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  4. Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism
 
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2022
Journal Article
Title

Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism

Abstract
The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causal agent of the COVID-19 pandemic. More than 274 million individuals have suffered from COVID-19 and over five million people have died from this disease so far. Therefore, there is an urgent need for therapeutic drugs. Repurposing FDA approved drugs should be favored since evaluation of safety and efficacy of de-novo drug design are both costly and time consuming. We report that imatinib, an Abl tyrosine kinase inhibitor, robustly decreases SARS-CoV-2 infection and uncover a mechanism of action. We show that imatinib inhibits the infection of SARS-CoV-2 and its surrogate lentivector pseudotype. In latter, imatinib inhibited both routes of viral entry, endocytosis and membrane-fusion. We utilized a system to quantify in real-time cell–cell membrane fusion mediated by the SARS-CoV-2 surface protein, Spike, and its receptor, hACE2, to demonstrate that imatinib inhibits this process in an Abl1 and Abl2 independent manner. Furthermore, cellular thermal shift assay revealed a direct imatinib-Spike interaction that affects Spike susceptibility to trypsin digest. Collectively, our data suggest that imatinib inhibits Spike mediated viral entry by an off-target mechanism. These findings mark imatinib as a promising therapeutic drug in inhibiting the early steps of SARS-CoV-2 infection.
Author(s)
Strobelt, Romano
Weizmann Institute of Science, Rehovot, Israel
Adler, Julia
Weizmann Institute of Science, Rehovot, Israel
Paran, Pir
Israel Institute for Biological Research, Ness Ziona, Israel
Yahalom-Ronen, Yfat
Israel Institute for Biological Research, Ness Ziona, Israel
Melamed, Sharon
Israel Institute for Biological Research, Ness Ziona, Israel
Politi, Boaz
Shulman, Ziv
Weizmann Institute of Science, Rehovot, Israel
Schmiedel, Dominik  
Fraunhofer-Institut für Zelltherapie und Immunologie IZI  
Shaul, Yosef
Weizmann Institute of Science, Rehovot, Israel
Journal
Scientific Reports  
Open Access
DOI
10.1038/s41598-022-09664-1
Additional full text version
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Language
English
Fraunhofer-Institut für Zelltherapie und Immunologie IZI  
Keyword(s)
  • SARS-CoV-2

  • Target identification

  • Target validation

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