COVID-19: Research on prevention of virus infection with iPS: ACE2-expressing iPS cells
CiRA
Center for iPS Cell Research and Application, Kyoto University
Outline of research
We found that “TMPRSS2 Note 2) and cathepsin B Note 3) play important roles in SARS-CoV-2 infection.
It was confirmed that “combination of TMPRSS2 inhibitor and cathepsin B inhibitor” “reduces SARS-CoV-2 infection efficiency”.
“CRISPR interference (CRISPRi) and ACE2-expressing iPS cells” are thought to be useful in elucidating the functions of SARS-CoV-2 related genes.
1. Summary
So far
‘Many receptors and proteases’
What is needed for SARS-CoV-2 infection
It has been reported.
Angiotensin converting enzyme 2 (ACE2):
In viral infection, “ACE2 is considered to be the most important receptor”.
However, until now, the “contribution of’other receptors and proteases’ to viral infections” has not been fully investigated.
CiRA Proliferation and Differentiation Mechanism:
The research group
Using ACE2-expressing iPS cells and CRISPRi technology,
Three receptors in SARS-CoV-2 infection and
We investigated the role of 6 proteases.
Verification result:
“Suppresses TMPRSS2 or cathepsin B expression,”
Viral load
It dropped to 20.6% or 0.84%, respectively.
“Simultaneously suppresses the expression of TMPRSS2 and cathepsin B,” he said.
Viral load
It dropped to 0.036%.
Similarly
In “Combination of Cathepsin B Inhibitor and TMPRSS2 Inhibitor”,
Viral load
It dropped to 0.0078%.
Similar results were observed with the four SARS-CoV-2 mutants.
Summary of research:
In this research,
By “Combination of CA-074 Me and camostat”
“Significant decrease in virus infection efficiency” was seen.
However, it was not possible to obtain a complete infection-inhibiting effect.
The receptors examined this time and
Besides proteases
It is expected that there will be important factors.
This technology:
The “ACE2-expressing iPS cells and CRISPRi technology” used this time may also be used for “search and evaluation of new SARS-CoV-2 related factors”.
CiRA
Center for iPS Cell Research and Application, Kyoto University
https://www.cira.kyoto-u.ac.jp/j/pressrelease/news/211021-000000.html
Dual inhibition of TMPRSS2 and Cathepsin B prevents SARS-CoV-2 infection in iPS cells:
Abstract
It has been reported
that many receptors and proteases are required for SARS-CoV-2 infection.Although angiotensin-converting enzyme2 (ACE2) is the most important of these receptors,
little is known about the contribution of other genes.
In this study,
we examined the roles ofneuropilin-1,
basigin,
transmembrane serine proteases (TMPRSSs),
cathepsins (CTSs)in SARS-CoV-2 infection using the CRISPR interference system and ACE2-expressing human iPS cells.
Double-knockdown of TMPRSS2 and 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.Molecular Therapy – Nucleic Acids
https://www.cell.com/molecular-therapy-family/nucleic-acids/fulltext/S2162-2531(21)00259-6