Novel peptide agonists of GLP-1 activity

Abstract

Novel peptide agonists of GLP-1 activity useful for lowering blood glucose levels. The novel peptides comprise variants of the GLP-1 or the exendin-4 polypeptide sequence and are pharmacologically active and stable. These peptides are useful in the treatment of diseases that benefit from regulation of excess levels of blood glucose and/or regulation of gastric emptying, such as diabetes and eating disorders.

1 . A peptide conjugate comprising a peptide X selected from the group consisting of 
 (a) an exendin having at least 90% homology to exendin-4;    (b) a variant of said exendin wherein said variant comprises a modification selected from the group consisting of between one and five deletions at positions 34-39 and contains a Lys at position 40 having a lipophilic substituent; or    (c) GLP-1 (7-36) (SEQ ID NO: 114) or GLP-1 (7-37) (SEQ ID NO: 123) having at least one modification selected from the group consisting of: 
 (i) substitution of D-alanine, glycine or alpha-amino isobutyric acid for alanine at position 8 and  
 (ii) a lipophilic substituent;  
 and Z, a peptide sequence of 4-20.amino acid units covalently bound to said variant, wherein each amino acid unit in said peptide sequence, Z is selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Lys, Arg, His, Met, Orn, and amino acid units of the general formula I  
 —NH—C(R 1 )(R 2 )—C(═O)—(1)  
 wherein R 1  and R 2  are selected from the group consisting of hydrogen, C 1-6 -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1  and R 2  together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid and 2,3-diaminopropanoic acid; and a pharmaceutically acceptable salt or the c-terminal amide of said peptide conjugate, with the proviso that x is not exendin-4 or exendin-3.  
   
     
     
         2 . The peptide conjugate according to  claim 1 , wherein the peptide X is further characterised in being effective in improving glucose tolerance in a diabetic mammal.  
     
     
         3 . The peptide conjugate according to  claim 1  or  2 , wherein Z comprises at least one Lys amino acid unit, preferably at least two Lys amino acid units, such as at least three Lys amino acid units, e.g. at least four Lys amino acid units, more preferably at least five Lys amino acid units, such as six or seven Lys amino acid units.  
     
     
         4 . A peptide conjugate according to any one of the preceding claims, characterised in that the ratio between the minimum effective dose of said peptide conjugate and the minimum effective oral dose of the peptide, X is at least 1:5.  
     
     
         5 . The peptide conjugate according to any one of the preceding claims, wherein the lipophilic substituent is a palmitoyl attached to the epsilon amino group of a Lys in peptide X.  
     
     
         6 . The peptide conjugate according to any one of the preceding claims, wherein X is selected from the group consisting of Gly 8 -GLP-1-(7-36)(Human)-NH 2 (SEQ ID NO: 87), Gly 8 -GLP-1-(7-36)(Human) (SEQ ID NO: 87), Gly 8 Lys 37 (palmitoyl)-GLP-1-(7-36)(Human) (SEQ ID NO: 111), Gly 8 Lys 34 (palmitoyl-GLP-1-(7-36)(Human) (SEQ ID NO: 90), des Ser 39 -exendin-4(1-39) (SEQ ID NO: 129), exendin-4(1-39) (SEQ ID NO: 102), des Pro-exendin-4(1-39) (SEQ ID NO: 101), des Ala 35 -exendin-4(1-39) (SEQ ID NO: 105), des Gly 34 -exendin-4(1-39) (SEQ ID NO: 106), des Ser 39 -(Lys 40  (palmitoyl))exendin-4(1-39) (SEQ ID NO: 107), des Gly 34 -(Lys (palmitoyl))exendin-4(1-39) (SEQ ID NO: 108), des Ala 35 -(Lys 40  (palmitoyl))exendin-4(1-39) (SEQ ID NO: 109), des Pro 36 -(Lys 40 (palmitoyl))exendin-4(1-39) (SEQ ID NO: 110) and Lys 40  (palmitoyl)exendin-4(1-39) (SEQ ID NO: 151), and the free acids or C-terminal primary amides and pharmaceutically acceptable salts thereof.  
     
     
         7 . A peptide conjugate according to any one of claims  1 - 5 , wherein said peptide X is selected from the group consisting of a GLP-1 (7-36)-NH 2  (SEQ ID NO: 114) having at least one modification selected from the group consisting of substitution of glycine for alanine at position 8 and a lipophilic palmitoyl group attached to a lysine at position 26, 34 or 37, and the free acid and a pharmaceutically acceptable salt thereof.  
     
     
         8 . The peptide conjugate according to the preceding claim, wherein the lipophilic substituent is attached to the epsilon amino group of a Lys in said GLP-1.  
     
     
         9 . A peptide conjugate according to any one of claims  1 - 5 , wherein said peptide X is selected from the group consisting of an exendin variant having an amino acid sequence wherein 1,2 or 3 of the Pro residues in positions 36-38 have been deleted from the amino acid sequence of exendin-4, preferably X is selected from the group consisting of exendin variants having an amino acid sequence wherein 1, 2 or 3 of the Pro residues in positions 36-38 have been deleted from the amino acid sequence of exendin-4(1-39) (SEQ ID NO: 102), the free acid or C-terminal primary amide thereof, and a pharmaceutically acceptable salt thereof.  
     
     
         10 . A peptide conjugate according to the preceding claim, wherein X is selected from the group consisting of 
 des Pro 36 -exendin-4(1-39)-NH 2 (SEQ ID NO: 101),    des Pro 36 , Pro 37 -exendin-4(1-39)-NH 2 (SEQ ID NO: 130), and    des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 132).    
     
     
         11 . A peptide conjugate according to any one of the preceding claims, characterised in that X is bound to Z via a peptide bond.  
     
     
         12 . The peptide conjugate according to  claim 1 , wherein Z is covalently bound to X at the C-terminal carbonyl function of X, or Z is covalently bound to the N-terminal nitrogen atom of said variant, or the first sequence (Z) is covalently bound to X at the C-terminal carbonyl function of said variant and the second sequence (Z) is covalently bound to the N-terminal nitrogen atom of X, or Z is covalently bound to a nitrogen atom on the side chain of a lysine, arginine or histidine residue or a carbonyl function on the side chain of glutamic acid or aspartic acid of said variant.  
     
     
         13 . The peptide conjugate according to any one of the preceding claims, wherein Z consists of 4-15, preferably 4-10, more preferably 4-7, most preferably 6-7 amino acid units.  
     
     
         14 . A peptide conjugate according to any one of the preceding claims, wherein the overall charge of the peptide sequence (Z) is in the range from 0 to +15 at pH 7, preferably in the range from 0 to +10, such as in the range from 0 to +8, more preferably in the range from 0 to +7 or 0 to +6.  
     
     
         15 . The peptide conjugate according to any one of the preceding claims, wherein each amino acid unit in Z is independently selected from the group consisting of Ser, Thr, Tyr, Asn, Gln, Asp, Glu, Lys, Arg, His, Orn, 2,4-diaminobutanoic acid, 2,3-diaminopropanoic acid and Met.  
     
     
         16 . A peptide conjugate according to any one of the preceding claims, wherein Z is (Lys) n , wherein n is an integer in the range from 4 to 15, preferably in the range from 4 to 10, such as in the range from 4 to 8, e.g. in the range from 4 to 7.  
     
     
         17 . A peptide conjugate according to the preceding claim wherein Z is Lys 6  (SEQ ID NO: 9) or Lys 7 (SEQ ID NO: 30).  
     
     
         18 . A peptide conjugate according to  claim 1  wherein Z is represented by Lys 6  bound to the C-terminal of X.  
     
     
         19 . A peptide conjugate according to  claim 1  wherein Z is attached to X N-terminally via a peptide bond and wherein the amino acid residues are selected from the group consisting of Asn, Asp, Glu, and Gin, preferably Asn and Glu, preferably Z has an amino acid sequence selected from the group consisting of Asn-(Glu) n  wherein n is an integer from 3 to 7, preferably 5.  
     
     
         20 . A peptide conjugate according to  claim 13 , wherein Z is 
 Lys-Lys-Lys-Lys (SEQ ID NO: 1), Xaa-Lys-Lys-Lys, Lys-Xaa-Lys-Lys, Lys-Lys-Xaa-Lys, Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys, Xaa-Lys-Xaa-Lys, Xaa-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys, Lys-Xaa-Lys-Xaa, Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Xaa (SEQ ID NO:2), Lys-Lys-Lys-Lys-Lys (SEQ ID NO:3), Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:4), Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:5), Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:6), Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:7), Lys-Lys-Lys-Lys-Xaa, Xaa-Xaa-Lys-Lys-Lys, Xaa-Lys-Xaa-Lys-Lys, Xaa-Lys-Lys-Xaa-Lys, Xaa-Lys-Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Lys, Lys-Xaa-Lys-Xaa-Lys, Lys-Xaa-Lys-Lys-Xaa, Lys-Lys-Xaa-Xaa-Lys, Lys-Lys-Xaa-Lys-Xaa, Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Xaa, Lys-Xaa-Lys-Xaa-Xaa, Lys-Xaa-Xaa-Lys-Xaa, Lys-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Lys-Xaa, Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa (SEQ ID NO:8), Lys-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:9), Xaa-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:10), Lys-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:11), Lys-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:12), Lys-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:13), Lys-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:14), Lys-Lys-Lys-Lys-Lys-Xaa (SEQ ID NO: 15), Xaa-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO: 16), Xaa-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:17), Xaa-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:18), Xaa-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO: 19), Xaa-Lys-Lys-Lys-Lys-Xaa (SEQ ID NO:20), Lys-Xaa-Xaa-Lys-Lys-Lys (SEQ ID NO:21), Lys-Xaa-Lys-Xaa-Lys-Lys (SEQ ID NO:22), Lys-Xaa-Lys-Lys-Xaa-Lys (SEQ ID NO:23), Lys-Xaa-Lys-Lys-Lys-Xaa (SEQ ID NO:24), Lys-Lys-Xaa-Xaa-Lys-Lys (SEQ ID NO:25), Lys-Lys-Xaa-Lys-Xaa-Lys (SEQ ID NO:26), Lys-Lys-Xaa-Lys-Lys-Xaa (SEQ ID NO:27), Lys-Lys-Lys-Xaa-Xaa-Lys (SEQ ID NO:28), Lys-Lys-Lys-Xaa-Lys-Xaa (SEQ ID NO:29), Lys-Lys-Lys-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Lys-Lys, Xaa-Xaa-Lys-Xaa-Lys-Lys, Xaa-Xaa-Lys-Lys-Xaa-Lys, Xaa-Xaa-Lys-Lys-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Lys-Lys, Xaa-Lys-Xaa-Lys-Xaa-Lys, Xaa-Lys-Xaa-Lys-Lys-Xaa, Xaa-Lys-Lys-Xaa-Xaa-Lys, Xaa-Lys-Lys-Xaa-Lys-Xaa, Xaa-Lys-Lys-Lys-Xaa-Xaa, Lys-Lys-Lys-Xaa-Xaa-Xaa, Lys-Lys-Xaa-Lys-Xaa-Xaa, Lys-Lys-Xaa-Xaa-Lys-Xaa, Lys-Lys-Xaa-Xaa-Xaa-Lys, Lys-Xaa-Lys-Lys-Xaa-Xaa, Lys-Xaa-Lys-Xaa-Lys-Xaa, Lys-Xaa-Lys-Xaa-Xaa-Lys, Lys-Xaa-Xaa Lys-Lys-Xaa, Lys-Xaa-Xaa-Lys-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Lys-Lys, Lys-Lys-Xaa-Xaa-Xaa-Xaa, Lys-Xaa-Lys-Xaa-Xaa-Xaa, Lys-Xaa-Xaa-Lys-Xaa-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Lys-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Lys-Lys, Xaa-Lys-Lys-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Lys-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Lys-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Lys-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Lys-Xaa, Xaa-Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Xaa, Xaa-Lys-Xaa-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Lys-Xaa-Xaa, Xaa-Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa-Xaa, Lys-Lys-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:30), Xaa-Lys-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:31), Lys-Xaa-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:32), Lys-Lys-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:33), Lys-Lys-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:34), Lys-Lys-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:35), Lys-Lys-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:36), Lys-Lys-Lys-Lys-Lys-Lys-Xaa (SEQ ID NO:37), Xaa-Xaa-Lys-Lys-Lys-Lys-Lys (SEQ ID NO:38), Xaa-Lys-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:39), Xaa-Lys-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:40), Xaa-Lys-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:41), Xaa-Lys-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:42), Lys-Xaa-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:43), Lys-Xaa-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:44), Lys-Xaa-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:45), Lys-Xaa-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:46), Lys-Lys-Xaa-Xaa-Lys-Lys-Lys (SEQ ID NO:47), Lys-Lys-Xaa-Lys-Xaa-Lys-Lys (SEQ ID NO:48), Lys-Lys-Xaa-Lys-Lys-Xaa-Lys (SEQ ID NO:49), Lys-Lys-Lys-Xaa-Xaa-Lys-Lys (SEQ ID NO:50), Lys-Lys-Lys-Xaa-Lys-Xaa-Lys (SEQ ID NO:51), Lys-Lys-Lys-Lys-Xaa-Xaa-Lys (SEQ ID NO:52), Xaa-Xaa-Xaa-Lys-Lys-Lys-Lys (SEQ ID NO:53), Xaa-Xaa-Lys-Xaa-Lys-Lys-Lys (SEQ ID NO:54), Xaa-Xaa-Lys-Lys-Xaa-Lys-Lys (SEQ ID NO:55), Xaa-Xaa-Lys-Lys-Lys-Xaa-Lys (SEQ ID NO:56), Xaa-Lys-Xaa-Xaa-Lys-Lys-Lys (SEQ ID NO:57), Xaa-Lys-Xaa-Lys-Xaa-Lys-Lys (SEQ ID NO:58), Xaa-Lys-Xaa-Lys-Lys-Xaa-Lys (SEQ ID NO:59), Xaa-Lys-Lys-Xaa-Xaa-Lys-Lys (SEQ ID NO:60), Xaa-Lys-Lys-Xaa-Lys-Xaa-Lys (SEQ ID NO:61), Xaa-Lys-Lys-Lys-Xaa-Lys-Xaa (SEQ ID NO:62). Xaa-Lys-Lys-Xaa-Lys-Lys-Xaa (SEQ ID NO:63), Xaa-Lys-Xaa-Lys-Lys-Lys-Xaa (SEQ ID NO:64), Xaa-Lys-Lys-Lys-Xaa-Xaa-Lys (SEQ ID NO:65), Lys-Xaa-Lys-Lys-Lys-Xaa-Xaa (SEQ ID NO:66), Xaa-Lys-Lys-Lys-Lys-Xaa-Xaa (SEQ ID NO:67), Xaa-Lys-Lys-Lys-Xaa-Lys-Xaa (SEQ ID NO:68), Xaa-Lys-Lys-Lys-Xaa-Xaa-Lys (SEQ ID NO:69), Lys-Lys-Lys-Lys-Xaa-Xaa-Xaa (SEQ ID NO:70), Lys-Lys-Lys-Xaa-Xaa-Xaa-Lys (SEQ ID NO:71). Lys-Lys-Lys-Xaa-Lys-Xaa-Xaa (SEQ ID NO:72), Lys-Lys-Xaa-Lys-Lys-Xaa-Xaa (SEQ ID NO:73), Lys-Lys-Xaa-Xaa-Lys-Xaa-Lys (SEQ ID NO:74), Lys-Lys-Xaa-Xaa-Xaa-Lys-Lys (SEQ ID NO:75), Lys-Lys-Xaa-Lys-Lys-Xaa-Xaa (SEQ ID NO:76), Lys-Xaa-Lys-Lys-Xaa-Xaa-Lys (SEQ ID NO:77), Lys-Xaa-Lys-Xaa-Lys-Xaa-Lys (SEQ ID NO:78), Lys-Xaa-Lys-Xaa-Xaa-Lys-Lys (SEQ ID NO: 79), Lys-Xaa-Xaa-Lys-Lys-Xaa-Lys (SEQ ID NO:80). Lys-Xaa-Xaa-Lys-Xaa-Lys-Lys (SEQ ID NO:81), Lys-Xaa-Xaa-Xaa-Lys-Lys-Lys (SEQ ID NO:82), Lys-Lys-Xaa-Xaa-Xaa-Xaa-Lys, Lys-Xaa-Lys-Xaa-Xaa-Xaa-Lys, Lys-Xaa-Xaa-Lys-Xaa-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Lys-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Lys-Lys, Xaa-Lys-Lys-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Xaa-Lys-Xaa-Xaa-Lys, Xaa-Lys-Xaa-Xaa-Lys-Xaa-Lys, Xaa-Lys-Xaa-Xaa-Xaa-Lys-Lys, Xaa-Xaa-Lys-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Lys-Xaa-Xaa-Lys-Lys, Xaa-Xaa-Xaa-Lys-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Xaa-Lys-Lys, Xaa-Xaa-Xaa-Xaa-Lys-Lys-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Lys-Xaa-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Lys-Xaa-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Lys-Xaa-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Lys-Xaa-Lys, Xaa-Xaa-Xaa-Xaa-Xaa-Lys-Lys, Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Lys, Lys-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Lys-Xaa-Xaa-Xaa-Xaa-Xaa, Xaa-Xaa-Lys-Xaa-Xaa-Xaa, Xaa-Xaa-Xaa-Xaa-Lys-Xaa, Xaa-Xaa-Xaa-Xaa-Xaa-Xaa-Xaa, wherein each Xaa is independently selected from the group consisting of Ala, Leu, Ser, Thr, Tyr, Asn, Gin, Asp, Glu, Arg, His, Met, Orn, and amino acids of the formula I    -NH—C(R 1 )(R 2 )—C(═O)—  (I)     wherein R and R 2  are selected from the group consisting of hydrogen, C 1-6 -alkyl, phenyl, and phenyl-methyl, wherein C 1-6 -alkyl is optionally substituted with from one to three substituents selected from halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, and phenyl and phenyl-methyl is optionally substituted with from one to three substituents selected from C 1-6 -alkyl, C 2-6 -alkenyl, halogen, hydroxy, amino, cyano, nitro, sulfono, and carboxy, or R 1  and R 2  together with the carbon atom to which they are bound form a cyclopentyl, cyclohexyl, or cycloheptyl ring, e.g. 2,4-diaminobutanoic acid (Dbu) and 2,3-diaminopropanoic acid (Dpr).    
     
     
         21 . A peptide conjugate according to any one of the preceding claims wherein said amino acid residues have an L-configuration.  
     
     
         22 . The peptide conjugate according to  claim 1 , wherein said conjugate is selected from the group consisting of 
 des Ser 39 -exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:91),    des Pro 36 -exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:93),    des Ala 35 -exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:94),    des Gly 34 -exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:95),    des Ser 39 -(Lys 40 (palmitoyl))exendin-4(1-39)-Lys 7 -NH 2 (SEQ ID NO:96),    des Gly 34 -(Lys 40 (palmitoyl))exendin-4(1-39)-Lys 7 -NH 2  (SEQ ID NO:97),    des Ala 35 -(Lys 40 (palmitoyl))exendin-4(1-39)-Lys 7 -NH 2  (SEQ ID NO:98),    des Pro 36 -(Lys 40 (palmitoyl))exendin-4 (1-39)-Lys 7 -NH 2  (SEQ ID NO:99),    Lys 40 (palmitoyl)exendin-4(1-39)-Lys 7 -NH 2  (SEQ ID NO: 100),    des Pro 36 (Pro 37 -exendin-4(1-39)Lys 6 -NH 2 (SEQ ID NO: 131),    Lys 6 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 134),    Asn(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 137),    Lys 6 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-Lys 6 -NH 2 (SEQ ID NO: 135),    Asn(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-Lys 6 -N 2 (SEQ ID NO: 136),    des Pro 36 , Pro 37 Pro 38 -exendin-4(1-39)-Lys 6 -NH 2 (SEQ ID NO: 133),    Gly 8 -GLP-1 (7-36)Lys 6 -NH 2  (SEQ ID NO:88)    Lys 6 -Gly 8 -GLP-1 (7-36)Lys 6 -NH 2 (SEQ ID NO: 118),    Lys 6 -Gly 8 -GLP-1(7-36)-NH 2 (SEQ ID NO:119)    (Gly 8 ,Lys 37 (palmitoyl)-GLP-1(7-36)(Human)-Lys 7 -NH 2 (SEQ ID NO:89),    (Gly 8 ,Lys 26 (palmitoyl)-GLP-1(7-36)(Human)-Lys 6 -NH 2  (SEQ ID NO: 103),    Gly 8 ,Lys 34 (palmitoyl)-GLP-1 (7-36)(Human)-Lys 6 -NH 2  (SEQ ID NO: 90),    Gly 8 GLP-1 (7-36)-Lys 8 -NH 2  (SEQ ID NO: 120),    Gly 8 -GLP-1 (7-36)-Lys 10 -NH 2  (SEQ ID NO: 121),    Gly 8 -GLP-1 (7-37)-Lys 6 -NH 2  (SEQ ID NO: 122), and    the free acid thereof and a pharmaceutically acceptable salt thereof.    
     
     
         23 . A novel peptide conjugate comprising X, a peptide agonist of GLP-1 activity and/or exendin-4 activity, wherein X is selected from the group consisting of: 
 des Pro 36 -exendin-4(1-39)-NH 2  (SEQ ID NO:101),    des Pro 36 -des Pro 37 -exendin-4(1-39)-NH 2 (SEQ ID NO: 130),    des Pro 36 -des Pro 37 -des Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 132),    des Ala 35 -exendin-4(1-39)-NH 2  (SEQ ID NO:105),    des Gly 34 -exendin-4(1-39)-NH 2  (SEQ ID NO: 106),    des Gly 34 -(Lys 40  (palmitoyl))exendin-4(1-39)-NH 2  (SEQ ID NO:108),    des Ala 35 -(Lys 40  (palmitoyl))exendin-4(1-39)-NH 2  (SEQ ID NO:109),    des Pro 36 -(Lys 40  (palmitoyl))exendin-4(1-39)-NH 2  (SEQ ID NO:110),    Gly 8 -Glp-1(7-36)-NH 2 (SEQ ID NO: 87), and Gly 8 -Glp-1(7-36) (SEQ ID NO: 87),    and wherein X is C-terminally bound via a peptide bond to a peptide sequence Z selected from the group consisting of (Lys) n  where n is an integer from 4 to 8, preferably n is 6, and the free acid thereof and a pharmaceutically acceptable salt thereof.    
     
     
         24 . The peptide conjugate which is exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:92) and the free acid thereof and a pharmaceutically acceptable salt thereof.  
     
     
         25 . A pharmaceutically active conjugate of any one of  claims 1  to  24  for use in therapy.  
     
     
         26 . A pharmaceutical composition comprising a pharmaceutically active peptide conjugate as defined in any one of  claims 1  to  24  and a pharmaceutical acceptable carrier.  
     
     
         27 . A pharmaceutical composition according to any one of claims  25  and  26  wherein the active peptide conjugate is selected from the group consisting of 
 des Pro 36 -exendin-4(1-39)-Lys 6 -NH 2  (SEQ ID NO:93),  
 LYs 6 -des Pro 36 ,Pro 37 , Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 134)  
 Asn(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)NH 2 SEQ ID NO: 137)  
 Asn(Glu) 5 -des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-Lys 6 -NH 2 (SEQ ID NO: 136),  
 des Pro 36 , Pro 37 , Pro 38 -exendin-4(1-39)-Lys 6 -NH 2 (SEQ ID NO: 133), and the free acid thereof and a pharmaceutically acceptable salt thereof.  
 
     
     
         28 . A pharmaceutical composition according to any one of claims  25  and  26  wherein the active peptide conjugate is selected from the group consisting of Gly 8 -GLP-1 (7-36)-Lys 6 -NH 2  (SEQ ID NO:88), Gly 8 -GLP-1 (7-36)-Lys 7 -NH 2 (SEQ ID NO: 117), and the free acid thereof and, a pharmaceutically acceptable salt thereof.  
     
     
         29 . A variant of a parent exendin, wherein said parent exendin has an amino acid sequence having at least an 90% homology to exendin-4 and wherein said variant lowers the blood glucose level and binds to a GLP-1 receptor in a mammal and has at least one modification selected from the group consisting of: 
 (a) between one and five deletions at positions 34-38, and    (b) contains a Lys at position 40 having a lipophilic substituent bound to the epsilon-amino group of Lys via an amide bond.    
     
     
         30 . The variant according to the preceding claim wherein said parent exendin is exendin-4.  
     
     
         31 . The variant according to the preceding claim wherein said exendin-4 is exendin-4(1-39).  
     
     
         32 . The variant according to any one of  claims 29  to  31 , wherein said variant comprises a Lys at position 40 having a palmitoyl group bound to the epsilon-amino group of Lys via an amide bond.  
     
     
         33 . The variant according to any one of  claims 29  to  32 , wherein said variant is selected from the group consisting of des Pro 36 -exendin-4(1-39)-NH 2 (SEQ ID NO: 101), des Pro 36  Pro 37  Pro 38 -exendin-4(1-39)-NH 2 (SEQ ID NO: 132), des Pro 36  Pro 37 -exendin-4(1-39)-NH 2 (SEQ ID NO: 130), des Ala 35 -exendin-4(1-39)-NH 2 (SEQ ID NO: 105), des Gly 34 -exendin-4(1-39)-NH 2 (SEQ ID NO: 106), des Ser 3     9   -(Lys 40  (palmitoyl) exendin-4(1-39)-NH 2 (SEQ ID NO: 107), des Gly 34 -(Lys 40 (palmitoyl)) exendin-4(1-39)-NH 2 (SEQ ID NO: 108), des Ala 35 -(Lys 40  (palmitoyl) exendin-4(1-39)-NH 2  (SEQ ID NO: 109) and the free acid thereof and a pharmaceutically acceptable salt thereof.  
     
     
         34 . A pharmaceutical composition comprising a variant of a parent exendin as defined in any of the  claims 29  to  33  and a physiologically acceptable carrier.  
     
     
         35 . A pharmaceutical composition according to the preceding claim wherein the variant is selected from the group consisting of des Pro 36 -exendin-4(1-39)-NH 2  (SEQ ID NO: 101) and the free acid thereof and a pharmaceutically acceptable salt thereof.  
     
     
         36 . The composition of the preceding claim for use in therapy.  
     
     
         37 . A method for producing the peptide conjugates of any one of claims  1 - 24  or the exendin variants of any one of claims  29 - 33  having a natural polypeptide sequence, comprising 
 a) introducing a nucleic acid sequence encoding a polypeptide sequence comprising the peptide sequence of said exendin variant or said peptide conjugate and a selectable marker contained within a nucleic acid construct or a vector into a host cell to obtain a recombinant host cell;  
 b) selecting said recombinant host cell;  
 c) culturing said recombinant host cells under conditions permitting the production of said polypeptide sequence;  
 d) isolating said polypeptide sequence from the culture; and  
 e) optionally cleaving said polypeptide sequence using an appropriate protease to obtain said peptide conjugate.  
 
     
     
         38 . A polypeptide sequence encoding the peptide conjugates of any one of the preceding claims having a natural polypeptide sequence.  
     
     
         39 . Use of a peptide conjugate according to any one of claims  1 - 24  or an exendin variant according to any one of claims  29 - 33  for the manufacture of a pharmaceutical composition.  
     
     
         40 . Use of a pharmaceutically active peptide conjugate as defined in any one of claims  1 - 24  or an exendin variant according to any one of claims  29 - 33  for the manufacture of a pharmaceutical composition for use in treatment of diabetes type I or type 2, insulin resistance syndrome, obesity, eating disorders, hyperglycemia, metabolic disorders, and gastric disease.  
     
     
         41 . Use of a pharmaceutically active peptide conjugate as defined in any one of claims  1 - 24  or an exendin variant as defined in any one of claims  29 - 33  for the manufacture of a pharmaceutical composition for use in the treatment of disease states associated with elevated blood glucose levels elicited by hormones known to increase blood glucose levels, such as catechol amines including adrenalin, glucocorticoids, growth hormone and glucagon.  
     
     
         42 . Use of a pharmaceutically active peptide conjugate as defined in any one of claims  1 - 24  or an exendin variant as defined in any one of claims  29 - 33  for the manufacture of a pharmaceutical composition for use in regulation of blood glucose levels.  
     
     
         43 . Use of a pharmaceutically active peptide conjugate as defined in any one of claims  1 - 24  or an exendin variant as defined in any one of claims  29 - 33  for the manufacture of a pharmaceutical composition for use in regulation of gastric emptying.  
     
     
         44 . A method of stimulating insulin release in a mammal comprising administering an effective insulinotropic amount of the peptide conjugate of  claims 1  to  24  or an exendin variant as defined in any one of claims  29 - 33 .  
     
     
         45 . A method of lowering blood glucose level in a mammal comprising administering an amount of the peptide conjugate of  claims 1  to  24  or an exendin variant as defined in any one of claims  29 - 33  effective to lower blood glucose level in said mammal.  
     
     
         46 . A method of lowering plasma lipid level in a mammal comprising administering an amount of the peptide conjugate of  claims 1  to  24  or an exendin variant as defined in any one of claims  29 - 33  effective to lower plasma lipid level in said mammal.  
     
     
         47 . A method of reducing mortality and morbidity after myocardial infarction in a mammal comprising administering an amount of the variant of the peptide conjugate of  claims 1  to  24  or an exendin variant as defined in any one of claims  29 - 33  effective to reduce mortality and morbidity after myocardial infarction.  
     
     
         48 . A method of increasing the plasma half life of exendin 4 and exendin 4 variants comprising linking a polypeptide sequence of preferably 6 lysine residues via a peptide bond to the C-terminal of said exendin 4 or exendin 4 variant.