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

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 murin...

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Autores principales: Liu, Zhongli, Guo, Xiaola, Guo, Aijiang, Zhang, Shengying, Zou, Yang, Wang, Yugui, Li, Xiaolu, He, Wei, Pu, Lixia, Zhang, Shaohua, Zeng, Qiaoying, Cai, Xuepeng, Wang, Shuai
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Elsevier 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294487/
https://www.ncbi.nlm.nih.gov/pubmed/35843171
http://dx.doi.org/10.1016/j.ebiom.2022.104177
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author Liu, Zhongli
Guo, Xiaola
Guo, Aijiang
Zhang, Shengying
Zou, Yang
Wang, Yugui
Li, Xiaolu
He, Wei
Pu, Lixia
Zhang, Shaohua
Zeng, Qiaoying
Cai, Xuepeng
Wang, Shuai
author_facet Liu, Zhongli
Guo, Xiaola
Guo, Aijiang
Zhang, Shengying
Zou, Yang
Wang, Yugui
Li, Xiaolu
He, Wei
Pu, Lixia
Zhang, Shaohua
Zeng, Qiaoying
Cai, Xuepeng
Wang, Shuai
author_sort Liu, Zhongli
collection PubMed
description 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. FUNDING: This work was supported by the National Natural Science Foundation of China (31802179), the Natural Science Foundation of Gansu Province, China (No. 21JR7RA027), and the State Key Laboratory of Veterinary Etiological Biology (No. SKLVEB2021YQRC01).
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spelling pubmed-92944872022-07-20 HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein Liu, Zhongli Guo, Xiaola Guo, Aijiang Zhang, Shengying Zou, Yang Wang, Yugui Li, Xiaolu He, Wei Pu, Lixia Zhang, Shaohua Zeng, Qiaoying Cai, Xuepeng Wang, Shuai eBioMedicine Articles 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. FUNDING: This work was supported by the National Natural Science Foundation of China (31802179), the Natural Science Foundation of Gansu Province, China (No. 21JR7RA027), and the State Key Laboratory of Veterinary Etiological Biology (No. SKLVEB2021YQRC01). Elsevier 2022-07-15 /pmc/articles/PMC9294487/ /pubmed/35843171 http://dx.doi.org/10.1016/j.ebiom.2022.104177 Text en © 2022 The Authors https://creativecommons.org/licenses/by-nc-nd/4.0/This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
spellingShingle Articles
Liu, Zhongli
Guo, Xiaola
Guo, Aijiang
Zhang, Shengying
Zou, Yang
Wang, Yugui
Li, Xiaolu
He, Wei
Pu, Lixia
Zhang, Shaohua
Zeng, Qiaoying
Cai, Xuepeng
Wang, Shuai
HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title_full HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title_fullStr HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title_full_unstemmed HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title_short HIV protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting Ddi1-like protein
title_sort hiv protease inhibitor nelfinavir is a potent drug candidate against echinococcosis by targeting ddi1-like protein
topic Articles
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9294487/
https://www.ncbi.nlm.nih.gov/pubmed/35843171
http://dx.doi.org/10.1016/j.ebiom.2022.104177
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