Bcr-Abl tyrosine kinase inhibitor imatinib as a potential drug for COVID-19
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Abstract
The rapid geographic expansion of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the infectious agent of Coronavirus Disease 2019 (COVID-19) pandemic, poses an immediate need for potent drugs. Enveloped viruses infect the host cell by cellular membrane fusion, a crucial mechanism required for virus replication. The SARS-CoV-2 spike glycoprotein, due to its primary interaction with the human angiotensin-converting enzyme 2 (ACE2) cell-surface receptor, is considered as a potential target for drug development. Based on in silico screening followed by in vitro studies, here we report that the existing FDA-approved Bcr-Abl tyrosine kinase inhibitor, imatinib, inhibits SARS-CoV-2 with an IC 50 of 130 nM. We provide evidence that although imatinib binds to the receptor-binding domain (RBD) of SARS-CoV-2 spike protein with an affinity at micromolar, i.e., 2.32 ± 0.9 μM levels, imatinib does not directly inhibit the spike RBD:ACE2 interaction – suggesting a Bcr-Abl kinase-mediated fusion inhibition mechanism is responsible for the inhibitory action. We also show that imatinib inhibits other coronaviruses, SARS-CoV, and MERS-CoV via fusion inhibition. Based on promising in vitro results, we propose the Abl tyrosine kinase inhibitor (ATKI), imatinib, to be a viable repurposable drug against COVID-19.
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SciScore for 10.1101/2020.06.18.158196: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Two hours post-infection, cells were washed three times with OptiMEM and replaced with medium containing anti-VSV-G neutralizing antibody (clone 8G5F11; Absolute Antibody) at a dilution of 1:50,000 to block remaining VSV-G pseudovirus. anti-VSV-G neutralizing antibodysuggested: NoneAfter the incubation, the cells were fixed and stained with a polyclonal rabbit anti-SARS-CoV antibody (Sino Biological; 1:500). anti-SARS-CoVsuggested: NoneExperimental Models: Cell Lines Sentences Resources Vero-TMPRSS2 cell line production: Vero-TMPRSS2 cells were produced by retroviral transduction. Vero-TMPRSS2suggested: …SciScore for 10.1101/2020.06.18.158196: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
NIH rigor criteria are not applicable to paper type.Table 2: Resources
Antibodies Sentences Resources Two hours post-infection, cells were washed three times with OptiMEM and replaced with medium containing anti-VSV-G neutralizing antibody (clone 8G5F11; Absolute Antibody) at a dilution of 1:50,000 to block remaining VSV-G pseudovirus. anti-VSV-G neutralizing antibodysuggested: NoneAfter the incubation, the cells were fixed and stained with a polyclonal rabbit anti-SARS-CoV antibody (Sino Biological; 1:500). anti-SARS-CoVsuggested: NoneExperimental Models: Cell Lines Sentences Resources Vero-TMPRSS2 cell line production: Vero-TMPRSS2 cells were produced by retroviral transduction. Vero-TMPRSS2suggested: JCRB Cat# JCRB1818, RRID:CVCL_YQ48)Briefly, a 70% confluent 10 cm dish of HEK-293T cells was transfected with 10μg pVSV-eGFP-dG, 2μg pCAG-VSV-N (nucleocapsid), 2μg pCAG-VSV-L (polymerase), 2μg pMD2. HEK-293Tsuggested: NoneCoronavirus S pseudovirus was titrated on VeroE6 cells as described above. VeroE6suggested: JCRB Cat# JCRB1819, RRID:CVCL_YQ49)Pseudovirus-imatinib mixes were added to monolayers of 2 × 104 Vero or Vero-TMPRSS2 cells in a 96-well plate. Verosuggested: NoneSoftware and Algorithms Sentences Resources The docking file of the protein model was prepared with MGLTools v1.5.4 [26] and the molecules were docked at the RBD of the spike protein via Autodock Vina 1.1.2 [27]. MGLToolssuggested: NoneAutodocksuggested: (AutoDock, RRID:SCR_012746)Plates were incubated for 16 hours before quantifying GFP-positive cells using an Amersham Typhoon scanner and ImageQuant TL software. ImageQuantsuggested: (ImageQuant, RRID:SCR_014246)anhydrous dimethyl sulfoxide (DMSO; Sigma Aldrich) DMSO; Sigma Aldrichsuggested: NoneResults from OddPub: Thank you for sharing your code and data.
Results from LimitationRecognizer: An explicit section about the limitations of the techniques employed in this study was not found. We encourage authors to address study limitations.Results from TrialIdentifier: We found the following clinical trial numbers in your paper:
Identifier Status Title NCT04346147 Recruiting Clinical Trial to Evaluate Efficacy of 3 Types of Treatment … NCT04357613 Not yet recruiting IMATINIB IN COVID-19 DISEASE IN AGED PATIENTS. NCT04356495 Recruiting Trial of COVID-19 Outpatient Treatment in Individuals With R… NCT04394416 Recruiting Trial of Imatinib for Hospitalized Adults With COVID-19 NCT04422678 Not yet recruiting The Safety & Efficacy of Imatinib for the Treatment of SARS-… Results from Barzooka: We found bar graphs of continuous data. We recommend replacing bar graphs with more informative graphics, as many different datasets can lead to the same bar graph. The actual data may suggest different conclusions from the summary statistics. For more information, please see Weissgerber et al (2015).
Results from JetFighter: We did not find any issues relating to colormaps.
Results from rtransparent:- Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
- Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
- No protocol registration statement was detected.
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