Repurposing Niclosamide as a Novel Anti-SARS-CoV-2 Drug by Restricting Entry Protein CD147
Zhe Yang, Qi Zhang, Xiaoqing Wu, Siyuan Hao, Xinbao Hao, Elizabeth Jones, Yuxia Zhang, Jianming Qiu, Liang Xu
Biomedicines, doi:10.3390/biomedicines11072019
The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to the global coronavirus disease 2019 (COVID-19) pandemic, and the search for effective treatments has been limited. Furthermore, the rapid mutations of SARS-CoV-2 have posed challenges to existing vaccines and neutralizing antibodies, as they struggle to keep up with the increased viral transmissibility and immune evasion. However, there is hope in targeting the CD147-spike protein, which serves as an alternative point for the entry of SARS-CoV-2 into host cells. This protein has emerged as a promising therapeutic target for the development of drugs against COVID-19. Here, we demonstrate that the RNA-binding protein Human-antigen R (HuR) plays a crucial role in the post-transcriptional regulation of CD147 by directly binding to its 3 -untranslated region (UTR). We observed a decrease in CD147 levels across multiple cell lines upon HuR depletion. Furthermore, we identified that niclosamide can reduce CD147 by lowering the cytoplasmic translocation of HuR and reducing CD147 glycosylation. Moreover, our investigation revealed that SARS-CoV-2 infection induces an upregulation of CD147 in ACE2-expressing A549 cells, which can be effectively neutralized by niclosamide in a dose-dependent manner. Overall, our study unveils a novel regulatory mechanism of regulating CD147 through HuR and suggests niclosamide as a promising therapeutic option against COVID-19.
Author Contributions: Z.Y. contributed to experimental design, execution, and data analysis as well as the writing of this manuscript; Q.Z. contributed to experimental execution, data analysis, and manuscript revision; S.H. contributed to the SARS-CoV-2 infection assay; X.H. contributed to experimental design and execution. E.J. contributed to the immunohistochemical staining assay; Y.Z., X.W., and J.Q. provided material support, assisted with experimental design, and revised the manuscript; L.X. oversaw all experimental design, execution, analysis, interpretation, and communication of results as well as manuscript revision. All authors have read and agreed to the published version of the manuscript.
Abbreviations
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'abstract': '<jats:p>The outbreak of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led '
'to the global coronavirus disease 2019 (COVID-19) pandemic, and the search for effective '
'treatments has been limited. Furthermore, the rapid mutations of SARS-CoV-2 have posed '
'challenges to existing vaccines and neutralizing antibodies, as they struggle to keep up with '
'the increased viral transmissibility and immune evasion. However, there is hope in targeting '
'the CD147-spike protein, which serves as an alternative point for the entry of SARS-CoV-2 '
'into host cells. This protein has emerged as a promising therapeutic target for the '
'development of drugs against COVID-19. Here, we demonstrate that the RNA-binding protein '
'Human-antigen R (HuR) plays a crucial role in the post-transcriptional regulation of CD147 by '
'directly binding to its 3′-untranslated region (UTR). We observed a decrease in CD147 levels '
'across multiple cell lines upon HuR depletion. Furthermore, we identified that niclosamide '
'can reduce CD147 by lowering the cytoplasmic translocation of HuR and reducing CD147 '
'glycosylation. Moreover, our investigation revealed that SARS-CoV-2 infection induces an '
'upregulation of CD147 in ACE2-expressing A549 cells, which can be effectively neutralized by '
'niclosamide in a dose-dependent manner. Overall, our study unveils a novel regulatory '
'mechanism of regulating CD147 through HuR and suggests niclosamide as a promising therapeutic '
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