Stabilization of Therapeutic Peptides by Non-Perturbative Chemical Modification

DESCRIPTION (provided by applicant): Type 2 diabetes is a particularly debilitating disease and is endemic for a large proportion of the world's population. The unmet challenges in disease management are the lack of long-term efficacy in reducing hyperglycemia and the inability to stop progression. Glucagon-like peptide-1 (GLP-1), a natural gut hormone, provides a platform for therapeutics to combat the disease. Peptides in general have potent and selective biological activities, making them highly desirable as therapeutics, but a major obstacle to more widespread use in medicine is limited proteolytic stability. The high potency of GLP-1 itself is nullified by a half-life of less than 2 min after injection. Our laboratory has been developing GLP 1 analogswith enhanced proteolytic stability for several years: we have now discovered that a simple N-terminal modification, designed to deliver large stability enhancements, preserves binding and activity of GLP-1 in cell- based assays. Historically, gains i