Combined computational and cellular screening identifies synergistic inhibition of SARS-CoV-2 by lenvatinib and remdesivir
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Abstract
Rapid repurposing of existing drugs as new therapeutics for COVID-19 has been an important strategy in the management of disease severity during the ongoing SARS-CoV-2 pandemic. Here, we used high-throughput docking to screen 6000 compounds within the DrugBank library for their potential to bind and inhibit the SARS-CoV-2 3 CL main protease, a chymotrypsin-like enzyme that is essential for viral replication. For 19 candidate hits, parallel in vitro fluorescence-based protease-inhibition assays and Vero-CCL81 cell-based SARS-CoV-2 replication-inhibition assays were performed. One hit, diclazuril (an investigational anti-protozoal compound), was validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro (IC 50 value of 29 µM) and modestly inhibited SARS-CoV-2 replication in Vero-CCL81 cells. Another hit, lenvatinib (approved for use in humans as an anti-cancer treatment), could not be validated as a SARS-CoV-2 3 CL main protease inhibitor in vitro , but serendipitously exhibited a striking functional synergy with the approved nucleoside analogue remdesivir to inhibit SARS-CoV-2 replication, albeit this was specific to Vero-CCL81 cells. Lenvatinib is a broadly-acting host receptor tyrosine kinase (RTK) inhibitor, but the synergistic effect with remdesivir was not observed with other approved RTK inhibitors (such as pazopanib or sunitinib), suggesting that the mechanism-of-action is independent of host RTKs. Furthermore, time-of-addition studies revealed that lenvatinib/remdesivir synergy probably targets SARS-CoV-2 replication subsequent to host-cell entry. Our work shows that combining computational and cellular screening is a means to identify existing drugs with repurposing potential as antiviral compounds. Future studies could be aimed at understanding and optimizing the lenvatinib/remdesivir synergistic mechanism as a therapeutic option.
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SciScore for 10.1101/2021.03.19.435806: (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 Time of addition experiments: Vero CCL81 cells were seeded in 96 well plates at a density of 1.2 × 104 cells/well. Vero CCL81suggested: NoneSoftware and Algorithms Sentences Resources The nearly 6000 approved and experimental drugs in DrugBank with more than 17 non-hydrogen atoms were docked by SEED. DrugBanksuggested: (DrugBank, RRID:SCR_002700), diclazuril (PubChem ID 25273624), pazopanib (LC laboratories, P-6706) or sunitinib … SciScore for 10.1101/2021.03.19.435806: (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 Time of addition experiments: Vero CCL81 cells were seeded in 96 well plates at a density of 1.2 × 104 cells/well. Vero CCL81suggested: NoneSoftware and Algorithms Sentences Resources The nearly 6000 approved and experimental drugs in DrugBank with more than 17 non-hydrogen atoms were docked by SEED. DrugBanksuggested: (DrugBank, RRID:SCR_002700), diclazuril (PubChem ID 25273624), pazopanib (LC laboratories, P-6706) or sunitinib (Selleckchem, S1042) at a final concentration of 0.1 % DMSO. PubChemsuggested: (PubChem, RRID:SCR_004284)Results 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:There are several caveats to the approach adopted in this study. Of note, we only tested the compounds at a single 10 μM concentration, and thus an immediate option to see stronger inhibition of virus replication would be to test higher concentrations of the inhibitors. However, this might result in the identification of additional compounds with antiviral potential but only in a non-physiologically achievable range of concentrations. Thus, extensive compound modification and optimization for increased antiviral potential would be required in subsequent studies and would slow immediate roll-out of a repurposed drug. Given that our goal was to rapidly identify approved drugs as treatment options for COVID-19 and circumvent the lengthy process of progressing inhibitors to approval, we set the threshold at 10 μM and did not consider higher drug concentrations. Options to improve the yield of our screening approach could be to use an alternative structure of 3CL Mpro that was subsequently solved by room temperature X-ray crystallography (27). It reveals the ligand-free structure of the active site and the conformation at near-physiological temperature, and was suggested to be a better target for in silico screening for inhibitors of 3CL Mpro (27). Moreover, additional libraries of approved drugs could be included, for example IUPHAR/BPS (https://www.guidetopharmacology.org/) and ChEMBL (https://www.ebi.ac.uk/chembl/), although they overlap substantially with DrugBank. A second ca...
Results from TrialIdentifier: No clinical trial numbers were referenced.
Results from Barzooka: We did not find any issues relating to the usage of bar graphs.
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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