Exendin-4类似物的生物活性及结构

针对Exendin-4的N端螺旋中第10~18位氨基酸序列LSKQMEEEA设计了Ex1, Ex2序列, 并进行活性、稳定性及其结构方面的研究, 为进一步设计具有Exendin-4活性的短肽抗酶解序列提供了理论依据, 进而为开发可供口服的类肽糖尿病药物奠定了结构理论基础.

Bioactivity and Structure of Analogues of Exendin-4

Exendin-4 is an incretin mimetic that has been studied as a potent drug for the treatment of the type 2 diabetes. To screen the shorter analogues of Exendin-4 that have the same bioactivity, we designed two analogues of Exendin-4: Ex1, deleting this sequence and Ex2, replacing this sequence with three Alas. The proliferation assay of RINm-5F cell using MTT suggested the bioactivity of Ex1 and Ex2 was lower compared to that of Exendin-4 caused by the deletion of LSKQMEEEA. Ex1 and Ex2 had the same strong stability against DPPⅣ with Exendin-4. CD data suggested the helix content of Ex1 had a significant lost, but the helix content of Ex2 was the same as that of Exendin-4. The emission maximum of Ex1 was red-shifted of 3 nm relative to Exendin-4, the absence of this sequence made Trp25 more apt to hydrophilic and the Trp-cage became looser. So we have designed Ex2, the mimetic of Exendin-4 that had the same bioactivity and strong stability against DPPⅣ with Exendin-4 successfully. It became a solid foundation for designing shorter analogues of Exendin-4 for oral drug of diabetes.