Polypeptide protracting tags

Abstract

Method for increasing (protracting) half-life of LGP analogs in plasma and novel derivatives of such peptides based on covalently linking them to a tetrazole moiety which acts as a carboxylic acid bioisostere.

1 . A method for increasing the plasma half-life of a molecule, said method comprising covalently linking said molecule to a heterocyclic carboxylic acid bioisostere. 
     
     
         2 . A method for increasing the plasma half-life of a molecule, said method comprising covalently linking said molecule to a 1H-tetrazole. 
     
     
         3 . A method for increasing the plasma half-life of a molecule, said method comprising converting said molecule into a compound of general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         G, X, and Y independently represent
 a bond, —S—, —O—, —NH—, —(CH 2 ) 1-15 —, —C(O)NH—, or 
 arylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, or 
 heteroarylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, and 
 
         Z represents a bond or
 —(CH 2 ) n —, —O—(CH 2 ) n —, —S—(CH 2 ) n —, —(OCH 2 CH 2 ) n —, —(CF 2 ) n —, —O—CH 2 —(CF 2 ) n —, —S—CH 2 —(CF 2 ) n —, 
 
         wherein n is 140, and 
         A represents
 —C(═O)—, —O—C(═O)—, —NH—C(═O)—, —C(C═O)NH—S(═O) 2 —, —S(═O) 2 NH—C(═O)—, —(CH 2 ) 1-5 —, —O—(CH 2 ) 1-5 —, or —O—(CH 2 ) 1-5 —C(═O)—, and 
 
         Q represents a bond or
 —[NH—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)] q —, or 
 —O—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)—, or 
 S—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)—, wherein E is a bond, O, S, or NH, and m, p, and q independently are 1-40, and 
 
         R represents a bond or a polyradical, such as [—NH(CH 2 ) 4 CH(NH—)—C(═O)—] 1-5 , and 
         t is 1-40, and 
         the term ‘molecule’ refers to a compound comprising an amino group or a mercapto group, to which the group A or Q may be covalently linked. 
       
     
     
         4 . A compound of he general formula (I): 
       
         
           
           
               
               
           
         
         wherein 
         G, X, and Y independently represent
 a bond, —S—, —O—, —NH—, —(CH 2 ) 1-10 —, or 
 arylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, or 
 heteroarylene, optionally substituted with one or more alkyl, amino, cycloalkyl, aryl, heteroaryl, halogen, nitro, lower alkoxy, hydroxy, MeCONH—, alkanoyl, or cyano, and 
 
         Z represents a bond or
 —(CH 2 ) n —, —O—(CH 2 ) n —, —S—(CH 2 ) n —, —(OCH 2 CH 2 ) n —, —(CF 2 ) n —, —O—CH 2 —(CF 2 ) n —, —S—CH 2 —(CF 2 ) n —, 
 
         wherein n is 1-40, and 
         A represents
 —C(═O)—, —O—C(═O)—, —NH—C(═O)—, —C(C═O)NH—S(═O) 2 —, —S(═O) 2 NH—C(═O)—, —(CH 2 ) 1-5 —, —O—(CH 2 ) 1-5 —, or —O—(CH 2 ) 1-5 —C(═O)—, and 
 
         Q represents a bond or
 —[NH—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)] q —, or 
 —O—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)—, or 
 —S—(CH 2 CH 2 O) m —(CH 2 ) p -E-C(═O)—, wherein E is a bond, O, S, or NH, and m, p, and q independently are 1-40, and 
 
         R represents a bond or a polyradical, such as [—NH(CH 2 ) 4 CH(NH—)—C(═O)—] 1-5 , and 
         t is 1-40, and 
         the term ‘molecule’ refers to a compound comprising an amino group or a mercapto group, to which the group A or Q may be covalently linked. 
       
     
     
         5 . A compound according to  claim 4 , wherein G, X and Y are all a bond. 
     
     
         6 . A compound according to  claim 4 , wherein G, X and Y are all selected from —(CH 2 ) 1-10 —. 
     
     
         7 . A compound according to  claim 4 , wherein t is 1. 
     
     
         8 . A compound according to  claim 7 , wherein 
       
         
           
           
               
               
           
         
       
       is 16-(5-tetrazolyl)hexadecanoyl, 4-[N-(16-{5-tetrazolyl}hexadecanoyl)sulfamoyl]butyryl, 2-(2-(2-(16-(tetrazol-5-yl)(hexadecanoylamino)ethoxy)ethoxy)acetyl) or 16-(1H-tetrazol-5-yl)hexadecanoic acid [2-(2-{[2-(2-carbamoylmethoxyethoxy)ethylcarbamoyl]methoxy}ethoxy)ethyl]amide. 
     
     
         9 . A compound according to  claim 4 , wherein the molecule is covalently linked to R via the ε-amino group of a lysine residue. 
     
     
         10 . A compound according to  claim 4 , wherein the molecule is covalently linked to R via the thiol group of a cysteine residue. 
     
     
         11 . A compound according to  claim 4 , wherein the molecule is a therapeutic agent. 
     
     
         12 . A compound according to  claim 1 , wherein the therapeutic agent is a biopolymer. 
     
     
         13 . A compound according to  claim 11 , wherein the therapeutic agent is a polypeptide. 
     
     
         14 . A compound according to  claim 11 , wherein the therapeutic agent is a small molecule drug. 
     
     
         15 . A compound according to  claim 13 , wherein the polypeptide is an insulinotropic peptide. 
     
     
         16 . (canceled) 
     
     
         17 . A compound according to  claim 15 , wherein the polypeptide is GLP-1(7-37), an analog of GLP-1(7-37) or a derivative of GLP-1(7-37) or an analog thereof. 
     
     
         18 . A compound according to  claim 17 , wherein said polypeptide comprises an amino acid sequence of formula (III):
   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   Formula (III) (SEQ ID No: 3)   wherein   Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-amino-3-(2-aminoimidazol-4-yl)propionic acid, 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-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 1-aminocycloheptanecarboxylic acid, or 1-aminocyclooctanecarboxylic 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.   
     
     
         19 . A compound according to  claim 18 , wherein said polypeptide comprises an amino acid sequence of formula (IV):
   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   Formula (IV) (SEQ ID No: 4)   wherein   Xaa 7  is L-histidine, D-histidine, desamino-histidine, 2-aminohistidine, 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-aminocyclopropanecarboxylic acid, 1-aminocyclobutanecarboxylic acid, 1-aminocyclopentanecarboxylic acid, 1-aminocyclohexanecarboxylic acid, 1-aminocycloheptanecarboxylic acid, or 1-aminocyclooctanecarboxylic acid;   Xaa 18  is Ser, Lys or Arg;   Xaa 22  is Gly, Glu or Aib;   Xaa 23  is Gln, Glu, Lys or Arg;   Xaa 26  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.   
     
     
         20 . A compound according to  claim 17 , wherein said polypeptide 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(740), GLP-1(7-41) or an analogue thereof. 
     
     
         21 . A compound according to  claim 17 , wherein said polypeptide comprises no more than fifteen amino acid residues which have been exchanged, added or deleted as compared to GLP-1(7-37) (SEQ ID No. 1), or 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). 
     
     
         22 . A compound according to  claim 21 , wherein said polypeptide 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). 
     
     
         23 . A compound according to  claim 21 , wherein said polypeptide comprises no more than 4 amino acid residues which are not encoded by the genetic code. 
     
     
         24 . A compound according to  claim 17 , wherein said polypeptide is a DPP-IV protected insulinotropic peptide. 
     
     
         25 . A compound according to  claim 17 , wherein said polypeptide comprises an Aib residue in position 8. 
     
     
         26 . A compound according to  claim 17 , wherein the amino acid residue in position 7 of said polypeptide is selected from the group consisting of D-histidine, desamino-histidine, 2-amino-3-(2-aminoimidazol-4-yl)propionic acid, β-hydroxy-histidine, homohistidine, N-acetyl-histidine, α-fluoromethyl-histidine, α-methyl-histidine, 3-pyridylalanine, 2-pyridylalanine and 4-pyridylalanine. 
     
     
         27 . A compound according to  claim 17 , wherein said polypeptide 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 16 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 Lys 38 GLP-1(7-38), Aib 8,35  Arg 26  Lys 38  GLP-1(7-38), Aib 8,22  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). 
     
     
         28 . A compound according to  claim 17 , wherein said polypeptide is attached to R via the amino acid residue in position 23, 26, 34, 36 or 38 relative to the amino acid sequence SEQ ID No: 1. 
     
     
         29 . A compound according to  claim 13 , wherein said polypeptide is exendin-4 or an analogue thereof. 
     
     
         30 . A compound according to  claim 29 , wherein said polypeptide is an exendin-4 analogue comprising no more than twelve amino acid residues which have been exchanged, added or deleted as compared to exendin-4(1-39) (SEQ ID No. 2), or no more than eight amino acid residues which have been exchanged, added or deleted as compared to exendin-4(1-39) (SEQ ID No. 2). 
     
     
         31 . A compound according to any  claim 30 , wherein said polypeptide is HGEGTFTSDLSKQMEEEAVRLFIEWLKNGGPSSGAPPSKKKKKK-amide (SEQ ID No. 5). 
     
     
         32 . A compound according to  claim 4 , wherein said compound is selected from the group consisting of N-ε-26-(16-[5-tetrazolyl]hexadecanoyl)Arg 34 GLP-1-(7-37), Gly 8 ,Arg 26,34 GLP-1(7-37)Lys(16-(5-tetrazolyl)hexadecanoyl), Gly 8 ,Arg 26,34 GLP-1(7-37)Lys {4-[N-(16-{5-tetrazolyl}hexadecanoyl)sulfamoyl]butyryl}, N-ε-26-{4-[N-(16-{5-tetrazolyl}hexadecanoyl)sulfamoyl]butyryl} Arg 34 GLP-1(7-37), N-ε-37-(2-(2-(2-(16-(tetrazol-5-yl)(hexadecanoylamino)ethoxy)ethoxy)acetyl)) Aib 8,22,35 Lys 37 GLP-1(7-37), Gly 8 ,Glu 22,23,30 Arg 18,26,34  GLP-1(7-37)Lys(16-(1H-tetrazol-5-yl)hexadecanoic acid [2-(2-{[2-(2-carbamoylmethoxyethoxy)ethylcarbamoyl]methoxy}ethoxy)ethyl]amide)-NH 2 , and Gly 8 Arg 26,34 GLP-1(7-37)Lys(4-(4-(4-(4-(5-tetrazolyl)phenyl)phenyl)phenoxy)butyryl).N- ε38 -(2-(2-(2-(16-(4-(5-tetrazolyl)phenoxy)hexadecanoyl)ethoxy)ethoxy)acetyl) [Gly8,Arg26,34,Lys38]GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(2-(2-(2-(16-(4-(5-Tetrazolyl)phenoxy)hexadecanoyl)ethoxy)ethoxy)acetyl)[Aib8,22,35,Lys37]GLP-1(7-37) 
       
         
           
           
               
               
           
         
       
       N ε38 -(2-(2-(2-(16-(Tetrazol-5-yl)hexadecanoyl)ethoxy)ethoxy)acetyl) [Aib8,Arg26,34,Lys38]GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε38 -(4-(N-(16-(Tetrazol-5-yl)hexadecanoyl)sulfamoyl)butyryl) [Aib8,Arg26,34,Lys38]GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon32-(4-[N-(16-{5-Tetrazolyl}hexadecanoyl)sulfamoyl]butyryl)-[Lys32]Exendin[1-39] peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(16-(4′-(Tetrazol-5-yl)biphenyl)-4-yloxy)hexadecanoyl) [3-(4-imidazolyl)propionyl7,Aib22,35,Arg26,34,Lys37]GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(16-(Tetrazol-5-yl)hexadecanoyl) [3-(4-imidazolyl)propionyl7,Aib22,35,Arg26,34,Lys37]GLP-1(7-37) 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(16-(4-(Tetrazol-5-yl)phenoxy)hexadecanoyl) [3-(4-imidazolyl)propionyl7,Aib22,35,Arg26,34,Lys37]GLP-1(7-37) 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(4-(4-(Tetrazol-5-yl)[1,1′,4′,1″]terphenyl-4″yloxy)butyroyl) [3-(4-imidazolyl)propionyl7,Aib22,35,Arg26,34,Lys37]GLP-1(7-37) 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(2-(2-(2-(16-(Tetrazol-5-yl)hexadecanoyl)amino)ethoxy)ethoxy)acetyl)[Aib8,22,35,Arg26,34,Lys37] GLP-1(7-37) 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(2-(2-(2-(16-(Tetrazol-5-yl) (hexadecanoylamino)ethoxy)ethoxy)acetyl))[3-(4-imidazolyl)propionyl7,Aib22,35,Arg26,34,Lys37] GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon37-(2-(2-(2-(16-(Tetrazol-5-yl)hexadecanoyl)amino)ethoxy)ethoxy)acetyl))[3-(4-imidazolyl)propionyl7,Aib8,22,35,Arg26,34,Lys37] GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N-epsilon20-(2-(2-(2-(2-(2-(2-(2-(2-(2-(16-(Tetrazol-5-yl)hexadecanoylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[Lys20] Exendin-4 (1-39)amide 
       
         
           
           
               
               
           
         
       
       N εB29 -(16-2H-Tetrazol-5-yl-hexadecanoyl)gamma-Glu-des(B30) human insulin, 
       N B29ε -4-[4″-(1H-Tetrazol-5-yl)-[1,1′;4′,1″]terphenyl-4-yloxy]-butyroyl des(B30) insulin 
       
         
           
           
               
               
           
         
       
       N B29ε -16-[4′-(1H-tetrazol-5-yl)-biphenyl-4-yloxy]-hexadecanoyl des(B30) insulin 
       
         
           
           
               
               
           
         
       
       N ε37 -16-(4-(4-(5-Tetrazolyl)phenyl)phenyloxy)hexadecanoyl)-[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε31 -(4-(4-(4-(4-(5-Tetrazolyl)phenyl)phenyl)phenoxy)butyryl)[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε37 -(17,17-Bis(5-tetrazolyl)heptadecanoyl)[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε37 -(4-(4′-{5-[4-(5-Tetrazolyl)phenyl]-[1,2,4]oxadiazol-3-yl}biphenyl-4-yloxy)butyryl)[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε37 -(16-(4,5-Bis(5-Tetrazolyl)imidazol-1-yl)hexadecanoyl)[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε37 -((2-(2-(16-(5-Tetrazolyl)hexadecanoylamino)ethoxy)ethoxy)acetyl)[Gly8,Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε26 -(4-{16-(Tetrazol-5-yl)hexadecanoylsulfamoyl}butyryl)[(3-(4-imidazolyl)propionyl7,Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε34 -(16-{Tetrazol-5-yl}hexadecanoyl)-[Gly8, Arg26] GLP-1(7-34) peptideamide 
       
         
           
           
               
               
           
         
       
       N ε26 -({2-[2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino)ethoxy]ethoxy}acetyl)-[Arg34] GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε34 -({2-[2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino)ethoxy]ethoxy}acetyl)-[Arg26] GLP-1(7-34) peptideamide 
       
         
           
           
               
               
           
         
       
       N ε26 -({2-[2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyrylamino)ethoxy]ethoxy}acetyl)-[(3-(4-imidazolyl)propionyl) 7 ,Arg34]GLP-1(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε26 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)-[Aib8,Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N α7 (Me)N ε26 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)-[Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε26 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)-[Gly8,Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε14  (4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[Lys 14;Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
         N ε18 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[Lys18;Arg26,34]GLP-1-(7-37) peptide 
       
       
         
           
           
               
               
           
         
       
       N ε18 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[Gly8;Lys18;Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε18 -(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[Aib8,Lys 18;Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε18 (4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[3-(4-imidazolyl)propionyl7;Lys 18;Arg26,34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε18  (4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)[Lys 18;Arg26]GLP-1-(7-33) peptideamide 
       
         
           
           
               
               
           
         
       
       N ε26 ((2-(2-(2-(2-(2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-[Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε26 -((2-(2-(2-(2-(2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)[Gly8, Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
       
       N ε26 -((2-(2-(2-(2-(2-(4-(16-(Tetrazol-5-yl)hexadecanoylsulfamoyl)butyryl)ethoxy)ethoxy)acetylamino)ethoxy)ethoxy)acetyl)-[Aib8,Arg34]GLP-1-(7-37) peptide 
       
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
         
           
           
               
               
           
         
       
     
     
         33 . A compound according to  claim 13 , wherein the therapeutic agent is human growth hormone or an analog thereof. 
     
     
         34 . A compound according to the  claim 13 , wherein the therapeutic agent is human insulin or an analog thereof. 
     
     
         35 . A compound according to  claim 13 , wherein the therapeutic agent is factor VII or an analog thereof. 
     
     
         36 . A compound of the general formula (II) 
       
         
           
           
               
               
           
         
         wherein G, X, Y, Z, A, Q, and R represent groups as defined in  claim 3 , and Lg is a leaving group, such as Cl, Br, I, OH, —OSO 2 Me, —OSO 2 CF 3 , —OTs, —SMe 2   + , —OSu, —OBt, —OAt, —OPh, or —O(4-NO 2 )Ph. 
       
     
     
         37 . (canceled) 
     
     
         38 . A pharmaceutical composition comprising a compound according to  claim 4 , and a pharmaceutically acceptable excipient. 
     
     
         39 . The pharmaceutical composition according to  claim 38 , which is suited for parenteral administration. 
     
     
         40 - 42 . (canceled) 
     
     
         43 . A method for treating hyperglycemia, type 2 diabetes, impaired glucose tolerance, type 1 diabetes, obesity, hypertension, syndrome X, dyslipidemia, disorders associated with toxic hypervolemia, cognitive disorders, atheroschlerosis, myocardial infarction, coronary heart disease, stroke and other cardiovascular disorders, inflammatory bowel syndrome, dyspepsia and gastric ulcers in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to  claim 15 . 
     
     
         44 . A method for delaying or preventing disease progression in type 2 diabetes in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to  claim 15 . 
     
     
         45 . A method for decreasing food intake, decreasing β-cell apoptosis, increasing β-cell function and β-cell mass, stimulating β-cell regeneration and/or for restoring glucose sensitivity to β-cells in a patient in need of such treatment, said method comprising administering to said patient a therapeutically effective amount of a compound according to  claim 15 .