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

作者：Zhong‐Li Liu, Xiaola Guo, Aijiang Guo, Shengying Zhang, Yang Zou, Yugui Wang, Xiaolu Li, Wei He, Lixia Pu, Shaohua Zhang, Qiaoying Zeng, Xuepeng Cai, Shuai Wang · 发表于：EBioMedicine · 年份：2022 · DOI：10.1016/j.ebiom.2022.104177 · 被引用次数：17 · 研究领域：Parasitic infections in humans and animals、Toxoplasma gondii Research Studies、Amoebic Infections and Treatments

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 demons...