Krstenansky J L, Zechel C, Trivedi D, Hruby V J
Department of Chemistry, University of Arizona, Tucson.
Int J Pept Protein Res. 1988 Dec;32(6):468-75. doi: 10.1111/j.1399-3011.1988.tb01377.x.
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.
合成胰高血糖素类似物[Glu21]胰高血糖素（2）和[Lys17,18,Glu21]胰高血糖素（3）是利用周-法斯曼计算法设计的，目的是提高形成C端两亲性α-螺旋构象的可能性。圆二色性表明，相对于胰高血糖素，这些类似物在溶液中的α-螺旋含量增加。类似物2和3的受体结合能力也分别提高了3倍和5倍。相对于胰高血糖素，2和3刺激腺苷酸环化酶的能力分别高出2.1倍和7倍。尝试通过在胰高血糖素的10-13区域进行进一步取代来进一步增强α-螺旋，如胰高血糖素类似物[Phe13,Lys17,18 Glu21]胰高血糖素（4）和[Phe10,13,Lys17,18,Glu21]胰高血糖素（5）所示。尽管通过圆二色光谱观察到溶液中的α-螺旋含量增加，但相对于3，后一种取代导致4和5的受体结合和腺苷酸环化酶能力降低。
