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GoSlo-SR-5-69对伊维菌素敏感的马来布鲁线虫SLO-1F和盘尾丝虫SLO-1A钾通道的正变构调节作用

Positive allosteric modulation of emodepside sensitive Brugia malayi SLO-1F and Onchocerca volvulus SLO-1A potassium channels by GoSlo-SR-5-69.

作者信息

McHugh Mark, Njeshi Charity N, Smith Nathaniel, Kashyap Sudhanva S, Datta Real, Sun Han, Robertson Alan P, Martin Richard J

机构信息

Department of Biomedical Sciences, College of Veterinary Medicine, Iowa State University, Ames, Iowa, United States of America.

Leibniz-Forschungsinstitut fur Molekulare Pharmacologie (FMP), Berlin, Germany.

出版信息

PLoS Pathog. 2025 Sep 11;21(9):e1012946. doi: 10.1371/journal.ppat.1012946. eCollection 2025 Sep.

DOI:10.1371/journal.ppat.1012946
PMID:40934261
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC12440207/
Abstract

Human lymphatic filariasis and onchocerciasis are Neglected Tropical Diseases (NTDs), of major public health concern. Prophylaxis and treatment rely on anthelmintics that effectively eliminate migrating microfilariae but lack efficacy against adult filarial worms. To expedite the elimination of both diseases, drugs with adulticidal activity are needed. The broad-spectrum anthelmintic emodepside, a nematode selective SLO-1 K channel activator, is a promising candidate for the treatment of onchocerciasis due to its macrofilaricidal activity against Onchocerca volvulus. Nevertheless, it is less effective against adult Brugia malayi, one of the causative agents of human lymphatic filariasis. Characterizing molecular and pharmacological disparities between highly conserved splice variant isoforms of B. malayi and O. volvulus SLO-1 K channels and identifying allosteric modulators that can increase emodepside potency on B. malayi SLO-1 K channels is necessary for therapeutic advance. In this study, we tested the effects of emodepside and the mammalian BK channel activator, GoSlo-SR-5-69 alone and in combination on Xenopus expressed B. malayi SLO-1F and O. volvulus SLO-1A channels. Additionally, binding poses of emodepside, and GoSlo-SR-5-69 were predicted on both channels using molecular docking. We observed that Ovo-SLO-1A was more sensitive to emodepside than Bma-SLO-1F, with EC50 values of 0.40 ± 0.05 µM and 1.4 ± 0.2 µM for Ovo-SLO-1A and Bma-SLO-1F respectively. GoSlo-SR-5-69 lacked agonist activity on both channel isoforms but acted as a positive allosteric modulator, potentiating the effects of emodepside. Molecular docking analysis revealed that emodepside binds at the S6 pocket below the selectivity filter for Bma-SLO-1F and Ovo-SLO-1A. In contrast, GoSlo-SR-5-69 binds at the RCK1 pocket. This study reveals for the first time, allosteric modulation of filarial nematode SLO-1 K channels by a mammalian BK channel activator and highlights its ability to increase emodepside potency on the B. malayi SLO-1 K channel.

摘要

人类淋巴丝虫病和盘尾丝虫病是被忽视的热带病（NTDs），是主要的公共卫生问题。预防和治疗依赖于驱虫药，这些药物能有效消除迁移的微丝蚴，但对成虫丝虫缺乏疗效。为了加速这两种疾病的消除，需要具有杀成虫活性的药物。广谱驱虫药依莫地肽是一种线虫选择性SLO-1钾通道激活剂，由于其对盘尾丝虫具有杀大丝蚴活性，是治疗盘尾丝虫病的一个有前景的候选药物。然而，它对人类淋巴丝虫病的病原体之一马来布鲁线虫成虫的效果较差。表征马来布鲁线虫和盘尾丝虫SLO-1钾通道高度保守的剪接变异体亚型之间的分子和药理学差异，并鉴定能提高依莫地肽对马来布鲁线虫SLO-1钾通道效力的变构调节剂，对于治疗进展是必要的。在本研究中，我们测试了依莫地肽和哺乳动物BK通道激活剂GoSlo-SR-5-69单独及联合作用于非洲爪蟾表达的马来布鲁线虫SLO-1F和盘尾丝虫SLO-1A通道的效果。此外，使用分子对接预测了依莫地肽和GoSlo-SR-5-69在这两种通道上的结合构象。我们观察到，盘尾丝虫SLO-1A对依莫地肽比马来布鲁线虫SLO-1F更敏感，盘尾丝虫SLO-1A和马来布鲁线虫SLO-1F的半数有效浓度（EC50）值分别为0.40±0.05μM和1.4±0.2μM。GoSlo-SR-5-69对这两种通道亚型均缺乏激动剂活性，但作为一种正变构调节剂，增强了依莫地肽的作用。分子对接分析表明，依莫地肽结合在马来布鲁线虫SLO-1F和盘尾丝虫SLO-1A选择性过滤器下方的S6口袋处。相比之下，GoSlo-SR-5-69结合在RCK1口袋处。本研究首次揭示了哺乳动物BK通道激活剂对丝虫线虫SLO-1钾通道的变构调节作用，并突出了其提高依莫地肽对马来布鲁线虫SLO-1钾通道效力的能力。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/a641d0f8826b/ppat.1012946.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/c64af2db3340/ppat.1012946.g001.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/9419bdffaadf/ppat.1012946.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/fd99377c0768/ppat.1012946.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/8464659feb1f/ppat.1012946.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/1fc18e2154f2/ppat.1012946.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/78c9bf174877/ppat.1012946.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/b16aab4015c4/ppat.1012946.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/a641d0f8826b/ppat.1012946.g009.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/c64af2db3340/ppat.1012946.g001.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/59bb608b4d2c/ppat.1012946.g002.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/9419bdffaadf/ppat.1012946.g003.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/fd99377c0768/ppat.1012946.g004.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/8464659feb1f/ppat.1012946.g005.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/1fc18e2154f2/ppat.1012946.g006.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/78c9bf174877/ppat.1012946.g007.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/b16aab4015c4/ppat.1012946.g008.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/0eed/12440207/a641d0f8826b/ppat.1012946.g009.jpg

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