Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile.
Characterization of a P-glycoprotein drug transporter from Toxocara canis with a novel pharmacological profile.
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DOI：
10.1016/j.ijpddr.2021.10.002
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发表时间：
2021-12
期刊：
影响因子：
--
通讯作者：
Brewer MT
中科院分区：
文献类型：
--
作者：
Jesudoss Chelladurai JRJ;Jones DE;Brewer MT
来自ATP结合盒转运蛋白家族的P-糖蛋白负责细菌病原体和肿瘤细胞的药物逃避。最近，这些多药耐药转运蛋白已被调查的贡献，耐药性的线虫寄生虫。在这项研究中，我们克隆和表征的P-糖蛋白Tca-Pgp-11.1犬弓蛔虫，犬肠道蛔虫。Tca-Pgp-11转录本在成虫和雌蠕虫的肠道中大量存在。异源表达研究证实了对已知P-糖蛋白抑制剂的敏感性。有趣的是，竞争性抑制剂维拉帕米的IC 50值低于设计用于变构调节哺乳动物P-糖蛋白的新一代抑制剂。与其他线虫P-糖蛋白一致，Tca-Pgp-11.1对伊维菌素和赛拉菌素敏感，但对莫昔克丁不敏感。综上所述，我们的数据表明，T.犬P-糖蛋白代表线虫特异性药物靶标，其可用于增强现有驱虫剂的功效。
P-glycoproteins from the ATP-binding cassette transporter family are responsible for drug evasion by bacterial pathogens and neoplastic cells. More recently, these multidrug resistance transporters have been investigated for contributions to drug resistance in nematode parasites. In this study, we cloned and characterized the P-glycoprotein Tca-Pgp-11.1 from Toxocara canis, the canine intestinal ascarid. Large numbers of Tca-Pgp-11 transcripts were observed in the intestine of adult male and female worms. Heterologous expression studies confirmed sensitivity to known P-glycoprotein inhibitors. Interestingly, the competitive inhibitor verapamil had lower IC50 values than newer generation inhibitors that are designed to allosterically modulate mammalian P-glycoprotein. Consistent with other nematode P-glycoproteins, Tca-Pgp-11.1 was sensitive to ivermectin and selamectin but not moxidectin. Taken together, our data suggests that T. canis P-glycoproteins represent nematode-specific drug targets that could be exploited to enhance efficacy of existing anthelmintics.
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