LAUSR

Abstract Although the peptide, exenatide, has been widely used as a drug for the treatment of type 2 diabetes, its short plasma half‐life requires frequent subcutaneous injection, resulting in poor patient compliance in addition to side effects such as infection at the sites of injection. Here, we report a novel long‐acting fusion peptide comprising exenatide and a human serum albumin (HSA)‐binding aptide. A phage display screen of a library of aptides, yielded an HSA‐specific aptide (APTHSA) that bound HSA with a Kd of 188 nM. The recombinant fusion peptide comprising exenatide and APTHSA (exenatide‐APTHSA) was expressed in Escherichia coli and purified by affinity and size‐exclusion chromatography. The resulting exenatide‐APTHSA fusion peptide showed glucose‐induced insulin secretion activity similar to that of native exenatide when tested in vitro using the INS‐1 cell line. A pharmacokinetic analysis of exenatide‐APTHSA after subcutaneous administration revealed a 4‐fold longer plasma half‐life (1.3 vs. 0.35 h) compared with exenatide. Furthermore, exenatide‐APTHSA showed significantly improved anti‐hyperglycemic effects in oral glucose tolerance tests and enhanced hypoglycemic effects compared with exenatide in a db/db type 2 diabetes mouse model. These results suggest that the exenatide‐APTHSA fusion peptide could be used as a potential anti‐diabetic agent for the treatment of type 2 diabetes. Graphical abstract Figure. No Caption available.