Stereochemical engineering of GLP-1 blocks proteolysis while preserving its metal-binding core

Abstract

Glucagon-like peptide-1 (GLP-1) is rapidly degraded by proteases, which limits its stability in biological systems. Here, we demonstrate that appropriate stereochemical engineering through selective D-amino acid substitutions efficiently blocks proteolysis while preserving the intrinsic metal-binding core of the peptide. Despite substantial modification of the primary structure, the engineered analogue retains its ability to coordinate metal ions through the conserved coordination motif. These findings reveal an unexpected robustness of the GLP-1 metal-binding site and show that proteolytic stability can be enhanced without disrupting metal-binding functionality. The work establishes stereochemical engineering as a strategy to decouple enzymatic stability from coordination properties in peptide systems.