Glucagon, New and Improved!

Glucagon Improvements via Pyridyl-Ala Substitutions

Glucagon is a critical peptide hormone that plays a critical physiological role in mobilization of hepatic glucose through stimulation of gluconeogenesis and glycogenolysis. For insulin dependent diabetics, who frequently encounter hypoglycemia, glucagon may be used as a subcutaneous injection in emergency situations to counter a bout with severe hypoglycemia. Certain properties of glucagon cause this peptide to be unusually unstable with a tendency to degrade rapidly and to form insoluble fibrils. Administration usually involves reconstitution in a sterile acidified diluent immediately prior to injection. Recently in the lab of Richard DiMarchi, glucagon analogs with substation of 3-and 4-pyridyl Ala 3-Pal and 4-Pal) in place of the aromatic amino acids Phe and Tyr were synthesized which had dramatic improvements to its biophysical properties while maintaining high potency relative to native glucagon. The glucagon analog with substitution of 3-Pal at positions 6,10 and 13 with an Aib16  demonstrated far superior properties in vivo in models of insulin-dependent hypoglycemia in pigs and rats (DOI: 10.1021/acs.jmedchem.6b00840).

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