The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro
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Abstract
Background
The COVID-19 pandemic is an enormous threat for healthcare systems and economies worldwide that urgently demands effective preventive and therapeutic strategies. Unlike the development of vaccines and new drugs specifically targeting SARS-CoV-2, repurposing of approved or clinically tested drugs can provide an immediate solution.
Methods
We applied a novel computational approach to search among approved and clinically tested drugs from the DrugBank database. Candidates were selected based on Shannon entropy homology and predefined activity profiles of three small molecules with proven anti-SARS-CoV activity and a published data set. Antiviral activity of a predicted drug, azelastine, was tested in vitro in SARS-CoV-2 infection assays with Vero E6 monkey kidney epithelial cells and reconstituted human nasal tissue. The effect on viral replication was assessed by quantification of viral genomes by droplet digital PCR.
Findings
The computational approach with four independent queries identified major drug families, most often and in overlapping fashion anti-infective, anti-inflammatory, anti-hypertensive, anti-histamine and neuroactive drugs. Azelastine, an histamine 1 receptor-blocker, was predicted in multiple screens, and based on its attractive safety profile and availability in nasal formulation, was selected for experimental testing. Azelastine significantly reduced cytopathic effect and SARS-CoV-2 infection of Vero E6 cells with an EC 50 of ∼6 μM both in a preventive and treatment setting. Furthermore, azelastine in a commercially available nasal spray tested at 5-fold dilution was highly potent in inhibiting viral propagation in SARS-CoV-2 infected reconstituted human nasal tissue.
Interpretations
Azelastine, an anti-histamine, available in nasal sprays developed against allergic rhinitis may be considered as a topical prevention or treatment of nasal colonization with SARS-CoV-2. As such, it could be useful in reducing viral spread and prophylaxis of COVID-19. Ultimately, its potential benefit should be proven in clinical studies.
Funding
provided by the Hungarian government to the National Laboratory of Virology and by CEBINA GmbH.
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SciScore for 10.1101/2020.09.15.296228: (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 SARS-CoV-2 infection assay with VERO E6 cell line: Vero E6 (African green monkey kidney epithelial) cells (ATCC CRL-1586) were seeded on 96-well plates at 4.5 104/well and used at approximately 90% confluence. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Relevant experimental information was available from a recent analysis of the KEGG pathways involved in SARS-CoV-2 infection. KEGGsuggested: (KEGG, RRID:SCR_012773)16 … SciScore for 10.1101/2020.09.15.296228: (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 SARS-CoV-2 infection assay with VERO E6 cell line: Vero E6 (African green monkey kidney epithelial) cells (ATCC CRL-1586) were seeded on 96-well plates at 4.5 104/well and used at approximately 90% confluence. Vero E6suggested: NoneSoftware and Algorithms Sentences Resources Relevant experimental information was available from a recent analysis of the KEGG pathways involved in SARS-CoV-2 infection. KEGGsuggested: (KEGG, RRID:SCR_012773)16 Secondly, we employed pathway information we predicted for drugs shown to be active against SARS-CoV and/or SARS-CoV-2. SARS-CoV-2suggested: (Active Motif Cat# 91351, RRID:AB_2847848)For all concentrations at least three replicates were prepared and the EC50 values were determined with nonlinear regression (log(inhibitor) vs. response – variable slope (four parameter)) using GraphPad Prism 8.4.3 (GraphPad Software, San Diego, California USA). GraphPad Prismsuggested: (GraphPad Prism, RRID:SCR_002798)GraphPadsuggested: (GraphPad Prism, RRID:SCR_002798)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: 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: 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.
- No funding statement was detected.
- No protocol registration statement was detected.
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