Pancreatic polypeptide family motifs, polypeptides and methods comprising the same

Abstract

The present invention provides novel Pancreatic Polypeptide Family (“PPF”) polypeptides and methods for their use.

What is claimed is: 
     
         1 . A method for treating diabetes, obesity, a gastrointestinal disorder, an eating disorder, insulin-resistance syndrome, a cardiovascular disease, nonalcoholic steatohepatitis, or lipodystrophy in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a PPF polypeptide to treat the obesity, diabetes, gastrointestinal disorder, eating disorder, insulin-resistance syndrome, cardiovascular disease, nonalcoholic steatohepatitis, or lipodystrophy. 
     
     
         2 . The method of  claim 1  for treating diabetes in the mammal in need thereof. 
     
     
         3 . The method of  claim 2 , wherein the diabetes is Type 1 diabetes. 
     
     
         4 . The method of  claim 2 , wherein the diabetes is Type 2 diabetes. 
     
     
         5 . The method of  claim 1  for treating obesity in the mammal in need thereof. 
     
     
         6 . The method of  claim 1 , wherein the PPF polypeptide comprises an amino acid sequence of Formula (VII) (SEQ ID NO: 482): 
       
         
           
                 
               
                   Xaa 1  Xaa 2  Pro Xaa 4  Pro Xaa 6  His Pro Xaa 9  Xaa 10   
                 
                     
                 
                   Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17  Ala 
                 
                     
                 
                   Xaa 19  Tyr Xaa 21  Xaa 22  Xaa 23  Leu Xaa 25  Xaa 26  Xaa 27   
                 
                     
                 
                   Xaa 28  Xaa 29  Xaa 30  Xaa 31  Thr Arg Gln Arg Tyr 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
       wherein:
 Xaa 1  is Tyr or absent; 
 Xaa 2  is Ile, Pro, or absent; 
 Xaa 4  is Lys, BH-modified Lys, Ala, Ser, or Arg; 
 Xaa 6  is Glu, Gln, Ala, Asn, Asp, or Val; 
 Xaa 9  is Gly or Ala; 
 Xaa 10  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 11  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 12  is Ala or Pro; 
 Xaa 13  is Ser or Pro; 
 Xaa 14  is Pro, Ala, or Ser; 
 Xaa 15  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 16  is Glu or Asp; 
 Xaa 17  is Leu or Ile; 
 Xaa 19  is Arg, Lys, BH-modified Lys, Gln, or N(Me)Ala; 
 Xaa 21  is Tyr, Ala, Phe, Lys, or BH-modified Lys; 
 Xaa 22  is Ala or Ser; 
 Xaa 23  is Ser, Ala, or Asp; 
 Xaa 25  is Arg, Lys or BH-modified Lys; 
 Xaa 26  is His, Ala, or Arg; 
 Xaa 27  is Tyr, or Phe; 
 Xaa 28  is Leu or Ile; 
 Xaa 29  is Asn, or Gln; 
 Xaa 30  is Leu or Met; and 
 Xaa 31  is Val, Ile, or Leu. 
 
     
     
         7 . The method of  claim 1 , wherein the PPF polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 266, 437, 438, 439, 442, 462, 469, 470, 471, and 472. 
     
     
         8 . The method of  claim 1 , wherein the PPF polypeptide further comprises an N-terminal cap. 
     
     
         9 . The method of  claim 1 , wherein the PPF polypeptide is linked to one or more water-soluble polymers. 
     
     
         10 . The method of  claim 9 , wherein the one or more water-soluble polymers are selected from at least one of the group consisting of polyethylene glycol and a fatty acid molecule, wherein the polymer is linked to the N- or C-terminus of the polypeptide, or the side chain of a lysine or serine amino acid residue within the sequence of the polypeptide. 
     
     
         11 . A method for reducing food intake, reducing nutrient availability, causing weight loss, affecting body composition, altering body energy content or energy expenditure, or improving lipid profile in a mammal in need thereof comprising administering to the mammal a therapeutically effective amount of a PPF polypeptide to reduce food intake, reduce nutrient availability, cause weight loss, affect body composition, alter body energy content or energy expenditure, or improve lipid profile. 
     
     
         12 . The method of  claim 11 , wherein the method for affecting body composition is a method for reducing body weight. 
     
     
         13 . The method of  claim 11 , wherein the PPF polypeptide comprises an amino acid sequence of Formula (VII) (SEQ ID NO: 482): 
       
         
           
                 
               
                   Xaa 1  Xaa 2  Pro Xaa 4  Pro Xaa 6  His Pro Xaa 9  Xaa 10   
                 
                     
                 
                   Xaa 11  Xaa 12  Xaa 13  Xaa 14  Xaa 15  Xaa 16  Xaa 17  Ala 
                 
                     
                 
                   Xaa 19  Tyr Xaa 21  Xaa 22  Xaa 23  Leu Xaa 25  Xaa 26  Xaa 27   
                 
                     
                 
                   Xaa 28  Xaa 29  Xaa 30  Xaa 31  Thr Arg Gln Arg Tyr 
                 
             
                
                
                
                
                
                
                
               
            
           
         
       
       wherein:
 Xaa 1  is Tyr or absent; 
 Xaa 2  is Ile, Pro, or absent; 
 Xaa 4  is Lys, BH-modified Lys, Ala, Ser, or Arg; 
 Xaa 6  is Glu, Gln, Ala, Asn, Asp, or Val; 
 Xaa 9  is Gly or Ala; 
 Xaa 10  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 11  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 12  is Ala or Pro; 
 Xaa 13  is Ser or Pro; 
 Xaa 14  is Pro, Ala, or Ser; 
 Xaa 15  is Glu, Ala, Asp, Asn, Gln, Gly, Pro, or Aib; 
 Xaa 16  is Glu or Asp; 
 Xaa 17  is Leu or Ile; 
 Xaa 19  is Arg, Lys, BH-modified Lys, Gln, or N(Me)Ala; 
 Xaa 21  is Tyr, Ala, Phe, Lys, or BH-modified Lys; 
 Xaa 22  is Ala or Ser; 
 Xaa 23  is Ser, Ala, or Asp; 
 Xaa 25  is Arg, Lys or BH-modified Lys; 
 Xaa 26  is His, Ala, or Arg; 
 Xaa 27  is Tyr, or Phe; 
 Xaa 28  is Leu or Ile; 
 Xaa 29  is Asn, or Gln; 
 Xaa 30  is Leu or Met; and 
 Xaa 31  is Val, Ile, or Leu. 
 
     
     
         14 . The method of  claim 11 , wherein the PPF polypeptide comprises an amino acid sequence selected from the group consisting of SEQ ID NOs: 266, 437, 438, 439, 442, 462, 469, 470, 471, and 472. 
     
     
         15 . The method of  claim 11 , wherein the PPF polypeptide further comprises an N-terminal cap. 
     
     
         16 . The method of  claim 1 , wherein the PPF polypeptide is linked to one or more water-soluble polymers. 
     
     
         17 . The method of  claim 16 , wherein the one or more water-soluble polymers are selected from at least one of the group consisting of polyethylene glycol and a fatty acid molecule, wherein the polymer is linked to the N- or C-terminus of the polypeptide, or the side chain of a lysine or serine amino acid residue within the sequence of the polypeptide.