Genome Mining-Based Discovery of Blenny Fish-Derived Peptides Targeting the Mouse κ-Opioid Receptor

Over the past years, peptides have attracted increasing interest for G protein-coupled receptor (GPCR) drug discovery and development. Peptides occupy a unique chemical space that is not easily accessible for small molecules and antibodies and provide advantages over these ligand classes such as lower toxicity and higher selectivity. The κ-opioid receptor (KOR) is a prototypic GPCR and an appealing therapeutic target for the development of safer and more effective analgesics. Recently, peptides have emerged as analgesic drug candidates with improved side effect profiles. We have previously identified plant-derived peptides, which activate KOR. Based on this precedent, here we relied on publicly available databases to discover novel KOR peptide ligands by genome mining. Using human preprodynorphin as a query, we identified blenny fish-derived peptides, referred to as blenniorphins, capable of binding to and activating KOR with nanomolar affinity and potency, respectively. Additionally, the blenniorphins altered β-arrestin-2 recruitment at the KOR. Our study demonstrates the utility of genome mining to identify peptide GPCR ligands with intriguing pharmacological properties and unveils the potential of blenny fishes as a source for novel KOR ligands.