Glucagon Analogs Exhibiting GIP Receptor Activity

Abstract

Provided herein are glucagon analogs which exhibit potent activity at the GIP receptor, and, as such are contemplated for use in treating diabetes and obesity. In exemplary embodiments, the glucagon analog of the present disclosures exhibit an EC50 at the GIP receptor which is within the nanomolar or picomolar range.

1 . An analog of glucagon (SEQ ID NO: 1), comprising:
 a. an amino acid comprising an imidazole side chain at position 1;   b. an DPP-IV protective amino acid at position 2, optionally, AIB;   c. an acylated amino acid or alkylated amino acid at any of positions 9, 10, 12, 16, 20, or 37-43, optionally wherein the acyl or alkyl group is linked to the amino acid via a spacer;   d. an alpha, alpha disubstituted amino acid at position 20; and   e. up to ten additional amino acid modifications relative to SEQ ID NO: 1;   wherein, when the glucagon analog lacks a hydrophilic moiety, the glucagon analog exhibits a GIP percentage potency of at least 0.1%, wherein the glucagon analog has less than 100-fold selectivity for the human GLP-1 receptor versus the GIP receptor.   
     
     
         2 . The glucagon analog of  claim 1 , wherein the α,α-disubstituted amino acid comprises R1 and R2, each of which is bonded to the alpha carbon, wherein each of R1 and R2 is independently selected from the group consisting of C1-C4 alkyl, optionally substituted with a hydroxyl, amide, thiol, halo, or R1 and R2 together with the alpha carbon to which they are attached form a ring. 
     
     
         3 . The glucagon analog of  claim 2 , wherein the α,α-disubstituted at position 20 is AIB. 
     
     
         4 . The glucagon analog of  claim 1 , wherein the amino acid at position 16 is an alpha helix stabilizing amino acid other than AIB. 
     
     
         5 . The glucagon analog of  claim 4 , wherein the amino acid at position 16 is a charged amino acid, optionally, a negative charged amino acid or a positive charged amino acid. 
     
     
         6 . The glucagon analog of  claim 5 , wherein the charged amino acid is Glu or Lys. 
     
     
         7 . An analog of glucagon (SEQ ID NO: 1), comprising:
 a. an amino acid comprising an imidazole side chain at position 1;   b. an DPP-IV protective amino acid at position 2, optionally, AIB;   c. an acylated amino acid or alkylated amino acid at any of positions 9, 10, 12, 16, 20, or 37-43, optionally wherein the acyl or alkyl group is linked to the amino acid via a spacer;   d. an alpha helix stabilizing amino acid at one or more of positions 16-21, optionally, position 16, wherein the analog does not comprise an alpha helix stabilizing amino acid at position 20; and   e. up to ten additional amino acid modifications relative to SEQ ID NO: 1;   wherein, when the glucagon analog lacks a hydrophilic moiety, the glucagon analog exhibits a GIP percentage potency of at least 0.1%, wherein the glucagon analog has less than 100-fold selectivity for the human GLP-1 receptor versus the GIP receptor.   
     
     
         8 . The glucagon analog of  claim 7 , comprising an alpha helix stabilizing amino acid at position 16, optionally, wherein the alpha helix stabilizing amino acid is a negative charged amino acid or an alpha, alpha disubstituted amino acid. 
     
     
         9 . The glucagon analog of  claim 8 , wherein the negative charged amino acid is Glu. 
     
     
         10 . The glucagon analog of  claim 8 , wherein the α,α-disubstituted amino acid comprises R1 and R2, each of which is bonded to the alpha carbon, wherein each of R1 and R2 is independently selected from the group consisting of C1-C4 alkyl, optionally substituted with a hydroxyl, amide, thiol, halo, or R1 and R2 together with the alpha carbon to which they are attached form a ring. 
     
     
         11 - 136 . (canceled)