Muratspahić Edin, Retzl Bernhard, Duerrauer Leopold, Freissmuth Michael, Becker Christian F W, Gruber Christian W
Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, Vienna, Austria.
Institute of Biological Chemistry, Faculty of Chemistry, University of Vienna, Vienna, Austria.
Front Pharmacol. 2021 Oct 22;12:773029. doi: 10.3389/fphar.2021.773029. eCollection 2021.
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.
在过去几年中，肽在G蛋白偶联受体（GPCR）药物研发中引起了越来越多的关注。肽占据了一个独特的化学空间，小分子和抗体难以进入该空间，并且与这些配体类别相比具有优势，例如更低的毒性和更高的选择性。κ-阿片受体（KOR）是一种典型的GPCR，是开发更安全、更有效的镇痛药的一个有吸引力的治疗靶点。最近，肽已成为具有改善副作用特征的镇痛药候选物。我们之前已经鉴定出了激活KOR的植物源肽。基于这一先例，在此我们依靠公开可用的数据库，通过基因组挖掘来发现新型KOR肽配体。以人前强啡肽原作为查询序列，我们鉴定出了鲇鱼来源的肽，称为鲇鱼强啡肽，它们能够分别以纳摩尔亲和力和效力结合并激活KOR。此外，鲇鱼强啡肽改变了KOR处β-抑制蛋白2的募集。我们的研究证明了基因组挖掘在鉴定具有有趣药理特性的肽GPCR配体方面的实用性，并揭示了鲇鱼作为新型KOR配体来源的潜力。
