Diphyllin elicits a doubled-pronged attack on the entry of SARS-CoV-2 by inhibiting cathepsin L and furin

Diphyllin elicits a doubled-pronged attack on the entry of SARS-CoV-2 by inhibiting cathepsin L and furin

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic, posing serious threats to global health. Effective broad-spectrum antiviral drugs for the treatment of COVID-19 are not sufficiently available. In the present study, we investiga...

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Main Authors: Binli Mao, Vu Thuy Khanh Le-Trilling, Haihuan Tang, Jie Hu, Mona S. Schmitz, Kimberly Barbet, Dan Xu, Zhen Wei, Beinu Guo, Denise Mennerich, Chun Yao, Jinxin Liu, Zhenghan Li, Yushun Wan, Xiaoyong Zhang, Kai Wang, Ni Tang, Zebo Yu, Mirko Trilling, Yong Lin
Format: Article
Language:English
Published: Elsevier 2024-12-01
Series:Virus Research
Subjects:
Diphyllin
SARS-CoV-2
Endocytosis
Cathepsin L
Cell surface entry
Furin
Online Access:http://www.sciencedirect.com/science/article/pii/S0168170224001783
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Summary:The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) caused the coronavirus disease 2019 (COVID-19) pandemic, posing serious threats to global health. Effective broad-spectrum antiviral drugs for the treatment of COVID-19 are not sufficiently available. In the present study, we investigated the antiviral activity of the natural lignan diphyllin (PubChem CID 100492) against different SARS-CoV-2 variants and explored the underlying molecular mechanisms. We found that diphyllin dose-dependently inhibits the SARS-CoV-2 spike (S)-mediated entry into different types of cells. The potent inhibition was evident against spike proteins derived from the original SARS-CoV-2 and from variants of concern such as Alpha, Beta, Delta or Omicron. Accordingly, diphyllin also significantly inhibited the in vitro infection of a clinical SARS-CoV-2 virus isolate. Mechanistically, diphyllin simultaneously inhibited the endosomal entry of SARS-CoV-2 by neutralizing the endosomal acidification and reducing the activity of the cysteine protease cathepsin L (CTSL) as well as S-meditated cell surface entry by impairing furin activity. Collectively, our findings establish diphyllin as novel inhibitor of CTSL and furin proteases, resulting in a double-pronged attack on SARS-CoV-2 entry along endosomal as well as cell surface routes. Therefore, diphyllin has the potential to be advanced as an inhibitor of SARS-CoV-2 entry.
ISSN:1872-7492

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