Peptides for treatment of diabetes

Abstract

The present disclosure concerns agents and their use in the treatment of endocrine, nutritional and/or metabolic diseases in a mammal. The disclosure furthermore concerns novel peptides.

1 . An agent comprising:
 a) a peptide or peptide analog comprising or consisting of the amino acid sequence KPLAEIDSIELSYGIK (SEQ ID NO: 136), KCLAECDSIELSYGIK (SEQ ID NO: 141), KPLAEDISIELSYGIK (SEQ ID NO: 145), KPLAEIGDIELSYGIK (SEQ ID NO: 146), KPLAEIDSIELTYGIK (SEQ ID NO: 149), KPLAEIDGIELSYGIK (SEQ ID NO: 150), KPLAEIDGIELTYGIK (SEQ ID NO: 151), KPLAEIGSIELSYGIK (SEQ ID NO: 152), KGLAEIDSIELSYGIK (SEQ ID NO: 153) and KPLAGIDSIGLSYGIK (SEQ ID NO: 154); CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KCLAEIDSCELSYGIK (SEQ ID NO: 155), or CFKPLAEIDSIEC (SEQ ID NO: 156);   b) a polynucleotide encoding upon expression, the peptide of a);   c) a vector comprising the polynucleotide of b); or   d) a cell comprising the polynucleotide of b), or the vector of c).   
     
     
         2 . The agent according to  claim 1 , wherein the peptide or peptide analog comprises an amino acid sequence of the general formula: 
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 162) 
                 
                     
                   KX 2 LAX 5 X 6 X 7 X 8 IX 10 LSYGIK 
                 
             
                
                
               
            
           
         
       
       wherein:
 X 2  is C, P or G; 
 X 5  is E or G; 
 X 5  is C, I or absent; 
 X 7  is D, G or absent; 
 X 8  is S, G or absent; 
 X 10  is E or G. 
 
     
     
         3 . The agent according to  claim 1 , wherein the agent comprises no more than 85, such as no more than 80, such as no more than 75, such as no more than 70, such as no more than 65, such as no more than 60, such as nor more than 55, such as no more than 50, such as no more than 55, such as no more than 40 amino acids, such as no more than 35, such as no more than 30, such as no more than 28, such as no more than 26, such as no more than 24, such as no more than 22, such as no more than 20, such as no more than 19, such as no more than 18, such as no more than 17, such as no more than 16, such as no more than 15, such as no more than 14, such as no more than 13, such as no more than 12, such as no more than 11, such as no more than 10 amino acids. 
     
     
         4 . The agent according to  claim 1 , wherein the agent comprises at least 2 additional amino acids, such as at least 3, such as at least 4, such as at least 5, such as at least 6, such as at least 7, such as at least 8, such as at least 9, such as at least 10, such as at least 15 or such as at least 20 amino acids conjugated to the N- or C-terminus of the peptide. 
     
     
         5 . The agent according to  claim 1 , wherein the agent is non-naturally occurring. 
     
     
         6 . The agent according to  claim 1 , wherein the agent is conjugated to a moiety. 
     
     
         7 . The agent according to  claim 1 , wherein the agent is further modified such as being glycosylated or by PEGylation, amidation, esterification, acylation, acetylation and/or alkylation. 
     
     
         8 . The agent according to  claim 1 , wherein the agent comprises or consists of tandem repeats. 
     
     
         9 . The agent according to  claim 1 , wherein the agent is fused to another polypeptide. 
     
     
         10 . The agent according to  claim 9 , wherein the said polypeptide is selected from the group consisting of glutathione-S-transferase (GST) and protein A. 
     
     
         11 . The agent according to  claim 1 , wherein the agent is fused to a tag. 
     
     
         12 . The agent according to  claim 1 , wherein the agent is cyclic. 
     
     
         13 . The agent according to  claim 1 , wherein the peptide or peptide analog comprises or consists of the amino acid sequence KPLAEIDSIELSYGIK (SEQ ID NO: 136), or a variant or fragment thereof. 
     
     
         14 . The agent according to  claim 1 , wherein one or more amino acids are conservatively substituted. 
     
     
         15 . The agent according to  claim 1 , wherein the peptide or peptide analog comprises or consists of one or more additional amino acids, inserted at the N- and/or C-terminus and/or internally within the sequence. 
     
     
         16 . The agent according to  claim 1 , wherein the agent further comprises a detectable moiety. 
     
     
         17 . An agent comprising:
 c) a peptide or peptide analog comprising or consisting of the amino acid sequence GDPNDGRGDSVVYGLR (SEQ ID NO: 137), VDTYDGGISVVYGLR (SEQ ID NO: 138), and VDTYDGDGSVVYGLR (SEQ ID NO: 139). VDVPEGDISLAYGLR (SEQ ID NO: 157), LDGLVRAYDNISPVG (SEQ ID NO: 158), GDPNGDISVVYGLR (SEQ ID NO: 159), VDVPNGDISLAYRLR (SEQ ID NO: 160) VDVPEGDISLAYRLR (SEQ ID NO: 161), V(beta-D)TYDGDISVVYGLR (SEQ ID NO:167), VDTY(beta-D)GDISVVYGLR (SEQ ID NO: 168), or VDTYDG(beta-D)ISVVYGLR (SEQ ID NO:169);   b) a polynucleotide encoding upon expression, the peptide of a);   c) a vector comprising the polynucleotide of b); or   d) a cell comprising the polynucleotide of b), or the vector of c).   
     
     
         18 . The agent according to  claim 17 , wherein the peptide or peptide analog comprises or consists of the amino acid sequence VDTYDGGISVVYGLR (SEQ ID NO: 138), or a variant or fragment thereof. 
     
     
         19 . A method of treating an endocrine disease and/or a metabolic disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of an agent comprising:
 a) a peptide or a peptide analog selected from the group consisting of:
 (i) a peptide comprising or consisting of an amino acid sequence of the general formula: 
   
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 140) 
                 
                     
                   KX 2 LAX 5 X 6 X 7 X 8 IX 10 LX 12 YGIK 
                 
             
                
                
               
            
           
         
         
           
             wherein:
 X 2  is C, P or G; 
 X 5  is E or G; 
 X 6  is C, D or I; 
 X 7  is D, I, S or G; 
 X 8  is S, D or G; 
 X 10  is E or G; 
 X 12  is S or T; 
 
           
           with the proviso that if X 12  is T, the peptide comprises no more than 25 amino acid residues; 
           (ii) a peptide comprising or consisting of an amino acid sequence of the general formula: 
         
       
       
         
           
                 
                 
               
                     
                   (SEQ ID NO: 68) 
                 
                     
                   VDZ 3 Z4Z 5 GZ 7 Z 8 SZ 10 Z 11 YGLR 
                 
             
                
                
               
            
           
         
         
           wherein:
 Z 3  is T or V; 
 Z 4  is Y or P; 
 Z 5  is D or N; 
 Z 7  is D or G; 
 Z 8  is I or G; 
 Z 10  is V or L; 
 Z 11  is V or A; 
 wherein the peptide is selected from the group consisting of VDTYDGDISVVYGLR (SEQ ID NO: 1), VDTYDGDISVVYGL (SEQ ID NO: 3), VDTYDGDISVVYG (SEQ ID NO: 6), GDISVVYGLR (SEQ ID NO: 26), VDTYDGDIS (SEQ ID NO: 28), VDTYDGRGDSVVYGLR (SEQ ID NO: 67), VDVPNGDISLAYGLR (SEQ ID NO: 69), VDVPNGDISLAYGL (SEQ ID NO: 71) DVPNGDISLAYGLR(SEQ ID NO: 72), VDVPNGDISLAYG (SEQ ID NO: 74), PNGDISLAYGLR (SEQ ID NO: 81), VDVPNGDISLA (SEQ ID NO: 83), GDISLAYGLR( 
 
           (iii) a peptide comprising or consists of an amino acid sequence selected from the group consisting of KCLAECDSIELSYGIK (SEQ ID NO: 141), CLAEIDSC (SEQ ID NO: 142), CFKPLAEIDSIECSYGIK (SEQ ID NO: 143), KPLAEGDIELSYGIK (SEQ ID NO: 147), KPLAEIELSYGIK (SEQ ID NO: 148), KCLAEIDSCELSYGIK (SEQ ID NO: 155) or CFKPLAEIDSIEC (SEQ ID NO: 156); 
         
         b) a polynucleotide encoding upon expression, the peptide of a); 
         c) a vector comprising the polynucleotide of b); or 
         d) a cell comprising the polynucleotide of b), or the vector of c). 
       
     
     
         20 . The method according  claim 19 , wherein said agent comprises a second or further active ingredient. 
     
     
         21 . The method according to  claim 20 , wherein the second or further active ingredient is selected from the group consisting of insulin, glucagon-like peptide-1 (GLP-1), sulfonylurea, a dipeptidyl peptidase-4 (DPP4) inhibitor, an alpha-glucosidase inhibitor, a thiazolidinedione, a meglitidine and a sodium-glucose cotransporter-2 (SGLT2) inhibitor. 
     
     
         22 . The method according to  claim 19 , wherein the endocrine disease and/or metabolic disease are selected from the group consisting of diabetes mellitus, type 1 diabetes mellitus, type 2 diabetes mellitus, malnutrition-related diabetes mellitus, disorders of glucose regulation and pancreatic internal secretion, insulin resistance syndrome, impaired glucose tolerance, hyperglycemia, hyperinsulinemia, and any combinations thereof. 
     
     
         23 . The method according to  claim 19 , wherein the endocrine disease and/or metabolic disease are selected from the group consisting of diabetes mellitus, disorders of the thyroid gland, disorders of glucose regulation and pancreatic internal secretion, disorders of endocrine glands, malnutrition, nutritional deficiencies, obesity, hyperalimentation, and metabolic disorders. 
     
     
         24 . The method according to  claim 19 , wherein the endocrine disease and/or a metabolic disease is diabetes mellitus selected from the group consisting of type 1 diabetes mellitus, type 2 diabetes mellitus, malnutrition-related diabetes mellitus, specified diabetes mellitus, and unspecified diabetes mellitus. 
     
     
         25 . The method according to  claim 19 , wherein the endocrine disease and/or a metabolic disease is a disorder of glucose regulation and pancreatic internal secretion selected from the group consisting of nondiabetic hypoglycaemic coma and disorders of pancreatic internal secretion. 
     
     
         26 . The method according to  claim 19 , wherein the endocrine disease and/or a metabolic disease is a disorder of obesity and hyperalimentation selected from the group consisting of localized adiposity, hyperalimentation, and sequelae of hyperalimentation. 
     
     
         27 . A method for delaying onset of diabetes and/or a diabetes associated disorder or disease, the method comprising administering a therapeutically effective amount of an agent according to  claim 1 , to an individual in need thereof. 
     
     
         28 . The method according to  claim 27 , wherein insulin secretion is increased. 
     
     
         29 . The method according to  claim 27 , wherein cellular uptake of glucose is increased.