Importance of the C‐terminal α‐helical structure for glucagon's biological activity

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Abstract
The synthetic glucagon analogues [Glu21]glucagon, 2, and [Lys17.18,Glu21]glucagon, 3, were designed using Chou-Fasman calculations for the purpose of enhancing the probability for the formation of a C-terminal amphipathic .alpha.-helical conformation. Circular dichroism indicates increased .alpha.-helical content for these analogues in solution relative to glucagon. Analogues 2 and 3 also exhibit a 3-fold and 5-fold increase in receptor binding potency, respectively. The adenylate cyclase stimulating potencies of 2 and 3 relative to glucagon are 2.1 and 7 times greater, respectively. Attempts were made at further .alpha.-helical enhancement by further substitutions in the 10-13 region of glucagon, as represented by the glucagon analogues [Phe13, Lys17,18 Glu21]glucagon, 4, and [Phe10,13, Lys17,18, Glu21]glucagon, 5. These latter substitutions resulted in lowered receptor binding and adenylate cyclase potencies for 4 and 5 relative to 3 despite increased .alpha.-helical content in solution as observed by circular dichroism spectroscopy.