Abstract
The multiple physiological properties of glucagon-like peptide-1 (GLP-1) make it a promising drug candidate for the treatment of type 2 diabetes. However, the in vivo half-life of GLP-1 is short due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. The poor stability of GLP-1 has significantly limited its clinical utility; however, many studies are focused on extending its stability. Fatty acid conjugation is a traditional approach for extending the stability of therapeutic peptides because of the high binding affinity of human serum albumin for fatty acids. However, the conjugate requires a complex synthetic approach, usually involving Lys and occasionally involving a linker. In the current study, we conjugated the GLP-1 molecule with fatty acid derivatives to simplify the synthesis steps. Human serum albumin binding assays indicated that the retained carboxyl groups of the fatty acids helped maintain a tight affinity to HSA. The conjugation of fatty acid-like molecules improved the stability and increased the binding affinity of GLP-1 to HSA. The use of fatty acid-like molecules as conjugating components allowed variant conjugation positions and freed carboxyl groups for other potential uses. This may be a novel, long-acting strategy for the development of therapeutic peptides.