Development of a C‐Terminal Site‐Specific PEGylated Analog of GLP‐1 with Improved Anti‐Diabetic Effects in Diabetic Mice

Preclinical Research

Glucagon‐like peptide‐1 (GLP‐1) is an attractive lead for antidiabetic drug development but its utility is limited due to poor in vivo stability. In this study, we developed a C‐terminal site‐specific PEGylated analog of GLP‐1 based on the structure‐activity relationship of GLP‐1. Using three steps of chromatography, we obtained the conjugate with a high purity. Polyethylene glycol (PEG) conjugation greatly enhanced GLP‐1 potency in vivo without changing its original conformation. In streptozotosin diabetic mice, this conjugate had an improved antidiabetic effect, as measured by fasting glucose/insulin/glycosylated serum protein, oral glucose tolerance test, and histochemical studies. Additionally, this PEG‐conjugated peptide delayed gastric emptying without significant effects on body weight gain. Our data indicate that this conjugate may be a promising lead for the development of antidiabetic drugs.