Analogs of Gastric Inhibitory Polypeptide and Their Use for Treatment of Diabetes

Abstract

The present invention provides peptides which stimulate the release of insulin. The peptides, based on GIP 1-42 include substitutions and/or modifications which enhance and influence secretion and/or have enhanced resistance to degradation. The invention also provides a process of N terminally modifying GIP and the use of the peptide analogues for treatment of diabetes.

1 - 11 . (canceled) 
     
     
         12 . A peptide analogue of GIP (1-42) comprising at least 15 amino acid residues from the N-terminal end of GIP (1-42), wherein those amino acids present at positions 15-30 of the peptide analogue are unsubstituted with respect to GIP (1-42), with the proviso that the peptide analogue is not tyrosine 1  glucitol GIP (1-42), and
 wherein   (a) the peptide analogue comprises two amino acid substitutions or modifications selected from the group consisting of:
 (i) an L- or D-amino acid substitution at position 1 selected from Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine or an amino acid modification at position 1; and
 one of an L- or D-amino acid substitution at position 2 or 3 selected from Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Serine, Threonine, Tryptophan, Tyrosine, Valine; or an amino acid modification at position 2 or 3; and 
 
 (ii) an amino acid substitution at position 2 selected from Alanine, Arginine, Asparagine, Aspartic acid, Cysteine, Glutamic acid, Glutamine, Glycine, Histidine, Isoleucine, Leucine, Lysine, Methionine, Phenylalanine, Proline, Threonine, Tryptophan, Tyrosine, Valine or an amino acid modification at position 2; and
 one of an L- or D-amino acid modification at position 1, an amino acid modification at position 1, an L- or D-amino acid modification at position 3, or an amino acid substitution at position 3; 
 
   or wherein
 (b) the peptide analogue comprises one amino acid substitution or modification selected from the group consisting of: an L- or D-amino acid substitution at position 1; an amino acid modification at position 1; an amino acid modification at position 2; an L-amino acid substitution at position 2; an D-amino acid substitution at position 2 by a D-amino acid selected from D-arginine, D-asparagine, D-aspartic acid, D-cysteine, D-glutamic acid, D-glutamine, D-glycine, D-histidine, D-isoleucine, D-leucine, D-lysine, D-methionine, D-phenylalanine, D-proline, D-serine, D-threonine, D-tryptophan, D-tyrosine and D-valine; an L- or D-amino acid substitution at position 3, and an amino acid modification at position 3; 
   and wherein the peptide analogue is DPP-IV resistant and is capable of binding a receptor of GIP.   
     
     
         13 . The peptide analogue of  claim 12 , wherein the peptide analogue comprises a peptide analogue consisting of up to between 15 to 30 amino acids of GIP(1-42). 
     
     
         14 . The peptide analogue of  claim 12 , wherein the peptide analogue activates the receptor of GIP to stimulate insulin release. 
     
     
         15 . The peptide analogue of  claim 12 , wherein the peptide analogue is capable of binding a receptor of GIP and wherein the peptide analogue comprises at least one amino acid substitution or modification at one of position 1, 2 or 3, with the proviso that the peptide analogue is not tyrosine 1  glucitol GIP (1-42), wherein the amino acid substitution or modification is selected from the group consisting of: substitution at position 1 by an amino acid; substitution at position 2 by an L-amino acid, amino isobutyric acid or sarcosine; substitution at position 3 by an amino acid, amino isobutyric acid or sarcosine; conversion of the Ala 2 -Glu 3  bond to a ψ[CH 2 NH] bond; conversion of the Ala 2 -Glu 3  bond to a stable isostere bond; and substitution by beta-alanine, an omega-amino acid, 3-amino propionic acid, 4-amino butyric acid, ornithine, citrulline, homoarginine, t-butylalanine, t-butylglycine, N-methylisoleucine, phenylglycine, cyclohexylalanine, norleucine, cysteic acid and methionine sulfoxide. 
     
     
         16 . The peptide analogue of  claim 12 , with the proviso that, when the analogue comprises one amino acid modification at position 1, the one modification is not glycation of the tyrosine residue at position 1. 
     
     
         17 . A method of stimulating insulin release, the method comprising administering to an individual an effective amount of the peptide analogue of  claim 12 . 
     
     
         18 . The method of  claim 17 , wherein the peptide analogue comprises a peptide analogue consisting of up to between 15 to 30 amino acids of GIP(1-42). 
     
     
         19 . A method of moderating blood glucose excursions, the method comprising administering to an individual an effective amount of the peptide analogue of  claim 12 . 
     
     
         20 . The method of  claim 19 , wherein the peptide analogue comprises a peptide analogue consisting of up to between 15 to 30 amino acids of GIP(1-42). 
     
     
         21 . A method of treating diabetes comprising administering to an individual an effective amount of the peptide analogue of  claim 12 . 
     
     
         22 . The method of  claim 21 , wherein the peptide analogue comprises a peptide analogue consisting of up to between 15 to 30 amino acids of GIP(1-42). 
     
     
         23 . The method of  claim 21 , wherein the diabetes is type 2 diabetes. 
     
     
         24 . The method of  claim 22 , wherein the diabetes is type 2 diabetes.