葵花籽来源稳定环肽镇痛剂的设计,靶向 κ-阿片受体治疗慢性腹痛。
Design of a Stable Cyclic Peptide Analgesic Derived from Sunflower Seeds that Targets the κ-Opioid Receptor for the Treatment of Chronic Abdominal Pain.
机构信息
Center for Physiology and Pharmacology, Institute of Pharmacology, Medical University of Vienna, 1090 Vienna, Austria.
Institute for Molecular Bioscience, Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, Queensland 4072, Australia.
出版信息
J Med Chem. 2021 Jul 8;64(13):9042-9055. doi: 10.1021/acs.jmedchem.1c00158. Epub 2021 Jun 23.
The rising opioid crisis has become a worldwide societal and public health burden, resulting from the abuse of prescription opioids. Targeting the κ-opioid receptor (KOR) in the periphery has emerged as a powerful approach to develop novel pain medications without central side effects. Inspired by the traditional use of sunflower () preparations for analgesic purposes, we developed novel stabilized KOR ligands (termed as helianorphins) by incorporating different dynorphin A sequence fragments into a cyclic sunflower peptide scaffold. As a result, helianorphin-19 selectively bound to and fully activated the KOR with nanomolar potency. Importantly, helianorphin-19 exhibited strong KOR-specific peripheral analgesic activity in a mouse model of chronic visceral pain, without inducing unwanted central effects on motor coordination/sedation. Our study provides a proof of principle that cyclic peptides from plants may be used as templates to develop potent and stable peptide analgesics applicable via enteric administration by targeting the peripheral KOR for the treatment of chronic abdominal pain.
阿片类药物滥用导致的阿片类药物危机日益严重,已成为全球范围内的社会和公共卫生负担。在外周靶向 κ-阿片受体(KOR)已成为开发新型无中枢副作用止痛药物的有效方法。受向日葵()制剂用于镇痛目的的传统应用启发,我们通过将不同的强啡肽 A 序列片段整合到环向日葵肽支架中,开发了新型稳定的 KOR 配体(称为贺莲诺啡)。结果,贺莲诺啡-19 选择性结合并以纳摩尔效力完全激活 KOR。重要的是,贺莲诺啡-19 在慢性内脏痛小鼠模型中表现出强烈的 KOR 特异性外周镇痛活性,而不会对运动协调/镇静产生不必要的中枢作用。我们的研究提供了一个原理证明,即来自植物的环肽可用作模板,通过靶向外周 KOR 开发有效的、稳定的肽类镇痛药,通过肠内给药治疗慢性腹痛。