Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells

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 stu...

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Autores principales:	Rina Hashimoto, Ayaka Sakamoto, Sayaka Deguchi, Renxing Yi, Emi Sano, Akitsu Hotta, Kazutoshi Takahashi, Shinya Yamanaka, Kazuo Takayama
Formato:	article
Lenguaje:	EN
Publicado:	Elsevier 2021
Materias:	human iPS cells SARS-CoV-2 TMPRSS2 Cathepsin B CRISPRi COVID-19 Therapeutics. Pharmacology RM1-950
Acceso en línea:	https://doaj.org/article/261a1d9f45ae40909ca57488eb8c5535
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spelling	oai:doaj.org-article:261a1d9f45ae40909ca57488eb8c55352021-11-04T04:28:42ZDual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells2162-253110.1016/j.omtn.2021.10.016https://doaj.org/article/261a1d9f45ae40909ca57488eb8c55352021-12-01T00:00:00Zhttp://www.sciencedirect.com/science/article/pii/S2162253121002596https://doaj.org/toc/2162-2531It 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.Rina HashimotoAyaka SakamotoSayaka DeguchiRenxing YiEmi SanoAkitsu HottaKazutoshi TakahashiShinya YamanakaKazuo TakayamaElsevierarticlehuman iPS cellsSARS-CoV-2TMPRSS2Cathepsin BCRISPRiCOVID-19Therapeutics. PharmacologyRM1-950ENMolecular Therapy: Nucleic Acids, Vol 26, Iss , Pp 1107-1114 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	human iPS cells SARS-CoV-2 TMPRSS2 Cathepsin B CRISPRi COVID-19 Therapeutics. Pharmacology RM1-950
spellingShingle	human iPS cells SARS-CoV-2 TMPRSS2 Cathepsin B CRISPRi COVID-19 Therapeutics. Pharmacology RM1-950 Rina Hashimoto Ayaka Sakamoto Sayaka Deguchi Renxing Yi Emi Sano Akitsu Hotta Kazutoshi Takahashi Shinya Yamanaka Kazuo Takayama Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
description	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.
format	article
author	Rina Hashimoto Ayaka Sakamoto Sayaka Deguchi Renxing Yi Emi Sano Akitsu Hotta Kazutoshi Takahashi Shinya Yamanaka Kazuo Takayama
author_facet	Rina Hashimoto Ayaka Sakamoto Sayaka Deguchi Renxing Yi Emi Sano Akitsu Hotta Kazutoshi Takahashi Shinya Yamanaka Kazuo Takayama
author_sort	Rina Hashimoto
title	Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
title_short	Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
title_full	Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
title_fullStr	Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
title_full_unstemmed	Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells
title_sort	dual inhibition of tmprss2 and cathepsin bprevents sars-cov-2 infection in ips cells
publisher	Elsevier
publishDate	2021
url	https://doaj.org/article/261a1d9f45ae40909ca57488eb8c5535
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Dual inhibition of TMPRSS2 and Cathepsin Bprevents SARS-CoV-2 infection in iPS cells

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