A Long-Acting Glucagon-like Peptide 2 Protracted by Coomassie Brilliant Blue to Enhance Intestinal Growth in Mice

Glucagon-like peptide 2 (GLP-2) has therapeutic potential in the treatment of intestinal diseases. Its analogue, teduglutide, is clinically used for the treatment of short bowel syndrome (SBS). Despite the benefit of reduced parenteral support and a consistent safety profile in patients with SBS, teduglutide requires subcutaneous injection once daily. Long-acting GLP-2 analogues and the associated lower injection-frequency compliance are an unmet medical need in drug development. Here, we conjugated the pan-protein binder Coomassie brilliant blue (CBB) to the Lys30 residue of teduglutide to obtain a long-acting analogue 8c that retains potency and selectivity comparable to teduglutide. In the rat subcutaneous pharmacokinetic study, the CBB protracted peptide 8c displays a greatly extended half-life (T1/2: 7.97 vs 0.56 h) in the circulation and a measured release (Tmax: 4 vs 0.33 h) from the subcutaneous depot, which is in line with its enhanced affinity to albumin and special protracting mechanism. The unique pharmacokinetic profile can translate into a significantly enhanced intestinal growth in mice, measured as the 1.25-fold greater weight of the small intestine, 1.75-fold higher villus of jejunum, and 1.1-fold deeper crypt compared to the vehicle control. Its prolonged kinetics and intestinotrophic action would be beneficial for a reduced dosing frequency and better treatment outcome in SBS.