The ubiquitous serine protease, dipeptidyl peptidase-4 (DPP4), is a key modulator of many physiological functions and achieves this by degrading peptides such as glucagon-like peptide-1 (GLP-1) and stromal cell-derived 1 α (SDF1α). GLP-1 is an important regulator of glucose homeostasis, and SDF-1α influences cardiovascular health. DPP4 cleaves two residues from the N–terminal end of these peptides recognizing the sequence XaaAla or XaaPro and often yields truncated analogues that are (near) completely inactive. One strategy to preserve the biological activities of these functional peptides is to create stabilized analogues using chemical modifications that disrupt DPP4 recognition but preserve receptor binding and activation. We have found that small perturbations at the N-terminus of GLP-1 and SDF1α were successful at generating DPP4 resistant analogues that maintained potency and efficacy at the cognate receptors, GLP-1R and CXCR4. We will report on the design, synthesis and biochemical characterization of these small molecules as well as DPP4 resistant peptide agonists as a starting point for further development of candidate therapeutic compounds useful for the amelioration of metabolic and cardiovascular diseases.

Molecular design of protease resistant analogues of therapeutic peptides

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ACS Fall 2022

The official archive and repository for all ACS Meetings & Expositions abstracts and select posters or presentations.