Novel Plasma Protein Affinity Tags

Abstract

Method for increasing half-life of therapeutic agents in plasma and novel polypeptide derivatives.

1 . A method of increasing intravascular half-life of an agent, said method comprising converting said agent into a compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is the radical of carboxylic acid R 1 —CO 2 H, which R 1 —CO 2 H can bind reversibly to a plasma protein, 
         G is NH or CHW, wherein W is hydrogen, fluorine, cyano, nitro, C(═O)-E 1 , S(═O) 2 -E 2 , S(═O)-E 3 , aryl, or C 1-6 -alkyl,
 wherein E 1 , E 2 , and E 3  independently represent C 1-6 -alkyl, aryl, heteroaryl, C 1-6 -alkoxy, amino, C 1-6 -alkyl-amino, or di-C 1-6 -alkyl-amino, 
 
         Z is S═O, S(═O) 2 , C(═O), C(═O)O, C(═O)NR 2 , or arylene which is optionally substituted with C 1-6 -alkyl, halogen, nitro, cyano, or heteroarylene, said heteroarylene optionally substituted with C 1-6 -alkyl, halogen, nitro, or cyano,
 wherein R 2  represents hydrogen, cyano, or C 1-6 -alkyl, 
 
         X represents a bond or a spacer, optionally selected from C 1 -C 20 -alkylene, arylene, heteroarylene, C 1 -C 20 -perfluoroalkylene, or combinations thereof, or —[(CQ 2 ) n A] m (CQ 2 ) p —, or —[(CQ 2 ) n A] m (CQ 2 ) p —[(CQ 2 ) n E] m (CQ 2 ) p —, wherein
 n and m independently are 1-20 and p independently is 0-10, 
 each A and E independently are —O—, —S—, —NR 3 —, —N(COR 4 )—, —PR 5 (O)—, - or P(OR 8 )(O)—, wherein
 R 3 , R 4 , R 5 , and R 6  independently represent hydrogen or C 1-6 -alkyl, 
 
 each Q is independently hydrogen or fluorine, 
 
         Y represents a functional group capable of serving as linker to the agent, optionally selected from —C(═O)—, —C(═S)—, —NR 7 (C═O)—, —OC(═O)—, —NR 8 (C═S)—, —CH 2 —, —CH(OH)—, —S(═O) 2 —, —NR 9 —S(═O) 2 —, —S—, —S—S—, wherein
 R 7 , R 8 , and R 6  independently represent hydrogen or C 1-6 -alkyl, 
 
         and the term ‘agent’ refers to a molecule for which a prolonged half-life in plasma is desired. 
       
     
     
         2 . The method according to  claim 1 , wherein said agent is a therapeutic agent. 
     
     
         3 . A method according to  claim 2 , wherein said therapeutic agent is a biopolymer. 
     
     
         4 . A method according to  claim 2 , wherein said therapeutic agent is a polypeptide. 
     
     
         5 . A method according to  claim 2 , wherein the therapeutic agent is a small molecule drug. 
     
     
         6 . A compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         R 1  is the radical of carboxylic acid R 1 —CO 2 H, which R 1 —CO 2 H can bind reversibly to a plasma protein, 
         G is NH or CHW, wherein W is hydrogen, fluorine, cyano, nitro, C(═O)-E′, S(═O) 2 -E 2 , S(═O)-E 3 , aryl, or C 1-6 -alkyl,
 wherein E 1 , E 2 , and E 3  independently represent C 1-6 alkyl, aryl, heteroaryl, C 1-6 -alkoxy, amino, C 1-6 -alkyl-amino, or di-C 1-6 alkyl-amino, 
 
         Z is S═O, S(═O) 2 , C(═O), C(═O)O, C(═O)NR 2 , or arylene which is optionally substituted with C 1-6 -alkyl, halogen, nitro, cyano, or heteroarylene, said heteroarylene optionally substituted with C 1-6 -alkyl, halogen, nitro, or cyano,
 wherein R 2  represents hydrogen, cyano, or C 1-6 -alkyl, 
 
         X represents a bond or a spacer, optionally selected from C 1 -C 20 -alkylene, arylene, heteroarylene, C 1 -C 20 -perfluoroalkylene, or combinations thereof, or —[(CQ 2 ) n A] m (CQ 2 ) p —, or —[(CQ 2 ) n A] m (CQ 2 ) p -[(CQ 2 ) n E] m (CQ 2 ) p -, wherein
 n and m independently are 1-20 and p independently is 0-10, 
 each A and E independently are —O—, —S—, —NR 3 —, —N(COR 4 )—, —PR 5 (O)—, - or P(OR 6 )(O)—, wherein
 R 3 , R 4 , R 5 , and R 6  independently represent hydrogen or C 1-6 alkyl, 
 
 each Q is independently hydrogen or fluorine, 
 
         Y represents a functional group capable of serving as linker to the agent, optionally selected from —C(═O)—, —C(═S)—, —NR 7 (C═O)—, —OC(═O)—, —NR 8 (C═S)—, —CH 2 —, —CH(OH)—, —S(═O) 2 —, —NR 9 —S(═O) 2 —, —S—, —S—S—, wherein
 R 7 , R 8 , and R 8  independently represent hydrogen or C 1-6 -alkyl, 
 
         and the term ‘agent’ refers to a molecule for which a prolonged half-life in plasma is desired. 
       
     
     
         7 . A compound according to  claim 6 , wherein the agent is a therapeutic agent. 
     
     
         8 . A method for preparation of a compound according to  claim 6 , comprising reacting the agent or therapeutic agent with a compound of general formula (III) 
       
         
           
           
               
               
           
         
         wherein R 1 , G, Z, and X are defined as in  claim 6 , and 
         Y 1  is a functional group capable of undergoing a bond-forming reaction with a compound to yield a compound of the general formula (I), Y 1  optionally selected from —C(═O)-L, —C(═S)-L, NR 2 (C═O)-L, —OC(═O)-L, —NR 2 (C═S)-L, —C(H 2 )-L, —C(C 1-6 alkyl)(═O), —CH(═O), —S(═O) 2 -L, NR 2 —S(═O) 2 -L, —SH, —S-L, —NCO, —NCS, —NCNR 2 , —NC, —O—NH 2 , wherein 
         L is a leaving group for nucleophilic displacement, optionally selected from hydroxy, halide, 2,6-dichlorobenzoyl, pivaloyl, 2- or 4-nitrophenyloxy, 2,4-dinitrophenloxy, benzotriazole-1-yloxy, 4-benzotriazol-3-yloxy, C 1-6 alkoxycarbonyloxy, 4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yloxy, perfluorophenyloxy, imidazolyl, 2,5-dioxopyrrolidin-1-yloxy, 1,3-dioxo-2,3-dihydro-1-1′-isondol-2-yloxy, 2,4,6-trichlorophenyloxy, or azide, and wherein R 2  represents hydrogen, cyano, or C 1-6 -alkyl. 
       
     
     
         9 . A compound of general formula (III). 
       
         
           
           
               
               
           
         
         wherein R 1  is the radical of carboxylic acid R 1 —CO 2 H, which R 1 —CO 2 H can bind reversibly to a plasma protein, 
         G is NH or CHW, wherein W is hydrogen, fluorine, cyano, nitro, C(═O)-E 1 , S(═O) 2 -E 2 , S(═O)-E 3 , aryl, or C 1-8 -alkyl,
 wherein E 1 , E 2 , and E 3  independently represent C 1-6 -alkyl, aryl, heteroaryl, C 1-6 -alkoxy, amino, C 1-6 -alkyl-amino, or di-C 1-6 -alkyl-amino, 
 
         Z is S═O, S(═O) 2 , C(═O), C(═O)O, C(═O)NR 2 , or arylene which is optionally substituted with C 1-6 -alkyl, halogen, nitro, cyano, or heteroarylene, said heteroarylene optionally substituted with C 1-6 -alkyl, halogen, nitro, or cyano,
 wherein R 2  represents hydrogen, cyano, or C 1-6 -alkyl, 
 
         X represents a bond or a spacer, optionally selected from C 1 -C 20 -alkylene, arylene, heteroarylene, C 1 -C 20 -perfluoroalkylene, or combinations thereof, or —[(CQ 2 ) n A] m (CQ 2 ) p -, or —[(CQ 2 ) n A] m (CQ 2 ) p -[(CQ 2 ) n E] m (CQ 2 ) p -, wherein
 n and m independently are 1-20 and p independently is 0-10, 
 each A and E independently are —O—, —S—, —NR 3 —, —N(COR 4 )—, —PR 5 (O)—, - or P(OR 6 )(O)—, wherein
 R 3 , R 4 , R 5 , and R 6  independently represent hydrogen or C 1-6 -alkyl, 
 
 each Q is independently hydrogen or fluorine, 
 
         and Y 1  is a functional group capable of undergoing a bond-forming reaction with a compound to yield a compound of the general formula (I), Y 1  optionally selected from —C(═O)-L, —C(═S)-L, —NR 2 (C═O)-L, —OC(═O)-L, —NR 2 (C═S)-L, —C(H 2 )-L, —C(C 1-6 alkyl)(═O), —CH(═O), —S(═O) 2 -L, NR 2 —S(═O) 2 -L, —SH, —S-L, —NCO, —NCS, —NCNR 2 , —NC, —O—NH 2 , wherein 
         L is a leaving group for nucleophilic displacement, optionally selected from hydroxy, halide, 2,6-dichlorobenzoyl, pivaloyl, 2- or 4-nitrophenyloxy, 2,4-dinitrophenloxy, benzotriazole-1-yloxy, 4-benzotriazol-3-yloxy, C 1-6 alkoxycarbonyloxy, 4-oxo-3,4-dihydro-1,2,3-benzotriazin-3-yloxy, perfluorophenyloxy, imidazolyl, 2,5-dioxopyrrolidin-1-yloxy, 1,3-dioxo-2,3-dihydro-1-H-isondol-2-yloxy, 2,4,6-trichlorophenyloxy, or azide, 
         and wherein R 2  represents hydrogen, cyano, or C 1-6 -alkyl. 
       
     
     
         10 . A compound according to  claim 6 , wherein the corresponding acid R 1 —CO 2 H has a binding affinity constant towards human serum albumin that is below about 10 μM. 
     
     
         11 . A compound according to  claim 6 , wherein R 1  is selected from
 C 1-30 -alkyl, optionally substituted with one or more —CO 2 H, —SO 3 H, —PO 2 OH, —SO 2 NH 2 , —NH 2 , —OH, —SH, halogen, or aryl, said aryl optionally substituted with —CO 2 H, —SO 3 H, —PO 2 OH, —SO 2 NH 2 , —NH 2 , —OH, —SH, or halogen, or   C 1-30 -perfluoroalkyl, optionally substituted with one or more —CO 2 H, —SO 3 H, —PO 2 OH, —SO 2 NH 2 , —NH 2 , —OH, —SH, halogen, or aryl, said aryl optionally substituted with —CO 2 H, —SO 3 H, —PO 2 OH, —SO 2 NH 2 , —NH 2 , —OH, —SH, or halogen.   
     
     
         12 . A compound according to  claim 6 , wherein R 1  is selected from a straight chain alkyl group, a branched alkyl group, a group which has an ω-carboxylic acid group, or a partially or completely hydrogenated cyclopentanophenanthrene skeleton. 
     
     
         13 . A compound according to  claim 6 , wherein R 1 —CO 2 H is selected from arylacetic acids, iophenoxate or dicarboxilic acids. 
     
     
         14 . A compound according to  claim 13 , wherein R 1 —CO 2 H is ketoprofen or 3-carboxy-4-methyl-5-propyl-2-furanpropionic acid (CMPF). 
     
     
         15 . A compound according to  claim 6 , wherein R 1  has from 6 to 40 carbon atoms. 
     
     
         16 . A compound according to  claim 6 , wherein R 1  is a peptide. 
     
     
         17 . A compound according to  claim 6 , wherein G is NH. 
     
     
         18 . A compound according to  claim 6 , wherein Z is S(═O) 2 . 
     
     
         19 . A compound according to  claim 6 , wherein Q is H. 
     
     
         20 . A compound according to  claim 6 , wherein A and E are both —O—. 
     
     
         21 . A compound according to  claim 6 , wherein n is 2. 
     
     
         22 . A compound according to  claim 6 , wherein X is a spacer which has a molecular weight in the range from about 80 Da to about 1000 Da. 
     
     
         23 . A compound according to  claim 7 , wherein the therapeutic agent is a biopolymer. 
     
     
         24 . A compound according to  claim 7 , wherein the therapeutic agent is a polypeptide. 
     
     
         25 . A compound according to  claim 24 , wherein said polypeptide is attached to Y via a E-amino group of a lysine residue in said polypeptide. 
     
     
         26 . A compound according to  claim 24 , wherein said polypeptide is attached to Y via an amino acid residue selected from cysteine, glutamate and aspartate. 
     
     
         27 . A compound according to  claim 24 , wherein said therapeutic polypeptide is a glucagon-like peptide 1 (GLP-1) peptide. 
     
     
         28 . A compound according to  claim 27 , wherein said GLP-1 peptide is selected from GLP-1(7-35), GLP-1(7-36), GLP-1(7-36)-amide, GLP-1(7-37), GLP-1(7-38), GLP-1(7-39), GLP-1(7-40), GLP-1(7-41) or an analogue thereof. 
     
     
         29 . A compound according to  claim 27 , wherein said GLP-1 peptide comprises no more than ten amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1). 
     
     
         30 . A compound according to  claim 29 , wherein said GLP-1 peptide comprises no more than six amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1). 
     
     
         31 . A compound according to  claim 29 , wherein said GLP-1 peptide comprises no more than 4 amino acid residues which are not encoded by the genetic code. 
     
     
         32 . A compound according to  claim 29 , wherein said GLP-1 peptide is a DPPIV protected GLP-1 peptide. 
     
     
         33 . A compound according to  claim 29 , wherein said GLP-1 peptide comprises an Aib residue in position 8. 
     
     
         34 . A compound according to  claim 27 , wherein the amino acid residue in position 7 of said GLP-1 compound is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-histidine, β-hydroxy-histidine, homohistidine, N α -acetyl-histidine, α-fluoromethyl-histidine, and α-methyl-histidine. 
     
     
         35 . A compound according to  claim 27 , wherein said polypeptide is a GLP-1 peptide comprising the amino acid sequence of the formula (IV): 
       
         
           
                 
               
                   Formula (IV) 
                 
                 
               
                   (SEQ ID No: 2) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Xaa 16 -Ser- 
                 
                     
                 
                   Xaa 18 -Xaa 19 -Xaa 20 -Glu-Xaa 22 -Xaa 23 -Ala-Xaa 25 -Xaa 26 - 
                 
                     
                 
                   Xaa 27 -Phe-Ile-Xaa 30 -Trp-Leu-Xaa 33 -Xaa 34 -Xaa 35 - 
                 
                     
                 
                   Xaa 36 -Xaa 37 -Xaa 38 -Xaa 39 -Xaa 40 -Xaa 41 -Xaa 42 -Xaa 43 - 
                 
                     
                 
                   Xaa 44 -Xaa 45 -Xaa 46   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  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; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, 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; 
         Xaa 16  is Val or Leu; 
         Xaa 18  is Ser, Lys or Arg; 
         Xaa 19  is Tyr or Gln; 
         Xaa 20  is Leu or Met; 
         Xaa 22  is Gly, Glu or Aib; 
         Xaa 23  is Gln, Glu, Lys or Arg; 
         Xaa 25  is Ala or Val; 
         Xaa 26  is Lys, Glu or Arg; 
         Xaa 27  is Glu or Leu; 
         Xaa 30  is Ala, Glu or Arg; 
         Xaa 33  is Val or Lys; 
         Xaa 34  is Lys, Glu, Asn or Arg; 
         Xaa 35  is Gly or Aib; 
         Xaa 36  is Arg, Gly or Lys; 
         Xaa 37  is Gly, Ala, Glu, Pro, Lys, amide or is absent; 
         Xaa 38  is Lys, Ser, amide or is absent. 
         Xaa 39  is Ser, Lys, amide or is absent; 
         Xaa 40  is Gly, amide or is absent; 
         Xaa 41  is Ala, amide or is absent; 
         Xaa 42  is Pro, amide or is absent; 
         Xaa 43  is Pro, amide or is absent; 
         Xaa 44  is Pro, amide or is absent; 
         Xaa 45  is Ser, amide or is absent; 
         Xaa 46  is amide or is absent; 
         provided that if Xaa 38 , Xaa 39 , Xaa 40 , Xaa 41 , Xaa 42 , Xaa 43 , Xaa 44 , Xaa 45  or Xaa 46  is absent then each amino acid residue downstream is also absent. 
       
     
     
         36 . A compound according to  claim 27 , wherein said polypeptide is a GLP-1 peptide comprising the amino acid sequence of formula (V): 
       
         
           
                 
               
                   Formula (V) 
                 
                 
               
                   (SEQ ID No: 3) 
                 
                 
               
                   Xaa 7 -Xaa 8 -Glu-Gly-Thr-Phe-Thr-Ser-Asp-Val-Ser- 
                 
                     
                 
                   Xaa 18 -Tyr-Leu-Glu-Xaa 22 -Xaa 23 -Ala-Ala-Xaa 26 -Glu- 
                 
                     
                 
                   Phe-Ile-Xaa 30 -Trp-Leu-Val-Xaa 34 -Xaa 35 -Xaa 36 -Xaa 37 - 
                 
                     
                 
                   Xaa 38   
                 
             
                
               
            
             
                
               
            
             
                
                
                
                
                
                
                
               
            
           
         
         wherein 
         Xaa 7  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; 
         Xaa 8  is Ala, Gly, Val, Leu, Ile, Lys, 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; 
         Xaa 18  is Set, Lys or Arg; 
         Xaa 22  is Gly, Glu or Aib; 
         Xaa 23  is Gln, Glu, Lys or Arg; 
         Xaa 28  is Lys, Glu or Arg; 
         Xaa 30  is Ala, Glu or Arg; 
         Xaa 34  is Lys, Glu or Arg; 
         Xaa 35  is Gly or Aib; 
         Xaa 36  is Arg or Lys; 
         Xaa 37  is Gly, Ala, Glu or Lys; 
         Xaa 38  is Lys, amide or is absent. 
       
     
     
         37 . A compound according to  claim 27 , wherein said GLP-1 peptide is selected from the group consisting of Arg 34 GLP-1(7-37), Lys 38 Arg 26,34 GLP-1(7-38), Lys 38 Arg 26,34 GLP-1(7-38)-OH, Lys 36 Arg 26,34 GLP-1(7-36), Aib 8,22,35  GLP-1(7-37), Aib 8,35  GLP-1(7-37), Aib 8,22  GLP-1(7-37), Aib 8,22,35  Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,35  Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22  Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35 Arg 26,34  Lys 38  GLP-1(7-38), Aib 8,35  Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35  Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,35 Arg 26,34 Lys 38 GLP-1(7-38), Aib 8,22,35  Arg 26 Lys 38 GLP-1(7-38), Aib 8,22,35  Arg 34 Lys 38 GLP-1(7-38), Aib 8,35 Arg 34 Lys 38 GLP-1(7-38), Aib 8,22 Arg 34 Lys 38 GLP-1(7-38), Aib 8,22,35 Ala 37 Lys 38 GLP-1(7-38), Aib 8,35 Ala 37 Lys 38 GLP-1(7-38), Aib 8,22 Ala 37 Lys 38 GLP-1(7-38), Aib 8,22,35  Lys 37 GLP-1(7-37), Aib 8,35 Lys 37 GLP-1(7-37) and Aib 8,22 Lys 37 GLP-1(7-38). 
     
     
         38 . A compound according to  claim 27 , wherein said GLP-1 peptide is attached to Y via the amino acid residue in position 23, 26, 34, 36 or 38 relative to the amino acid sequence SEQ ID No:1. 
     
     
         39 . A compound according to  claim 27 , wherein said GLP-1 peptide is exendin-4 (SEQ ID No:4). 
     
     
         40 . A compound according to  claim 27 , wherein said GLP-1 peptide is 
       
         
           
                 
               
                   (SEQ ID No: 5) 
                 
                 
                 
               
                     
                   HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK- 
                 
                     
                     
                 
                     
                   amide. 
                 
             
                
               
            
             
                
                
                
               
            
           
         
       
     
     
         41 . A compound according to  claim 27 , wherein R 1 —C(═O)-G-Z—X—Y— is attached to said GLP-1 peptide on the C-terminal amino acid residue of said GLP-1 peptide. 
     
     
         42 . A compound according to  claim 41 , wherein a second R 1 —C(═O)-G-Z—X—Y— moiety is attached to an amino acid residue which is not the C-terminal amino acid residue. 
     
     
         43 . A compound according to  claim 24 , wherein said therapeutic polypeptide is a glucagon-like peptide 2 (GLP-2) peptide. 
     
     
         44 . A compound according to  claim 43 , wherein said GLP-2 peptide is a DPPIV-protected GLP-2 peptide. 
     
     
         45 . A compound according to  claim 43 , wherein said GLP-2 peptide is Gly 2 -GLP-2(1-33). 
     
     
         46 . A compound according to  claim 43 , wherein said GLP-2 peptide is Lys 17 ,Arg 30 -GLP-2(1-33). 
     
     
         47 . A compound according to  claim 43 , which is
 N ε17 -(6-((2-(3-(Benzoyl)phenyl)propionylamino)sulfonyl)hexanoyl)[Lys 17 ,Arg 30 ]GLP-2(1-33) or   N δ17 -(lauroylsulfamoyl)benzyl-[Glu 3 ,Gln 17 ]GLP-2(1-33).   
     
     
         48 . A compound according to  claim 24 , wherein said therapeutic polypeptide is human insulin or an analogue thereof. 
     
     
         49 . A compound according to  claim 48 , wherein said therapeutic polypeptide is selected from the group consisting of is Asp B28 -human insulin, Lys B28 ,Pro B29 -human insulin, Lys B3 ,Glu B29 -human insulin, Gly A21 ,Arg B31 ,Arg B32 -human insulin and des(B30) human insulin. 
     
     
         50 . A compound according to  claim 24 , wherein said therapeutic polypeptide is human growth hormone or an analogue thereof. 
     
     
         51 . A compound according to  claim 24 , wherein said therapeutic polypeptide is parathyroid hormone or an analogue thereof. 
     
     
         52 . A compound according to  claim 24 , wherein said therapeutic polypeptide is human follicle stimulating hormone or an analogue thereof. 
     
     
         53 . A compound according to  claim 24 , wherein said therapeutic polypeptide has a molar weight of less than 100 kDa. 
     
     
         54 . A compound according to  claim 24 , wherein said therapeutic polypeptide is selected from the group consisting of a growth factor, a somatomedin, interferon, pro-urokinase, urokinase, tissue plasminogen activator (t-PA), plasminogen activator inhibitor 1, plasminogen activator inhibitor 2, von Willebrandt factor, a cytokine, a colony stimulating factor (CFS), stem cell factor, a tumor necrosis factor, a protease inhibitor, an opioid, a hormone, a neuropeptide, and melanocortins. 
     
     
         55 . A compound selected from the group consisting of 
       
         
           
           
               
               
           
         
       
     
     
         56 . A pharmaceutical composition comprising a compound according to  claim 6  and a pharmaceutically acceptable excipient. 
     
     
         57 . The pharmaceutical composition according to  claim 57  which is suited for parenteral administration. 
     
     
         58 . A method for treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease and other cardiovascular disorders, stroke, inflammatory bowel syndrome, dyspepsia or gastric ulcers, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to  claim 27 . 
     
     
         59 . A method for delaying or preventing disease progression in type 2 diabetes in a subject, said method comprising administering to said subject an effective amount of a compound according to  claim 27 . 
     
     
         60 . A method for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, and/or for restoring glucose sensitivity to β-cells in a subject, said method comprising administering to said subject an effective amount of a compound according to  claim 27 . 
     
     
         61 . A method for treating small bowel syndrome, inflammatory bowel syndrome or Crohns disease, said method comprising administering to a subject In need of such treatment an effective amount of a compound according to  claim 43 . 
     
     
         62 . A method for treating hyperglycemia, type 1 diabetes, type 2 diabetes or 6-cell deficiency in a subject, said method comprising administering to a subject in need of such treatment an effective amount of a compound according to  claim 48 .