Stabilized Opioid Peptides

Millions of people worldwide suffer from chronic and inflammatory pain, which severely impacts their quality of life and poses significant challenges to healthcare systems. While opioids remain essential in pain management, their use is limited by severe side effects, such as addiction, tolerance, and respiratory depression, leading to tens of thousands of deaths annually, particularly in the United States. Peptides derived from nature, such as plants or insects, offer a promising starting point for developing optimized molecular tools or therapeutic candidates for inflammatory pain. Building on our prior research, we have isolated peptides from sunflower seeds and chemically synthesized them to selectively activate the kappa-opioid receptor, one of four cellular opioid receptors in the body, and a prototypic member of the G protein-coupled receptor family. This project builds on the hypothesis to modify the endogenous peptide hormone dynorphin and graft it into the sunflower peptide scaffold, to derive biologically stabilized and pharmacologically active molecules. These engineered peptides will allow us to investigate the molecular mechanisms of opioid receptor signalling, with a focus on improving receptor-subtype selectivity and signalling specificity for distinct ligand-mediated pathways in our cells. By employing advanced methods of molecular pharmacology and structural biology, we aim to improve our understanding of the biochemical details of receptor-mediated cellular signalling and to develop drug candidates for inflammatory pain while minimizing unwanted effects associated with conventional opioids. Our long-term goal is to deliver detailed insights into the selective and specific activation of G protein-coupled receptors, paving the way for the rational design of safer and more effective drugs.