Abstract
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.
Highlights
G protein-coupled receptors (GPCRs) are the largest, most versatile and most ubiquitous family of cell surface receptors involved in regulating a myriad of physiological processes (Lagerström and Schiöth, 2008; Rajagopal et al, 2010)
Mining of publicly available databases such as provided by the National Center for Biotechnology Information (NCBI) provides an opportunity for the discovery of novel genederived peptides
The observed precursor hit was found in the transcriptome of the blenny fish Meicanthus atrodorsalis and it contained the YGGF motif typical for endogenous human opioid peptides (Naqvi et al, 1998)
Summary
G protein-coupled receptors (GPCRs) are the largest, most versatile and most ubiquitous family of cell surface receptors involved in regulating a myriad of physiological processes (Lagerström and Schiöth, 2008; Rajagopal et al, 2010) They are amongst the most commonly targeted receptor classes: more than 475 approved drugs mediate their pharmacological effects by targeting these receptors (Hauser et al, 2017). Opioid receptors are prototypic class A GPCRs comprising four subtypes referred to as the κ-opioid receptor (KOR), μ-opioid receptor (MOR), δ-opioid receptor (DOR), and nociceptin receptor (NOP), which represents a related nonclassical opioid receptor (Che et al, 2021) They constitute primary targets for opioids including morphine and fentanyl, which continue to be the cornerstone of today’s pain therapy (Darcq and Kieffer, 2018). The use of opioids as analgesics for Discovery and Pharmacology of Fish-Derived Opioid-Like Peptides medical purposes and as illegal substances for drug misuse has recently escalated into a global “opioid crisis” affecting public health as well as social and economic welfare (Volkow and Collins, 2017; Darcq and Kieffer, 2018)
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