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Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147

BACKGROUND: The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existi...

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Autores principales: Yang, Zhe, Zhang, Qi, Wu, Xiaoqing, Hao, Siyuan, Hao, Xinbao, Jones, Elizabeth, Zhang, Yuxia, Qiu, Jianming, Xu, Liang
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Journal Experts 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120763/
https://www.ncbi.nlm.nih.gov/pubmed/37090542
http://dx.doi.org/10.21203/rs.3.rs-2763207/v1
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author Yang, Zhe
Zhang, Qi
Wu, Xiaoqing
Hao, Siyuan
Hao, Xinbao
Jones, Elizabeth
Zhang, Yuxia
Qiu, Jianming
Xu, Liang
author_facet Yang, Zhe
Zhang, Qi
Wu, Xiaoqing
Hao, Siyuan
Hao, Xinbao
Jones, Elizabeth
Zhang, Yuxia
Qiu, Jianming
Xu, Liang
author_sort Yang, Zhe
collection PubMed
description BACKGROUND: The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existing vaccines and neutralizing antibodies due to the increased viral transmissibility and immune escape. CD147-spike protein, one of the entries of SRAR-CoV-2 into host cells, has been reported as a promising therapeutic target for developing drugs against COVID-19. METHODS: CRISPR-Cas9 induced gene knockout, western blotting, tet-off protein overexpression, ribonucleoprotein IP and RNA-IP were used to confirm the regulation of HuR on mRNA of CD147. Regulation of niclosamide on HuR nucleo-translocation was assessed by immunofluorescence staining of cell lines, IHC staining of tissue of mouse model and western blotting. Finally, the suppression of niclosamide on SARS-CoV-2 infection induced CD147 was evaluated by ACE2-expressing A549 cells and western blotting. RESULTS: We first discovered a novel regulation mechanism of CD147 via the RNA-binding protein HuR. We found that HuR regulates CD147 post-transcription by directly bound to its 3’-UTR. The loss of HuR reduced CD147 in multiple cell lines. Niclosamide inhibited CD147 function by blocking HuR cytoplasmic translocation and diminishing CD147 glycosylation. SARS-CoV-2 infection induced CD147 in ACE2-expressing A549 cells, which could be neutralized by niclosamide in a dose-dependent manner. CONCLUSION: Together, our study reveals a novel regulation mechanism of CD147 and niclosamide can be repurposed as an effective COVID-19 drug by targeting the virus entry, CD147-spike protein.
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spelling pubmed-101207632023-04-22 Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147 Yang, Zhe Zhang, Qi Wu, Xiaoqing Hao, Siyuan Hao, Xinbao Jones, Elizabeth Zhang, Yuxia Qiu, Jianming Xu, Liang Res Sq Article BACKGROUND: The burst of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is causing the global COVID-19 pandemic. But until today only limited numbers of drugs are discovered to treat COVID-19 patients. Even worse, the rapid mutations of SARS-CoV-2 compromise the effectiveness of existing vaccines and neutralizing antibodies due to the increased viral transmissibility and immune escape. CD147-spike protein, one of the entries of SRAR-CoV-2 into host cells, has been reported as a promising therapeutic target for developing drugs against COVID-19. METHODS: CRISPR-Cas9 induced gene knockout, western blotting, tet-off protein overexpression, ribonucleoprotein IP and RNA-IP were used to confirm the regulation of HuR on mRNA of CD147. Regulation of niclosamide on HuR nucleo-translocation was assessed by immunofluorescence staining of cell lines, IHC staining of tissue of mouse model and western blotting. Finally, the suppression of niclosamide on SARS-CoV-2 infection induced CD147 was evaluated by ACE2-expressing A549 cells and western blotting. RESULTS: We first discovered a novel regulation mechanism of CD147 via the RNA-binding protein HuR. We found that HuR regulates CD147 post-transcription by directly bound to its 3’-UTR. The loss of HuR reduced CD147 in multiple cell lines. Niclosamide inhibited CD147 function by blocking HuR cytoplasmic translocation and diminishing CD147 glycosylation. SARS-CoV-2 infection induced CD147 in ACE2-expressing A549 cells, which could be neutralized by niclosamide in a dose-dependent manner. CONCLUSION: Together, our study reveals a novel regulation mechanism of CD147 and niclosamide can be repurposed as an effective COVID-19 drug by targeting the virus entry, CD147-spike protein. American Journal Experts 2023-04-13 /pmc/articles/PMC10120763/ /pubmed/37090542 http://dx.doi.org/10.21203/rs.3.rs-2763207/v1 Text en https://creativecommons.org/licenses/by/4.0/This work is licensed under a Creative Commons Attribution 4.0 International License (https://creativecommons.org/licenses/by/4.0/) , which allows reusers to distribute, remix, adapt, and build upon the material in any medium or format, so long as attribution is given to the creator. The license allows for commercial use. https://creativecommons.org/licenses/by/4.0/License: his work is licensed under a Creative Commons Attribution 4.0 International License. Read Full License (https://creativecommons.org/licenses/by/4.0/)
spellingShingle Article
Yang, Zhe
Zhang, Qi
Wu, Xiaoqing
Hao, Siyuan
Hao, Xinbao
Jones, Elizabeth
Zhang, Yuxia
Qiu, Jianming
Xu, Liang
Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title_full Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title_fullStr Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title_full_unstemmed Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title_short Repurposing niclosamide as a novel anti-SARS-Cov-2 drug by restricting entry protein CD147
title_sort repurposing niclosamide as a novel anti-sars-cov-2 drug by restricting entry protein cd147
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10120763/
https://www.ncbi.nlm.nih.gov/pubmed/37090542
http://dx.doi.org/10.21203/rs.3.rs-2763207/v1
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