Dependent Insulinotropic Polypeptide May Enhance Fatty Acid Re-esterification in Subcutaneous Abdominal Adipose Tissue in Lean Humans", DIABETES, vol. 59, no. 9, 2010, pages 2160 - 2163
BAGGIO LLDRUCKER DJ: "Biology of Incretins: GLP-1 and GIP", GASTROENTEROLOGY, vol. 132, no. 6, 2007, pages 2131 - 2157, XP022072503, DOI: 10.1053/j.gastro.2007.03.054
BRANS CJENSEN CBSTORGAARD H ET AL.: "Impact of short-term high-fat feeding on glucose and insulin metabolism in young healthy men", THE JOURNAL OF PHYSIOLOGY, vol. 587, no. 10, 2009, pages 2387 - 2397
BRUNICARDI FCDRUCK PSEYMOUR NESUN YSELAHI DANDERSEN DK: "Selective neurohormonal interactions in islet cell secretion in the isolated perfused human pancreas", JOURNAL OF SURGICAL RESEARCH, vol. 48, no. 4, 1990, pages 273 - 278, XP026318521, DOI: 10.1016/0022-4804(90)90058-A
CALANNA SCHRISTENSEN MHOIST JJ ET AL.: "Secretion of Glucose-Dependent Insulinotropic Polypeptide in Patients With Type 2 Diabetes: Systematic review and meta-analysis of clinical studies", DIABETES CARE, vol. 36, no. 10, 2013, pages 3346 - 3352
CHRISTENSEN MBCALANNA SHOIST JJVILSBOELL TKNOP FK: "Glucose-dependent Insulinotropic Polypeptide: Blood Glucose Stabilizing Effects in Patients With Type 2 Diabetes", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 99, no. 3, 2013, pages E418 - E426
CHRISTENSEN MCALANNA SSPARRE-ULRICH AH ET AL.: "Glucose-Dependent Insulinotropic Polypeptide Augments Glucagon Responses to Hypoglycemia in Type 1 Diabetes", DIABETES, 2014
CHRISTENSEN MVEDTOFTE LHOIST JJVILSBOELL TKNOP FK: "Glucose-Dependent Insulinotropic Polypeptide: A Bifunctional Glucose-Dependent Regulator of Glucagon and Insulin Secretion in Humans", DIABETES, vol. 60, no. 12, 2011, pages 3103 - 3109
DEACON CFPLAMBOECK AROSENKILDE MMDE HEER JHOIST JJ: "GIP-(3-42) does not antagonize insulinotropic effects of GIP at physiological concentrations", AMERICAN JOURNAL OF PHYSIOLOGY - ENDOCRINOLOGY AND METABOLISM, vol. 291, no. 3, 2006, pages E468 - E475
DESCHAMPS IHEPTNER WDESJEUX JFBALTAKSE VMACHINOT SLESTRADET H: "Effects of diet on insulin and gastric inhibitory polypeptide levels in obese children", PEDIATR RES, vol. 14, no. 4, 1980, pages 300 - 303
DING WGRENSTROM ERORSMAN PBUSCHARD KGROMADA J: "Glucagon-like peptide I and glucose-dependent insulinotropic polypeptide stimulate Ca2+-induced secretion in rat alpha-cells by a protein kinase A-mediated mechanism", DIABETES, vol. 46, no. 5, 1997, pages 792 - 800
DUPRE JCAUSSIGNAC YMCDONALD TJVAN VLIET S: "Stimulation of Glucagon Secretion by Gastric Inhibitory Polypeptide in Patients with Hepatic Cirrhosis and Hyperglucagonemia", THE JOURNAL OF CLINICAL ENDOCRINOLOGY & METABOLISM, vol. 72, no. 1, 1991, pages 125 - 129
EBERT RILLMER KCREUTZFELDT W: "Release of gastric inhibitory polypeptide (GIP) by intraduodenal acidification in rats and humans and abolishment of the incretin effect of acid by GIP-antiserum in rats", GASTROENTEROLOGY, vol. 76, no. 3, 1979, pages 515 - 523
FUJITA YASADI AYANG GKKWOK YNKIEFFER TJ: "Differential processing of pro-glucose-dependent insulinotropic polypeptide in gut", AMERICAN JOURNAL OF PHYSIOLOGY - GASTROINTESTINAL AND LIVER PHYSIOLOGY, vol. 298, no. 5, 2010, pages G608 - G614
FULURIJA ALUTZ TASLADKO K ET AL.: "Vaccination against GIP for the Treatment of Obesity", PLOS ONE, vol. 3, no. 9, 2008, pages e3163, XP002554578, DOI: 10.1371/journal.pone.0003163
GAULT VAO'HARTE FPMHARRIOTT PFLATT PR: "Characterization of the Cellular and Metabolic Effects of a Novel Enzyme-Resistant Antagonist of Glucose-Dependent Insulinotropic Polypeptide", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 290, no. 5, 2002, pages 1420 - 1426, XP002255743, DOI: 10.1006/bbrc.2002.6364
GELLING RWCOY DHPEDERSON RA ET AL.: "GIP(6-30amide) contains the high affinity binding region of GIP and is a potent inhibitor of GIP1-42 action in vitro", REGULATORY PEPTIDES, vol. 69, no. 3, 1997, pages 151 - 154, XP000853559, DOI: 10.1016/S0167-0115(97)00009-8
GETTY-KAUSHIK LSONG DHBOYLAN MOCORKEY BEWOLFE MM: "Glucose-Dependent Insulinotropic Polypeptide Modulates Adipocyte Lipolysis and Reesterification", OBESITY, vol. 14, no. 7, 2006, pages 1124 - 1131
GOETZE JPHUNTER ILIPPERT SKBARDRAM LREHFELD JF: "Processing-independent analysis of peptide hormones and prohormones in plasma", FRONT BIOSCI, vol. 17, 2012, pages 1804 - 1815
GOETZE JPREHFELD JF: "Peptide hormones and their prohormones as biomarkers", BIOMARKERS MED, vol. 3, no. 4, 2009, pages 335 - 338
GRAHAM FLVAN DER EB AJ: "A new technique for the assay of infectivity of human adenovirus 5 DNA", VIROLOGY, vol. 52, no. 2, 1973, pages 456 - 467, XP023052128, DOI: 10.1016/0042-6822(73)90341-3
GUTNIAK MORSKOV CHOIST JJAHREN BEFENDIC S: "Antidiabetogenic Effect of Glucagon-like Peptide-1 (7-36)amide in Normal Subjects and Patients with Diabetes Mellitus", N ENGL J MED, vol. 326, no. 20, 1992, pages 1316 - 1322
HANSEN LSSPARRE-ULRICH AH ET AL.: "N-terminally and C-terminally truncated forms of glucosedependent insulinotropic polypeptide are high-affinity competitive antagonists of the human GIP receptor", BRITISH JOURNAL OF PHARMACOLOGY, vol. 173, 2016, pages 826 - 838
HAUNER HGLATTING GKAMINSKA DPFEIFFER EF: "Effects of gastric inhibitory polypeptide on glucose and lipid metabolism of isolated rat adipocytes", ANN NUTR METAB, vol. 32, no. 5-6, 1988, pages 282 - 288
HEER JRASMUSSEN CCOY DHHOIST JJ: "Glucagon-like peptide-1, but not glucose-dependent insulinotropic peptide, inhibits glucagon secretion via somatostatin (receptor subtype 2) in the perfused rat pancreas", DIABETOLOGIA, vol. 51, no. 12, 2008, pages 2263 - 2270, XP019651331, DOI: 10.1007/s00125-008-1149-y
HINKE SAMANHART SPAMIR N ET AL.: "Identification of a bioactive domain in the amino-terminus of glucose-dependent insulinotropic polypeptide (GIP", BIOCHIMICA ET BIOPHYSICA ACTA (BBA) - PROTEIN STRUCTURE AND MOLECULAR ENZYMOLOGY, vol. 1547, no. 1, 2001, pages 143 - 155, XP004239382, DOI: 10.1016/S0167-4838(01)00181-9
HOEJBERG PVVILSBOELL TRABOEL R ET AL.: "Four weeks of near-normalisation of blood glucose improves the insulin response to glucagon-like peptide-1 and glucose-dependent insulinotropic polypeptide in patients with type 2 diabetes", DIABETOLOGIA, vol. 52, no. 2, 2009, pages 199 - 207, XP019698478
HOIST JJ: "On the Physiology of GIP and GLP-1", HORM METAB RES, vol. 36, no. 11/12, 2004, pages 747 - 754
IRWIN NGREEN BDPARKER JCGAULT VAO'HARTE FPMFLATT PR: "Biological activity and antidiabetic potential of synthetic fragment peptides of glucose-dependent insulinotropic polypeptide, GIP(1-16) and (Pro3)GIP(1-16", REGULATORY PEPTIDES, vol. 135, no. 1, 2006, pages 45 - 53, XP025033132, DOI: 10.1016/j.regpep.2006.03.006
IRWIN NMCCLEAN PLPATTERSON SHUNTER KFLATT PR: "Active immunisation against gastric inhibitory polypeptide (GIP) improves blood glucose control in an animal model of obesity-diabetes", BIOLOGICAL CHEMISTRY, BCHM 390, vol. 75, 16 July 2014 (2014-07-16), pages 2009
J. BIOL. CHEM., vol. 243, 1969, pages 3552 - 59
JORGENSEN NBDIRKSEN CBOJSEN-MOLLER KN ET AL.: "Exaggerated Glucagon-Like Peptide 1 Response Is Important for Improved β-Ceii Function and Glucose Tolerance After Roux-en-Y Gastric Bypass in Patients With Type 2 Diabetes", DIABETES, vol. 62, no. 9, 2013, pages 3044 - 3052
KERR BDFLATT AJSFLATT PRGAULT VA: "Characterization and biological actions of N-terminal truncated forms of glucose-dependent insulinotropic polypeptide", BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS, vol. 404, no. 3, 2011, pages 870 - 876, XP028167265, DOI: 10.1016/j.bbrc.2010.12.077
KIM SJNIAN CKARUNAKARAN SCLEE SMISALES CMMCINTOSH CHS: "GIP-Overexpressing Mice Demonstrate Reduced Diet-Induced Obesity and Steatosis, and Improved Glucose Homeostasis", PLOS ONE, vol. 7, no. 7, 2012, pages e40156
KISSOW HHARTMANN BHOIST JJ ET AL.: "Glucagon-like peptide-1 (GLP-1) receptor agonism or DPP-4 inhibition does not accelerate neoplasia in carcinogen treated mice", REGULATORY PEPTIDES, vol. 179, no. 1-3, 2012, pages 91 - 100, XP028516152, DOI: 10.1016/j.regpep.2012.08.016
MEIER JJGALLWITZ BSIEPMANN N ET AL.: "Gastric inhibitory polypeptide (GIP) dose-dependently stimulates glucagon secretion in healthy human subjects at euglycaemia", DIABETOLOGIA, vol. 46, no. 6, 2003, pages 798 - 801
MIYAWAKI KYAMADA YBAN N ET AL.: "Inhibition of gastric inhibitory polypeptide signaling prevents obesity", NAT MED, vol. 8, no. 7, 2002, pages 738 - 742, XP008073828, DOI: 10.1038/nm727
MIYAWAKI KYAMADA YYANO H ET AL.: "Glucose intolerance caused by a defect in the entero-insular axis: A study in gastric inhibitory polypeptide receptor knockout mice", PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES, vol. 96, no. 26, 1999, pages 14843 - 14847
NAKAMURA TTANIMOTO HMIZUNO YTSUBAMOTO YNODA H: "Biological and functional characteristics of a novel lowGQomolecular weight antagonist of glucose-dependent insulinotropic polypeptide receptor, SKL-14959, in vitro and in vivo", DIABETES, OBESITY AND METABOLISM, vol. 14, no. 6, 2012, pages 511 - 517
NASTESKA DHARADA NSUZUKI K ET AL.: "Chronic Reduction of GIP Secretion Alleviates Obesity and Insulin Resistance Under High-Fat Diet Conditions", DIABETES, vol. 63, no. 7, 2014, pages 2332 - 2343
NIGEL IRWIN ET AL: "GIP(Lys 16 PAL) and GIP(Lys 37 PAL):? Novel Long-Acting Acylated Analogues of Glucose-Dependent Insulinotropic Polypeptide with Improved Antidiabetic Potential", JOURNAL OF MEDICINAL CHEMISTRY, vol. 49, no. 3, 1 February 2006 (2006-02-01), pages 1047 - 1054, XP055044385, ISSN: 0022-2623, DOI: 10.1021/jm0509997 *
PATHAK V ET AL: "Antagonism of gastric inhibitory polypeptide (GIP) by palmitoylation of GIP analogues with N- and C-terminal modifications improves obesity and metabolic control in high fat fed mice", MOLECULAR AND CELLULAR ENDOCRINOLOGY, vol. 401, 1 January 2015 (2015-01-01), pages 120 - 129, XP029191523, ISSN: 0303-7207, DOI: 10.1016/J.MCE.2014.10.025 *
PATHAK VARUN ET AL: "Sequential induction of beta cell rest and stimulation using stable GIP inhibitor and GLP-1 mimetic peptides improves metabolic control in C57BL/KsJdb/dbmice", DIABETOLOGIA, SPRINGER, BERLIN, DE, vol. 58, no. 9, 6 June 2015 (2015-06-06), pages 2144 - 2153, XP035858863, ISSN: 0012-186X, [retrieved on 20150606], DOI: 10.1007/S00125-015-3653-1 *
PEDERSON RBROWN J: "Interaction of Gastric Inhibitory Polypeptide, Glucose, and Arginine on Insulin and Glucagon Secretion from the Perfused Rat Pancreas", ENDOCRINOLOGY, vol. 103, no. 2, 1978, pages 610 - 615
PURE & APPL. CHEM., vol. 56, no. 5, 1984, pages 595 - 624
RAUFMAN JPSINGH L: "Eng J. Exendin-3, a novel peptide from Heloderma horridum venom, interacts with vasoactive intestinal peptide receptors and a newly described receptor on dispersed acini from guinea pig pancreas. Description of exendin-3(9-39) amide, a specific exendin receptor antagonist", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 266, no. 5, 1991, pages 2897 - 2902
RAVN PMADHURANTAKAM CKUNZE S ET AL.: "Structural and Pharmacological Characterization of Novel Potent and Selective Monoclonal Antibody Antagonists of Glucose-dependent Insulinotropic Polypeptide Receptor", JOURNAL OF BIOLOGICAL CHEMISTRY, vol. 288, no. 27, 2013, pages 19760 - 19772, XP055355497, DOI: 10.1074/jbc.M112.426288
SONG DHGETTY-KAUSHIK LTSENG ESIMON JCORKEY BEWOLFE MM: "Glucose-Dependent Insulinotropic Polypeptide Enhances Adipocyte Development and Glucose Uptake in Part Through Akt Activation", GASTROENTEROLOGY, vol. 133, no. 6, 2007, pages 1796 - 1805, XP022421688, DOI: 10.1053/j.gastro.2007.09.005
STARICH GHBAR RSMAZZAFERRI EL: "GIP increases insulin receptor affinity and cellular sensitivity in adipocytes", AM J PHYSIOL, vol. 249, no. 6, 1985, pages E603 - E607
TSENG CCKIEFFER TJJARBOE LAUSDIN TBWOLFE MM: "Postprandial stimulation of insulin release by glucose-dependent insulinotropic polypeptide (GIP). Effect of a specific glucose-dependent insulinotropic polypeptide receptor antagonist in the rat", J CLIN INVEST, vol. 98, no. 11, 1996, pages 2440 - 2445
WIDENMAIER SBKIM SJYANG GK ET AL.: "A GIP Receptor Agonist Exhibits beta-Cell Anti-Apoptotic Actions in Rat Models of Diabetes Resulting in Improved beta-Cell Function and Glycemic Control", PLOS ONE, vol. 5, no. 3, 2010, pages e9590

Cited By (10)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
WO2022007805A1 (zh) * 2020-07-06 2022-01-13 鸿绪生物医药科技（北京）有限公司 新型多肽及其治疗用途
WO2022007809A1 (zh) * 2020-07-06 2022-01-13 鸿绪生物医药科技（北京）有限公司 新型多肽制剂及其治疗用途
CN116113429A (zh) * 2020-07-06 2023-05-12 鸿绪生物医药科技（北京）有限公司 新型多肽及其治疗用途
CN116133677A (zh) * 2020-07-06 2023-05-16 鸿绪生物医药科技（北京）有限公司 新型多肽制剂及其治疗用途
AU2021304762B2 (en) * 2020-07-06 2024-05-02 Vitalixir (Beijing) Co., Ltd Novel polypeptide and therapeutic use thereof
WO2022258805A1 (en) * 2021-06-10 2022-12-15 Antag Therapeutics Aps Treatment of obesity and obesity-related disorders
WO2023139106A2 (en) 2022-01-18 2023-07-27 Novo Nordisk A/S Long-acting gipr antagonists
WO2023139106A3 (en) * 2022-01-18 2023-09-07 Novo Nordisk A/S Long-acting gipr antagonists
WO2025154020A1 (en) * 2024-01-19 2025-07-24 Takeda Pharmaceutical Company Limited Improved gip receptor agonist peptide compounds and uses thereof
WO2025154021A1 (en) * 2024-01-19 2025-07-24 Takeda Pharmaceutical Company Limited Improved gip receptor agonist peptide compounds and uses thereof

Also Published As

Publication number Publication date
US12297250B2 (en) 2025-05-13
US20220025010A1 (en) 2022-01-27
MX2021006505A (es) 2021-10-01
BR112021010447A2 (pt) 2021-08-24
CN113366014B (zh) 2025-10-21
WO2020115049A1 (en) 2020-06-11
US20250376499A1 (en) 2025-12-11
CA3121043A1 (en) 2020-06-11
CN113366014A (zh) 2021-09-07
SG11202105586YA (en) 2021-06-29
IL283385A (en) 2021-07-29
AU2019391300A1 (en) 2021-07-01
AU2025237957A1 (en) 2025-10-16
EP3891174A1 (en) 2021-10-13
AU2019391300B2 (en) 2025-06-26
JP7605747B2 (ja) 2024-12-24
EP3891173A1 (en) 2021-10-13
US12187773B2 (en) 2025-01-07
KR20210102911A (ko) 2021-08-20
JP2022509568A (ja) 2022-01-20
US20220298218A1 (en) 2022-09-22

Similar Documents

Publication Publication Date Title
US20250376499A1 (en) Modified gip peptide analogues
JP7788376B2 (ja) 最適化されたｇｉｐペプチド類縁体
CN108135981A (zh) 胰高血糖素受体激动剂
CN102573888A (zh) 长效y2 受体激动剂
CN114787183A (zh) 肠促胰岛素类似物及其用途
US11572399B2 (en) Long-acting GIP peptide analogues
RU2817673C2 (ru) Модифицированные аналоги GIP пептида
KR102906485B1 (ko) 변형된 gip 펩티드 유사체
CA3064510C (en) Long-acting gip peptide analogues

Legal Events

Date Code Title Description
121 Ep: the epo has been informed by wipo that ep was designated in this application

Ref document number: 19812788

Country of ref document: EP

Kind code of ref document: A1

ENP Entry into the national phase

Ref document number: 3121043

Country of ref document: CA

ENP Entry into the national phase

Ref document number: 2021552785

Country of ref document: JP

Kind code of ref document: A

NENP Non-entry into the national phase

Ref country code: DE

REG Reference to national code

Ref country code: BR

Ref legal event code: B01A

Ref document number: 112021010447

Country of ref document: BR

ENP Entry into the national phase

Ref document number: 20217019677

Country of ref document: KR

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019391300

Country of ref document: AU

Date of ref document: 20191203

Kind code of ref document: A

ENP Entry into the national phase

Ref document number: 2019812788

Country of ref document: EP

Effective date: 20210705

ENP Entry into the national phase

Ref document number: 112021010447

Country of ref document: BR

Kind code of ref document: A2

Effective date: 20210528

WWG Wipo information: grant in national office

Ref document number: 17298512

Country of ref document: US

WWG Wipo information: grant in national office

Ref document number: 201980090373.3

Country of ref document: CN