2. Academic Validation
  3. 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

  • Virus Res. 2024 Oct 19:350:199485. doi: 10.1016/j.virusres.2024.199485.
Binli Mao 1,  Vu Thuy Khanh Le-Trilling 2,  Haihuan Tang 3,  Jie Hu 4,  Mona S Schmitz 5,  Kimberly Barbet 5,  Dan Xu 3,  Zhen Wei 3,  Beinu Guo 3,  Denise Mennerich 6,  Chun Yao 7,  Jinxin Liu 7,  Zhenghan Li 7,  Yushun Wan 8,  Xiaoyong Zhang 9,  Kai Wang 3,  Ni Tang 3,  Zebo Yu 10,  Mirko Trilling 11,  Yong Lin 12
Affiliations

Affiliations

  • 1 Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing 400016, China; Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China.
  • 2 Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany.
  • 3 Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing 400016, China.
  • 4 Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing 400016, China; Department of Laboratory Medicine, Bishan Hospital of Chongqing Medical University, Chongqing 402760, China.
  • 5 Department of Pulmonary Medicine, University Medical Center Essen, Ruhrlandklinik, Essen 45239, Germany.
  • 6 Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany.
  • 7 Chongqing Yucai Secondary School, Chongqing 400050, China.
  • 8 College of Basic Medicine, Chongqing Medical University, Chongqing 400016, China.
  • 9 Hepatology Unit and Department of Infectious Diseases, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.
  • 10 Department of Blood Transfusion, The First Affiliated Hospital of Chongqing Medical University, Chongqing 400016, China. Electronic address: yuzebo2001@163.com.
  • 11 Institute for the Research on HIV and AIDS-associated Diseases, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany; Institute for Virology, University Hospital Essen, University of Duisburg-Essen, Essen 45147, Germany. Electronic address: mirko.trilling@uni-due.de.
  • 12 Key Laboratory of Molecular Biology of Infectious Diseases (Chinese Ministry of Education), Chongqing Medical University, Chongqing 400016, China. Electronic address: linyong@cqmu.edu.cn.
PMID: 39424146 DOI: 10.1016/j.virusres.2024.199485
Abstract

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.

Keywords

Cathepsin L; Cell surface entry; Diphyllin; Endocytosis; Furin; SARS-CoV-2.

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