Formulations and Uses of Exendins and Exendin Agonist Analogs

Abstract

Provided herein are formulations containing exendins, exendin agonists and/or exendin analogs and methods of using the exendins, exendin agonists and/or exendin analogs and formulations thereof to treat glucagonoma and necrolytic migratory erythema, or to suppress glucagon secretion.

What is claimed is: 
     
         1 . A method for treating glucagonoma or necrolytic migratory erythema in a human in need thereof, the method comprising identifying a human in need of treating glucagonoma or necrolytic migratory erythema; and
 administering to the human a therapeutically effective amount of a peptide comprising the amino acid sequence of SEQ ID NO:45, thereby treating the glucagonoma or the necrolytic migratory erythema in the human; wherein SEQ ID NO:45 is:   
       
         
           
                 
                 
               
                     
                   Xaa 1  Xaa 2  Xaa 3  Gly Xaa 5  Xaa 6  Xaa 7  Xaa 8  Xaa 9   
                 
                     
                   Xaa 10  Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17   
                 
                     
                   Ala Xaa 19  Xaa 20  Xaa 21  Xaa 22  Xaa 23  Xaa 24  Xaa 25   
                 
                     
                   Xaa 26  X 1 -Z 1 ; 
                 
             
                
                
                
                
               
            
           
         
       
       wherein
 Xaa 1  is 4-imidazopropionyl; 
 Xaa 2  is Ser, Gly, Ala or Thr; 
 Xaa 3  is Ala, Asp or Glu; 
 Xaa 5  is Ala or Thr; 
 Xaa 6  is Ala, Phe, Tyr or naphthylalanine; 
 Xaa 7  is Thr or Ser; 
 Xaa 8  is Ala, Ser or Thr; 
 Xaa 9  is Ala, Asp or Glu; 
 Xaa 10  is Ala, Leu, Ile, Val, pentylglycine or Met; 
 Xaa 11  is Ala or Ser; 
 Xaa 12  is Ala or Lys; 
 Xaa 13  is Ala or Gln; 
 Xaa 14  is Ala, Leu, Ile, pentylglycine, Val or Met; 
 Xaa 15  is Ala or Glu; 
 Xaa 16  is Ala or Glu; 
 Xaa 17  is Ala or Glu; 
 Xaa 19  is Ala or Val; 
 Xaa 20  is Ala or Arg; 
 Xaa 21  is Ala, Leu or Lys-NH ε —R where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl; 
 Xaa 22  is Phe, Tyr or naphthylalanine; 
 Xaa 23  is Ile, Val, Leu, pentylglycine, tert-butylglycine or Met; 
 Xaa 24  is Ala, Glu or Asp; 
 Xaa 25  is Ala, Tip, Phe, Tyr or naphthylalanine; 
 Xaa 26  is Ala or Leu; 
 X 1  is Lys Asn, Asn Lys, Lys-NW—R Asn, Asn Lys-NW—R, Lys-NW—R Ala, Ala Lys-NH ε —R, where R is Lys, Arg, C 1 -C 10  straight chain or branched alkanoyl or cycloalkylalkanoyl; 
 Z 1  is OH, NH 2 , Gly-Z 2 , Gly Gly-Z 2 , Gly Gly Xaa 31 -Z 2 , Gly Gly Xaa 31  Ser-Z 2 , Gly Gly Xaa 31  Ser Ser-Z 2 , Gly Gly Xaa 31  Ser Ser Gly-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala-Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36 -Z 2 , Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37 -Z 2  or Gly Gly Xaa 31  Ser Ser Gly Ala Xaa 36  Xaa 37  Xaa 38 -Z 2 ; 
 wherein Xaa 31 , Xaa 36 , Xaa 37  and Xaa 38  are independently selected from the group consisting of Pro, homoproline, 3Hyp, 4Hyp, thioproline, N-alkylglycine, N-alkylpentylglycine and N-alkylalanine; and 
 Z 2  is —OH or —NH 2 ; 
 provided that no more than three of Xaa 3 , Xaa 5 , Xaa 6 , Xaa 8 , Xaa 10 , Xaa 11 , Xaa 12 , Xaa 13 , Xaa 14 , Xaa 15 , Xaa 16 , Xaa 17 , Xaa 19 , Xaa 20 , Xaa 21 , Xaa 24 , Xaa 25 , and Xaa 26  are Ala. 
 
     
     
         2 . The method of  claim 1 , wherein the peptide further comprises one or more molecules linked to the peptide, wherein said molecule is polyethylene glycol. 
     
     
         3 . The method of  claim 2 , wherein each of said one or more molecules has a molecular weight of from about 500 to about 20,000 kilodalton (kD). 
     
     
         4 . The method of  claim 2 , wherein said one or more molecules is linked to the peptide at an amino, carboxyl, thiol group, diamine or dicarboxylic group. 
     
     
         5 . The method of  claim 2 , wherein said one or more molecules is linked to the peptide at a side chain of a lysine, aspartic acid, glutamic acid or cysteine. 
     
     
         6 . The method of  claim 5 , wherein said one or more molecules is linked to said peptide at the epsilon amino group of the lysine.