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抗心律失常药物胺碘酮和决奈达隆抑制百日咳毒素对细胞的中毒作用。

The antiarrhythmic drugs amiodarone and dronedarone inhibit intoxication of cells with pertussis toxin.

机构信息

Institute of Experimental and Clinical Pharmacology, Toxicology and Pharmacology of Natural Products, Ulm University Medical Center, Ulm, Germany.

Department of Respiratory Medicine, Shanghai Sixth People's Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, 600 Yishan Road, Shanghai, 200233, China.

出版信息

Naunyn Schmiedebergs Arch Pharmacol. 2024 Dec;397(12):9991-10003. doi: 10.1007/s00210-024-03247-9. Epub 2024 Jul 3.

DOI:10.1007/s00210-024-03247-9
PMID:38958734
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11582147/
Abstract

Pertussis toxin (PT) is a virulent factor produced by Bordetella pertussis, the causative agent of whooping cough. PT exerts its pathogenic effects by ADP-ribosylating heterotrimeric G proteins, disrupting cellular signaling pathways. Here, we investigate the potential of two antiarrhythmic drugs, amiodarone and dronedarone, in mitigating PT-induced cellular intoxication. After binding to cells, PT is endocytosed, transported from the Golgi to the endoplasmic reticulum where the enzyme subunit PTS1 is released from the transport subunit of PT. PTS1 is translocated into the cytosol where it ADP-ribosylates inhibitory α-subunit of G-protein coupled receptors (Gαi). We showed that amiodarone and dronedarone protected CHO cells and human A549 cells from PT-intoxication by analyzing the ADP-ribosylation status of Gαi. Amiodarone had no effect on PT binding to cells or in vitro enzyme activity of PTS1 but reduced the signal of PTS1 in the cell suggesting that amiodarone interferes with intracellular transport of PTS1. Moreover, dronedarone mitigated the PT-mediated effect on cAMP signaling in a cell-based bioassay. Taken together, our findings underscore the inhibitory effects of amiodarone and dronedarone on PT-induced cellular intoxication, providing valuable insights into drug repurposing for infectious disease management.

摘要

百日咳毒素（PT）是由百日咳博德特氏菌产生的一种毒力因子，是百日咳的病原体。PT 通过 ADP-核糖基化异三聚体 G 蛋白发挥其致病作用，破坏细胞信号通路。在这里，我们研究了两种抗心律失常药物胺碘酮和决奈达隆在减轻 PT 诱导的细胞中毒中的潜在作用。PT 与细胞结合后被内吞，从高尔基体运输到内质网，其中酶亚单位 PTS1 从 PT 的转运亚单位中释放出来。PTS1 易位到细胞质中，在那里它 ADP-核糖基化 G 蛋白偶联受体（Gαi）的抑制性α亚单位。我们通过分析 Gαi 的 ADP-核糖基化状态，表明胺碘酮和决奈达隆可保护 CHO 细胞和人 A549 细胞免受 PT 中毒。胺碘酮对 PT 与细胞的结合或体外 PTS1 酶活性没有影响，但降低了细胞中 PTS1 的信号，表明胺碘酮干扰了 PTS1 的细胞内运输。此外，决奈达隆在基于细胞的生物测定中减轻了 PT 介导的 cAMP 信号转导的影响。总之，我们的研究结果强调了胺碘酮和决奈达隆对 PT 诱导的细胞中毒的抑制作用，为传染病管理的药物再利用提供了有价值的见解。

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