Old drug repurposing for neglected disease: Pyronaridine as a promising candidate for the treatment of Echinococcus granulosus infections

文献类型： 外文期刊

第一作者： Li, Jun

作者： Li, Jun;Wang, Tian;Qi, Wenjing;Ren, Yuan;Guo, Gang;Guo, Baoping;Zhang, Wenbao;Wang, Weisi;Yao, Junmin;Li, Shizhu;Han, Shuai;Dang, Zhisheng;Duan, Liping;Han, Xiumin;Duan, Liping;Wang, Liqin

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关键词： Echinococcus granulosus sensu stricto; Pyronaridine; Cystic echinococcosis; Drug repurposing; Topoisomerase I

期刊名称：EBIOMEDICINE （ 影响因子：8.143； 五年影响因子：8.333 ）

ISSN： 2352-3964

年卷期： 2020 年 54 卷

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收录情况： SCI

摘要： Background: Cystic echinococcosis (CE), a condition caused by the larval stage of the dog tapeworm Echinococcus granulosus sensu stricto, is a globally distributed zoonotic disease. Current treatment options for CE are limited, and an effective and safe anti-echinococcal drug is urgently required. Methods: Drug repurposing strategy was employed to identify new therapeutic agents against echinococcal cysts. An in vitro protoscolicidal assay along with in vivo murine models was applied in the drug screening. A microinjection procedure was employed to mimic the clinical PAIR (puncture, aspiration, injection and reaspiration) technique to evaluate the potential application of the candidate drug in clinical practice. Findings: We repurposed pyronaridine, an approved antimalarial drug, for the treatment of CE. Following a three-dose intraperitoneal regimen (57 mg/kg, q.d. for 3 days), pyronaridine caused 100% cyst mortality. Oral administration of pyronaridine at 57 mg/kg, q.d. for 30 days significantly reduced the parasitic burden in the pre-infected mice compared with albendazole group (p < 0.001). Using a microinjection of drug into cysts, pyronaridine (200 mu M) showed highly effective in term of inhibition of cyst growth (p < 0.05, compared with saline group). Pharmacokinetic analysis revealed that pyronaridine was highly distributed in the liver and lungs, the most affected organs of CE. Function analysis showed that pyronaridine inhibited the activity of topoisomerase I (IC50 = 209.7 +/- 1.1 mu M). In addition, classical apoptotic hallmarks, including DNA fragmentation and caspase activation, were triggered. Interpretation: Given its approved clinical safety, the repurposing of pyronaridine offers a rapidly translational option for treating CE including PAIR. (C) 2020 The Author(s). Published by Elsevier B.V.

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