Dual agonist glp-1 and neurotensin fusion peptide

Patent metadata

Field	Value
Publication number	US-2022056077-A1
Application number	US-201917420110-A
Country	US
Kind code	A1
Filing date	Dec 4, 2019
Priority date	Dec 4, 2018
Publication date	Feb 24, 2022
Grant date	—

Abstract

The present invention relates to a polypeptide comprising a first peptide linked to a second peptide, optionally via a linker molecule, which first peptide comprises an appetite regulating hormone peptide, e.g. glucagon like peptide 1 (GLP-1), such as amino acids 7-37 of the initial GLP-1 product (1-37), and a Neurotensin (NT) like peptide, targeting both the GLP-1 receptor (GLP-1R) and NT receptors (NTR1-3) and display an increased effect on decrease of appetite and food intake and body weight compared to simultaneous administration of both peptides.

First claim

1 - 30 . (canceled)

31 . A fusion peptide comprising a first peptide linked to a second peptide, which first peptide comprises the sequence:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 wherein X 1 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine; X 2 is A, G, V, L, I, K, S, aminoisobutyric acid (Aib), (1-aminocyclopropyl) carboxylic acid, (1 aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1 aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid; X 3 is E, D or Q; X 4 is G or A; X 5 is T, V, S or I; X 6 is F or Y; X 7 is T, or S; X 8 is S, V, or D; X 9 is S, D, E, N or is not present, or the first peptide comprising the sequence laid out in SEQ ID NO: 40 or SEQ ID NO: 41 or SEQ ID NO: 42, and which second peptide has an amino acid sequence with at least 70% identity with any one of SEQ ID NO:24 to SEQ ID NO:31, or wherein the second peptide is selected from the list consisting of: X 10 -X 11 -P-X 12 -I-L; P-X 10 -X 11 -P-X 12 -I-L; K-P-X 10 -X 11 -P-X 12 -I-L; N-K-P-X 10 -X 11 -P-X 12 -I-L; E-N-K-P-X 10 -X 11 -P-X 12 -I-L; Y-E-N-K-P-X 10 -X 11 -P-X 12 -I-L; L-Y-E-N-K-P-X 10 -X 11 -P-X 12 -I-L; Q-L-Y-E-N-K-P-X 10 -X 11 -P-X 12 -I-L; or E-L-Y-E-N-K-P-X 10 -X 11 -P-X 12 -I-L wherein X 10 is R or K; X 11 is R or K; and X 12 is Y, S, C or T, and wherein the fusion peptide is a dual agonist of both a glucagon like peptide 1 receptor and a neurotensin receptor.

32 . The fusion peptide according to claim 31 comprising a first peptide linked to a second peptide, which first peptide comprises the sequence:
X 1 -X 2 -X 3 -X 4 -X 5 -X 6 -X 7 -X 8 -X 9 -X 10
wherein
X 1 is L-histidine, D-histidine, desamino-histidine, 2-amino-histidine, β hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine or 4-pyridylalanine;
X 2 is A, G, V, L, I, K, S, aminoisobutyric acid (Aib), (1-aminocyclopropyl) carboxylic acid, (1 aminocyclobutyl) carboxylic acid, (1-aminocyclopentyl) carboxylic acid, (1 aminocyclohexyl) carboxylic acid, (1-aminocycloheptyl) carboxylic acid, or (1-aminocyclooctyl) carboxylic acid;
X 3 is E, D or Q;
X 4 is G or A;
X 5 is T, V, S or I;
X 6 is F or Y;
X 7 is T, or S;
X 8 is S, V, or D;
X 9 is S, D, E, N or is not present;
X 10 is V or
the first peptide comprising the sequence laid out in SEQ ID NO: 40 or SEQ ID NO: 41 or SEQ ID NO: 42.

33 . The fusion peptide according to claim 31 , wherein the first peptide has at least 70% identity with any one of SEQ ID NO:2 to SEQ ID NO: 23 or SEQ ID NO: 34 to SEQ ID NO: 39.

34 . The fusion peptide according to claim 31 , wherein the second peptide is any of the sequences laid out in SEQ ID NO: 24-30.

35 . The fusion peptide according to claim 31 , wherein the first peptide is the N-terminus of the fusion peptide.

36 . The fusion peptide according to claim 31 , wherein the C-terminus of the fusion peptide has the amino acid sequence laid out in SEQ ID NO:30.

37 . The fusion peptide according to claim 31 , wherein the fusion peptide is a peptide having at least 70% identity with SEQ ID NO:32 or a peptide having at least 70% identity with SEQ ID NO:33.

38 . The fusion peptide according to claim 31 , wherein the first peptide is linked to the second peptide via a linker molecule.

39 . The fusion peptide according to claim 31 , wherein the first peptide is H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q (SEQ ID No: 15).

40 . The fusion peptide according to claim 39 , wherein the second peptide is E-L-Y-E-N-K-P-R-R-P-Y-I-L.

41 . The fusion peptide according to claim 31 , wherein the first peptide has the sequence H-A-E-G-T-F-T-S-D-V-S-S-Y-L-E-G-Q-A-A-K-E-F-I-A-W-L-V-K-G-R (SEQ ID No: 2) and the second peptide is E-L-Y-E-N-K-P-R-R-P-Y-I-L.

42 . The fusion peptide according to claim 31 , wherein the C-terminal end of said fusion peptide is amidated.

43 . The fusion peptide according to claim 31 , wherein the fusion peptide is pegylated.

44 . The fusion peptide according to claim 35 , wherein the second peptide is pegylated.

45 . The fusion peptide according to claim 40 , wherein the second peptide is pegylated and the pegylation site is the lysine of the second peptide.

46 . The fusion peptide according to claim 31 , wherein the fusion peptide is linked to an albumin binding moiety via a spacer.

47 . The fusion peptide according to claim 46 , wherein the albumin binding moiety linked via a spacer is attached to said fusion peptide via the s-amino group of a lysine residue.

48 . A nucleic acid molecule having a sequence encoding a fusion peptide according to claim 31 .

49 . A vector comprising the nucleic acid molecule according to claim 48 .

50 . A host cell comprising the nucleic acid molecule according to claim 48 .

51 . A pharmaceutical composition comprising the fusion peptide according to claim 31 .

52 . A method of reducing appetite in a mammal comprising administering the fusion peptide according to claim 31 to the mammal.

Assignees

• Univ Copenhagen

Inventors

• Holst Birgitte
• Ratner Cecilia

Classifications

• C07K7/22

  {Tachykinins, e.g.} Eledoisins {, Substance P}; Related peptides · CPC title

• C07K7/083 Primary

  Neurotensin · CPC title

• C07K2319/00

  Fusion polypeptide · CPC title

• C07K2319/75

  containing a fusion for activation of a cell surface receptor, e.g. thrombopoeitin, NPY and other peptide hormones · CPC title

• C07K14/605 Primary

  Glucagons · CPC title