Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling,Journal of Natural Products

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Plant-Derived Cyclotides Modulate κ-Opioid Receptor Signaling
Journal of Natural Products ( IF 3.3 ) Pub Date : 2021-07-26 , DOI: 10.1021/acs.jnatprod.1c00301
Edin Muratspahić ₁ , Nataša Tomašević ₁ , Shahrooz Nasrollahi-Shirazi _{1,

2} , Jasmin Gattringer ₁ , Fabiola Susanna Emser ₁ , Michael Freissmuth _{1,

2} , Christian W Gruber ₁

Affiliation

Cyclotides are plant-derived disulfide-rich peptides comprising a cyclic cystine knot, which confers remarkable stability against thermal, proteolytic, and chemical degradation. They represent an emerging class of G protein-coupled receptor (GPCR) ligands. In this study, utilizing a screening approach of plant extracts and pharmacological analysis we identified cyclotides from Carapichea ipecacuanha to be ligands of the κ-opioid receptor (KOR), an attractive target for developing analgesics with reduced side effects and therapeutics for multiple sclerosis (MS). This prompted us to verify whether [T20K]kalata B1, a cyclotide in clinical development for the treatment of MS, is able to modulate KOR signaling. T20K bound to and fully activated KOR in the low μM range. We then explored the ability of T20K to allosterically modulate KOR. Co-incubation of T20K with KOR ligands resulted in positive allosteric modulation in functional cAMP assays by altering either the efficacy of dynorphin A_1–13 or the potency and efficacy of U50,488 (a selective KOR agonist), respectively. In addition, T20K increased the basal response upon cotreatment with U50,488. In the bioluminescence resonance energy transfer assay T20K negatively modulated the efficacy of U50,488. This study identifies cyclotides capable of modulating KOR and highlights the potential of plant-derived peptides as an opportunity to develop cyclotide-based KOR modulators.

中文翻译：

植物源环肽调节 κ-阿片受体信号传导

环肽是源自植物的富含二硫键的肽，包含环状胱氨酸结，具有显着的抗热、蛋白水解和化学降解稳定性。它们代表了一类新兴的 G 蛋白偶联受体 (GPCR) 配体。在这项研究中，利用植物提取物筛选方法和药理学分析，我们鉴定了来自Carapichea ipecacuanha的环肽是 κ-阿片受体 (KOR) 的配体，这是开发副作用减少的镇痛药和治疗多发性硬化症 (MS) 的有吸引力的目标）。这促使我们验证 [T20K]kalata B1（一种正在临床开发中用于治疗多发性硬化症的环肽）是否能够调节 KOR 信号传导。 T20K 在低 μM 范围内与 KOR 结合并完全激活。然后我们探索了 T20K 变构调节 KOR 的能力。 T20K 与 KOR 配体的共孵育通过分别改变强啡肽 A _1-13的功效或 U50,488（选择性 KOR 激动剂）的效力和功效，在功能性 cAMP 测定中产生正向变构调节。此外，T20K 与 U50,488 联合治疗时增加了基础反应。在生物发光共振能量转移测定中，T20K 负向调节 U50,488 的功效。这项研究鉴定了能够调节 KOR 的环肽，并强调了植物源肽作为开发基于环肽的 KOR 调节剂的机会的潜力。

更新日期：2021-08-27

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