Journal
MOLECULAR THERAPY-NUCLEIC ACIDS
Volume 26, Issue -, Pages 1107-1114Publisher
CELL PRESS
DOI: 10.1016/j.omtn.2021.10.016
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Funding
- iPS Cell Research Fund
- COVID-19 Private Fund
- Joint Usage/Research Center program of Institute for Frontier Life and Medical Sciences Kyoto University
- Japan Agency for Medical Research and Development (AMED) [20fk0108533h0001]
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This study investigated the roles of neuropilin-1, basigin, TMPRSSs, and CTSs in SARS-CoV-2 infection using the CRISPR interference system and ACE2-expressing human iPS cells. Double knockdown of TMPRSS2 and CTSB significantly reduced the viral load. Combination of CTPB and TMPRSS2 inhibitors showed highly efficient antiviral effects against various SARS-CoV-2 variants, independent of gender.
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.
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