Glp1/gip/npy2 receptor triple agonists
AssigneeBoehringer Ingelheim International GmbH
InventorsPeter Wilhelm HAEBEL, Robert AUGUSTIN, Charlotte Stahl MADSEN, Anthony MURRAY, Daniel Paul TEUFEL
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Abstract
Hybrid polypeptides that agonize the GIP, GLP-1 and neuropeptide Y2 (NPY2) receptors and their medical use in the treatment of a variety of diseases, conditions or disorders, such as obesity, diabetes, and/or NASH are disclosed. The polypeptides have the general structure Z1-Z2-Z3, wherein Z1 is a hybrid polypeptide providing GIPR and GLP1R agonism, Z2 is a linker, and Z3 is a polypeptide providing hY2R agonism.
Claims16
A polypeptide according to the general structure of Formula (I),
- Z1-Z2-Z3 (I),
- wherein,
- Z1 is a hybrid polypeptide consisting of the amino acid sequence X1-X28 Y-Aib-E-G-T-F-T-S-D-Y-S-I-Aib-L-E-K-Q-A-Q-Aib-A-F-V-E-W-L-I-K (SEQ ID NO:
- 306),
- or a derivative thereof having 1, 2, or 3 amino acid substitution(s);
- Z2 is a peptide consisting of the amino acid sequence X29-X34 GGPSEG (SEQ ID NO:
- 311),
- or a derivative thereof having 1, 2, 3 or 4 amino acid substitution(s);
- Z3 is a polypeptide consisting of the amino acid sequence X35-X49 A-S-L-R-H-Y-Y-N-W-L-T-R-Q-R-Y (SEQ ID NO:
- 307),
- or a derivative thereof having 1, 2, 3, 4, or 5 amino acid substitution(s).
A polypeptide according to the general structure of Formula (I),
- Z1-Z2-Z3 (I) (SEQ ID NO:
- 647),
- wherein,
- Z1 is a hybrid polypeptide consisting of the amino acid sequence,
- (SEQ ID NO:
- 646)
- Y-Aib-X3-G-T-F-T-S-D-X10-S-I-X13-L-X15-X16-X17-A-X19-
- X20-X21-F-X23-X24-X25-L-X27-K,
- wherein X3 is selected as E or D;
- X10 is selected as Y or L;
- X13 is selected as Aib or L;
- X15 is selected as E, D, or A;
- X16 is selected as K, E, D, Aib, G, LysAc, A, L, S, Q, or R;
- X17 is selected as Q, E, K, or A;
- X19 is selected as Q or E;
- X20 is selected as Aib, D-Asp, or D-Arg;
- X21 is selected as A, E or K;
- X23 is selected as V or I;
- X24 is selected as E or Q;
- X25 is selected as W or Y;
- X27 is I or L;
- Z2 is a linker consisting of the amino acid sequence G-G-X31-X32-X33-X34, wherein X31 is selected as P, G, or Q;
- X32 is selected as S, E, or R;
- X33 is selected as S, E, Y, or T;
- X34 is selected as G, P, Y, or A;
- Z3 is a polypeptide consisting of the amino acid sequence,
- X35-X36-X37-X38-X39-Y-X41-X42-X43-X44-T-X46-X47-X48-X49,
- wherein X35 is selected as A, Q, I, V, E, or L;
- X36 is selected as S, E, T, D, or L;
- X37 is selected as L, Aib, V, D-Leu, I or Tle;
- X38 is selected as R, L, or Aib;
- X39 is selected as H, Aib, D-His, or Tle;
- X41 is selected as Y, L, Aib, I, or Tle;
- X42 is selected as N or Aib;
- X43 is selected as W, H, L, R, or Aib;
- X44 is selected as L, Aib, D-Arg, D-Asp, or Tle;
- X46 is selected as R, hArg, or D-Arg;
- X47 is selected as Q, bh-Gln, or NMeQ;
- X48 is selected as R or NMeR;
- X49 is selected as Y, Tle, Chg, D-Tyr, Phg.
Dependencies are inferred from the claim text.