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 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.
Authors
- M Schmitz
- Denise Mennerich (ORCID: https://orcid.org/0000-0002-3267-0944)
- Baofeng Guo (ORCID: https://orcid.org/0000-0001-6085-7004)
- Vu Thuy Khanh Le‐Trilling (ORCID: https://orcid.org/0000-0002-2733-3732)
- Kai Wang (ORCID: https://orcid.org/0000-0002-0137-1247)
- Yong Lin (ORCID: https://orcid.org/0000-0001-9171-0195)
- Chun Yao
- Binli Mao
- Z Li
- Mirko Trilling (ORCID: https://orcid.org/0000-0003-3659-3541)
- Dan Xu (ORCID: https://orcid.org/0000-0002-6367-9132)
- Yushun Wan (ORCID: https://orcid.org/0000-0003-0496-6315)
- Zhen Wei (ORCID: https://orcid.org/0009-0003-2018-4601)
- Ni Tang (ORCID: https://orcid.org/0000-0001-5830-8786)
- K Barbet
- Xiaoyong Zhang (ORCID: https://orcid.org/0000-0002-6930-9423)
- Jin‐Xin Liu (ORCID: https://orcid.org/0000-0003-1310-547X)
- Jie Hu (ORCID: https://orcid.org/0000-0002-3368-0183)
- Zebo Yu
- Haoran Tang (ORCID: https://orcid.org/0009-0006-2939-8173)
Institutions
- Ruhrlandklinik (DE)
- Nanfang Hospital (CN)
- Essen University Hospital (DE)
- Ministry of Education (TH)
- The Affiliated Yongchuan Hospital of Chongqing Medical University (CN)
- Children's Hospital of Chongqing Medical University (CN)
- Southern Medical University (CN)
- University of Duisburg-Essen (DE)
- Chongqing Medical University (CN)
Publication Details
- Journal
- Virus Research
- Published
- 2024-10-19
- DOI
- https://doi.org/10.1016/j.virusres.2024.199485
- Citations
- 1
- Primary Topic
- SARS-CoV-2 and COVID-19 Research
- Type
- article
- Field-Weighted Citation Impact
- 0.39
Funders
- Deutsche Forschungsgemeinschaft
- Chongqing Medical University
- Natural Science Foundation of Chongqing
- Chongqing Municipal Education Commission
- Key Technologies Research and Development Program
- National Key Research and Development Program of China