Abstract: Based on the helical character of Exendin-4,  we modified the N terminal α-helix and C terminal α-helix by deleting helix,  replacing the helix with 3 Alas and changing Gln13 with Tyr13， and  designed 4 structral mimetics. Combined with the bioactivity experiment of the mimetics, we analyzed the relationship between the helical structure and bioactivity of Exendin-4 by  circular dichroism analysis and fluorescent spectroscopy analysis. The results show that N terminal α-helix is more important than C terminal α-helix to promote the bioactivity of Exendin-4；  C terminal α-helix is more effective than N terminal α-helix to maitain the stability of Exendin-4 to DPPⅣ；  Tyr13 in the helical structure can be used as an important optimized site to improve the bioactivity of Exendin-4.

Key words: Exendin-4； , helix； bioactivity； , stability