A site‐specific PEGylated analog of exendin‐4 with improved pharmacokinetics and pharmacodynamics in vivo

Objectives Our aim was to improve the in vivo pharmacokinetics and pharmacodynamics of exendin‐4 by using site‐specific PEGylation. Methods We designed the PEGylated peptide based on its structure and activity relationship and prepared the conjugate by two steps of chromatographic purification. After obtained the conjugate we confirmed its glucose‐lowering activity in normal mice and determined its half‐life in SD rats. Then we evaluated its anti‐diabetic activity in a multiple low‐dose Streptozocin (STZ)‐induced diabetic mice model. Key findings With the process established in this study the product conjugate was obtained with a yield of over 60% and purity of above 99%. The conjugate maintained its original conformation after modification. In SD rats its half‐life was prolonged to 27.12 ± 5.75 h which was 17.61‐fold longer than that of the natural exendin‐4 for which the half‐life was only 1.54 ± 0.47 h. Its anti‐diabetic activity was significantly improved in the diabetic mice. Conclusions Compare with native exendin‐4, the C‐terminal site‐specific PEGylated analog of exendin‐4 obtained in this study has an improved pharmacokinetics and pharmacodynamics in vivo and could be regarded as a potential candidate for the future development of anti‐diabetic drugs.