Host-Directed FDA-Approved Drugs with Antiviral Activity against SARS-CoV-2 Identified by Hierarchical In Silico/In Vitro Screening Methods
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Abstract
The unprecedent situation generated by the COVID-19 global emergency has prompted us to actively work to fight against this pandemic by searching for repurposable agents among FDA approved drugs to shed light into immediate opportunities for the treatment of COVID-19 patients. In the attempt to proceed toward a proper rationalization of the search for new antivirals among approved drugs, we carried out a hierarchical in silico/in vitro protocol which successfully combines virtual and biological screening to speed up the identification of host-directed therapies against COVID-19 in an effective way. To this end a multi-target virtual screening approach focused on host-based targets related to viral entry, followed by the experimental evaluation of the antiviral activity of selected compounds, has been carried out. As a result, five different potentially repurposable drugs interfering with viral entry—cepharantine, clofazimine, metergoline, imatinib and efloxate—have been identified.
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SciScore for 10.1101/2020.11.26.399436: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For SARS-CoV-2 Spike pseudotyped particle (SARS2pp) entry experiments, Vero-E6 cells (104 cells/well) were seeded onto 96-well plates the day before. Vero-E6suggested: NoneOne hundred μL of the mixture was applied onto the Vero E6 cell monolayer in biological triplicates and cells were cultured at 37 °C in a 5% CO2 incubator. Vero E6suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. …
SciScore for 10.1101/2020.11.26.399436: (What is this?)
Please note, not all rigor criteria are appropriate for all manuscripts.
Table 1: Rigor
Institutional Review Board Statement not detected. Randomization not detected. Blinding not detected. Power Analysis not detected. Sex as a biological variable not detected. Cell Line Authentication not detected. Table 2: Resources
Experimental Models: Cell Lines Sentences Resources For SARS-CoV-2 Spike pseudotyped particle (SARS2pp) entry experiments, Vero-E6 cells (104 cells/well) were seeded onto 96-well plates the day before. Vero-E6suggested: NoneOne hundred μL of the mixture was applied onto the Vero E6 cell monolayer in biological triplicates and cells were cultured at 37 °C in a 5% CO2 incubator. Vero E6suggested: NoneResults from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).
Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:These limitations could be dampened by the application of broad-spectrum antiviral agents simultaneously acting on more than one target at the same time (37). Furthermore, to reduce the likelihood of resistance in future treatments, the design of antivirals able to block host targets involved in viral infection is an emerging and promising strategy (38). In fact, this is the approach followed in this study. Thus, we screened in silico the same chemical library against eight different entry SARS-CoV-2 targets, being all of them human proteins. Specifically, to fight against COVID-19 great attention was paid to molecular events associated to virus entry, which are primarily mediated by the S glycoprotein. According to recent studies, S protein of SARS-CoV-2 is translated into an uncleaved and inactive form (S0) (39), which is generally activated by proteolytic cleavage by host proteases such as TMPRSS2 during protein egress (15). Once primed and exposed on the viral membrane, the fusion event can occur and is initiated by recognition of specific host receptors as ACE2 (39) by the receptor binding domain (S1-RBD), located at the S1 subunit of the protein. The priming activity can also be managed by other host proteases as furin, and Cathepsin L in a compensatory mechanism. After host-virus recognition, the viral material is internalized by endocytosis and trafficked into the host cell. This process is mediated by several host factors, which are currently a matter of intense inve...
Results from TrialIdentifier: No clinical trial numbers were referenced.
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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