G protein-coupled receptors (GPCRs) have been extremely valuable drug targets and approx. ⅓ of approved therapeutics target these cellular receptors. Current challenges in the field include the understanding and design of receptor-subtype and pathway specific ligands and modulators to reduce undesired effects that limit clinical translation. As compared to “classical” small molecule GPCR drugs, peptides gain a lot of attention, since they offer high target specificity, enhanced potency, improved selectivity, reduced off-target toxicity, as well as modularity and versatility from a synthetic point of view.

Building on these assets, we explore state-of-the-art medicinal chemistry and computational tools such as molecular grafting, macrocyclization, late-stage functionalization and de novo design, for developing novel ligands of the k-opioid receptor, a prototypical GPCR, which is a promising candidate as next-generation analgesic drug target. As proof-of-concept, several lead candidates derived this variety of approaches, exhibited potent in vivo efficacy in mouse models of chronic pain and chronic visceral hypersensitivity.

Specifically, the computational de novo platform paired with innovative peptide chemistry overcomes extensive lead optimization encountered in ultra-large library docking and virtual small molecule screening campaigns and offers innovation for GPCR ligand discovery. This may aid the development of next-generation therapeutics for peripheral pain and inflammatory bowel conditions.