tetano
Editor, Senior Moderator
Sci Rep
. 2022 Apr 6;12(1):5758.
doi: 10.1038/s41598-022-09664-1.
Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism
Romano Strobelt[SUP] 1 [/SUP], Julia Adler[SUP] 1 [/SUP], Nir Paran[SUP] 2 [/SUP], Yfat Yahalom-Ronen[SUP] 2 [/SUP], Sharon Melamed[SUP] 2 [/SUP], Boaz Politi[SUP] 2 [/SUP], Ziv Shulman[SUP] 3 [/SUP], Dominik Schmiedel[SUP] 3 4 [/SUP], Yosef Shaul[SUP] 5 [/SUP]
Affiliations
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.
. 2022 Apr 6;12(1):5758.
doi: 10.1038/s41598-022-09664-1.
Imatinib inhibits SARS-CoV-2 infection by an off-target-mechanism
Romano Strobelt[SUP] 1 [/SUP], Julia Adler[SUP] 1 [/SUP], Nir Paran[SUP] 2 [/SUP], Yfat Yahalom-Ronen[SUP] 2 [/SUP], Sharon Melamed[SUP] 2 [/SUP], Boaz Politi[SUP] 2 [/SUP], Ziv Shulman[SUP] 3 [/SUP], Dominik Schmiedel[SUP] 3 4 [/SUP], Yosef Shaul[SUP] 5 [/SUP]
Affiliations
- PMID: 35388061
- DOI: 10.1038/s41598-022-09664-1
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.