Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
| Autor: | Emi Sano, Rina Hashimoto, Ayaka Sakamoto, Akitsu Hotta, Shinya Yamanaka, Kazuo Takayama, Kazutoshi Takahashi, Sayaka Deguchi, Renxing Yi |
|---|---|
| Jazyk: | angličtina |
| Rok vydání: | 2021 |
| Předmět: |
Camostat
Proteases ACE2 camostat RM1-950 Biology Cathepsin B human iPS cells chemistry.chemical_compound Drug Discovery Receptor TMPRSS2 Cathepsin Gene knockdown CA-074 methyl ester SARS-CoV-2 COVID-19 CRISPRi Molecular biology chemistry Basigin Molecular Medicine Original Article Therapeutics. Pharmacology Viral load |
| Zdroj: | Molecular Therapy: Nucleic Acids, Vol 26, Iss, Pp 1107-1114 (2021) Molecular Therapy. Nucleic Acids |
| ISSN: | 2162-2531 |
| Popis: | It has been reported that many receptors and proteases are required for severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection. Although angiotensin-converting enzyme 2 (ACE2) is the most important of these receptors, little is known about the contribution of other genes. In this study, we examined the roles of neuropilin-1, basigin, transmembrane serine proteases (TMPRSSs), and cathepsins (CTSs) in SARS-CoV-2 infection using the CRISPR interference system and ACE2-expressing human induced pluripotent stem (iPS) cells. Double knockdown of TMPRSS2 and cathepsin B (CTSB) reduced the viral load to 0.036% ± 0.021%. Consistently, the combination of the CTPB inhibitor CA-074 methyl ester and the TMPRSS2 inhibitor camostat reduced the viral load to 0.0078% ± 0.0057%. This result was confirmed using four SARS-CoV-2 variants (B.1.3, B.1.1.7, B.1.351, and B.1.1.248). The simultaneous use of these two drugs reduced viral load to less than 0.01% in both female and male iPS cells. These findings suggest that compounds targeting TMPRSS2 and CTSB exhibit highly efficient antiviral effects independent of gender and SARS-CoV-2 variant. Graphical abstract Hashimoto et al. used iPS cells and the CRISPRi system to compare the functions of receptors and proteases involved in SARS-CoV-2 infection. Dual inhibition of TMPRSS2 and CTSB prevented SARS-CoV-2 infection. The combination of TMPRSS2 and CTSB inhibitor treatment exhibited highly efficient antiviral effects independent of gender and SARS-CoV-2 variant. |
| Databáze: | OpenAIRE |
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