Abstract:

Peptide therapeutics bridge the gap between small molecules and biologics, offering high potency and selectivity. Since the introduction of the first therapeutic peptide, insulin, peptides have been recognized as a viable option. A recent example showcasing their potential is glucagon-like peptide-1 (GLP-1). Released from the gut upon food ingestion, GLP-1 stimulates glucose-dependent insulin secretion, called the incretin effect. Along with restoring normoglycemia, it also suppresses appetite while delaying gastric emptying, both contributing to weight loss. GLP-1 analogues have become blockbuster drugs as they maintain glucose homeostasis and regulate satiety signaling to the extent that they are deemed as the first-line therapy for the treatment of type 2 diabetes (T2D) prior to insulin. Despite its effectiveness, GLP-1 is vulnerable to rapid inactivation by a ubiquitous serine protease called dipeptidyl peptidase-4 (DPP4). Our laboratory has implemented a unique N-alkylation approach that maintains full activity at its cognate receptor, GLP-1 receptor (GLP-1R), while simultaneously resisting enzyme-mediated degradation involving functionalities varying in size, shape, charge, polarity, and stereochemistry. Building on our GLP-1 results, we expanded our work to other peptides, driven by the current emphasis on unimolecular chimeric therapies where combining GLP-1 with other peptide hormones, like glucose-dependent insulinotropic polypeptide (GIP) and/or glucagon, enhances therapeutic potential. Initially, we observed altered potencies among mono-agonists of GLP-1, GIP, and glucagon with the same N-terminal alkylation. Subsequently, we applied promising N-alkylation moieties to multi-receptor ligands, which enabled us to fine-tune receptor activity. As interest in multi-receptor agonists grows, N-terminal alkylation not only provides DPP4 protection but also aids in achieving optimal receptor selectivity without altering the peptide sequence.