Department of Pharmacology, University of Minnesota, Minneapolis, MN, 55455, USA.
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, CA, 92093, USA.
Nat Commun. 2017 Dec 5;8(1):1910. doi: 10.1038/s41467-017-02084-0.
Schistosomiasis is a debilitating tropical disease caused by infection with parasitic blood flukes. Approximately 260 million people are infected worldwide, underscoring the clinical and socioeconomic impact of this chronic infection. Schistosomiasis is treated with the drug praziquantel (PZQ), which has proved the therapeutic mainstay for over three decades of clinical use. However, the molecular target(s) of PZQ remain undefined. Here we identify a molecular target for the antischistosomal eutomer - (R)-PZQ - which functions as a partial agonist of the human serotoninergic 5HT receptor. (R)-PZQ modulation of serotoninergic signaling occurs over a concentration range sufficient to regulate vascular tone of the mesenteric blood vessels where the adult parasites reside within their host. These data establish (R)-PZQ as a G-protein-coupled receptor ligand and suggest that the efficacy of this clinically important anthelmintic is supported by a broad, cross species polypharmacology with PZQ modulating signaling events in both host and parasite.
血吸虫病是一种由寄生性血吸虫感染引起的使人虚弱的热带病。全世界约有 2.6 亿人受到感染，突出表明这种慢性感染的临床和社会经济影响。血吸虫病用药物吡喹酮（PZQ）治疗，该药物已被证明是三十多年临床应用的治疗支柱。然而，PZQ 的分子靶标仍然不明确。在这里，我们确定了抗血吸虫的 eutomer（R）-PZQ 的一个分子靶标，它作为人类血清素能 5HT 受体的部分激动剂发挥作用。（R）-PZQ 对血清素能信号的调节发生在足以调节肠系膜血管血管紧张度的浓度范围内，成年寄生虫在其宿主中存在于肠系膜血管中。这些数据将（R）-PZQ 确立为 G 蛋白偶联受体配体，并表明这种临床上重要的驱虫药的疗效得到了广泛的、跨物种的多药理学的支持，PZQ 调节宿主和寄生虫中的信号事件。
