HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein

文献类型： 外文期刊

第一作者： Liu, Zhongli

作者： Liu, Zhongli;Guo, Xiaola;Guo, Aijiang;Zhang, Shengying;Zou, Yang;Wang, Yugui;Li, Xiaolu;He, Wei;Pu, Lixia;Zhang, Shaohua;Cai, Xuepeng;Wang, Shuai;Liu, Zhongli;Zeng, Qiaoying;Guo, Aijiang;Pu, Lixia;Zhang, Shaohua;Wang, Shuai

作者机构：

关键词： Echinococcosis; HIV protease inhibitors; Nelfinavir; Co-infection; Ddi1-like protein

期刊名称：EBIOMEDICINE （ 影响因子：11.205； 五年影响因子：10.481 ）

ISSN： 2352-3964

年卷期： 2022 年 82 卷

页码：

收录情况： SCI

摘要： Background Alveolar echinococcosis (AE), which is caused by larval Echinococcus multilocularis, is one of the world's most dangerous neglected diseases. Currently, no fully effective treatments are available to cure this disease. Methods In vitro protoscolicidal assay along with in vivo murine models was applied in repurposing drugs against AE. Genome-wide identification and homology-based modeling were used for predicting drug targets. RNAi, enzyme assay, and RNA-Seq analyses were utilized for investigating the roles in parasite survival and validations for the drug target. Findings We identified nelfinavir as the most effective HIV protease inhibitor against larval E. multilocularis. Once-daily oral administration of nelfinavir for 28 days resulted in a remarkable reduction in parasite infection in either immune-competent or immunocompromised mice. E. multilocularis DNA damage-inducible 1 protein (EmuDdi1) is predicted as a target candidate for nelfinavir. We proved that EmuDdi1 is essential for parasite survival and protein excretion and acts as a functionally active protease for this helminth. We found nelfinavir is able to inhibit the proteolytic activity of recombinant EmuDdi1 and block the EmuDdi1-related pathways for protein export. With other evidence of drug efficacy comparison, our results suggest that inhibition of EmuDdi1 is a mechanism by which this HIV proteinase inhibitor mediates its antiparasitic action on echinococcosis. Interpretation This study demonstrates that nelfinavir is a promising candidate for treating echinococcosis. This drug repurposing study proves that the widely prescribed drug for AIDS treatment is potent in combating E. multilocularis infection and thus provides valuable insights into the development of single-drug therapy for highly prevalent co-infection between HIV and helminth diseases. Copyright (C) 2022 The Authors. Published by Elsevier B.V.

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