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The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro

View ORCID ProfileRobert Konrat, Henrietta Papp, Valéria Szijártó, Tanja Gesell, Gábor Nagy, Mónika Madai, Safia Zeghbib, Anett Kuczmog, Zsófia Lanszki, Zsuzsanna Helyes, Gábor Kemenesi, Ferenc Jakab, Eszter Nagy
doi: https://doi.org/10.1101/2020.09.15.296228
Robert Konrat
aDepartment of Structural and Computational Biology, Max F. Perutz Laboratories, University of Vienna, Vienna Biocenter Campus 5, A-1030 Vienna, Austria
bCalyxha Biotechnologies GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
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  • ORCID record for Robert Konrat
  • For correspondence: robert.konrat@univie.ac.at eszter.nagy@cebina.eu
Henrietta Papp
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Valéria Szijártó
dCEBINA (Central European Biotech Incubator and Accelerator) GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
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Tanja Gesell
bCalyxha Biotechnologies GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
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Gábor Nagy
dCEBINA (Central European Biotech Incubator and Accelerator) GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
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Mónika Madai
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Safia Zeghbib
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Anett Kuczmog
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Zsófia Lanszki
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Zsuzsanna Helyes
eDepartment of Pharmacology and Pharmacotherapy, Medical School & Szentágothai Research Center, University of Pécs, Pécs, Hungary
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Gábor Kemenesi
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Ferenc Jakab
cNational Laboratory of Virology, Szentágothai Research Centre, University of Pécs, Pécs, Hungary
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Eszter Nagy
bCalyxha Biotechnologies GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
dCEBINA (Central European Biotech Incubator and Accelerator) GmbH, Karl-Farkas-Gasse 22, A-1030 Vienna, Austria
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  • For correspondence: robert.konrat@univie.ac.at eszter.nagy@cebina.eu
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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 EC50 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.

Competing Interest Statement

EN, GN and VS are employees and shareholders of CEBINA GmbH. TG is employee and shareholder of Calyxha GmbH. RK receives consultancy fee from Calyxha GmbH and holds shares in the company. This research was funded by CEBINA GmbH, the Hungarian Scientific Research Fund OTKA KH129599, the European Social Fund: Comprehensive Development for Implementing Smart Specialization Strategies at the University of Pecs (EFOP-3.6.1.-16-2016-00004) and the Higher Education Institutional Excellence Program of the Ministry for Innovation and Technology in Hungary, within the framework of the "Innovation for a sustainable life and environment" thematic program of the University of Pecs (TUDFO/47138/2019-ITM).

Copyright 
The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-NC-ND 4.0 International license.
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The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro
Robert Konrat, Henrietta Papp, Valéria Szijártó, Tanja Gesell, Gábor Nagy, Mónika Madai, Safia Zeghbib, Anett Kuczmog, Zsófia Lanszki, Zsuzsanna Helyes, Gábor Kemenesi, Ferenc Jakab, Eszter Nagy
bioRxiv 2020.09.15.296228; doi: https://doi.org/10.1101/2020.09.15.296228
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The Anti-histamine Azelastine, Identified by Computational Drug Repurposing, Inhibits SARS-CoV-2 Infection in Reconstituted Human Nasal Tissue In Vitro
Robert Konrat, Henrietta Papp, Valéria Szijártó, Tanja Gesell, Gábor Nagy, Mónika Madai, Safia Zeghbib, Anett Kuczmog, Zsófia Lanszki, Zsuzsanna Helyes, Gábor Kemenesi, Ferenc Jakab, Eszter Nagy
bioRxiv 2020.09.15.296228; doi: https://doi.org/10.1101/2020.09.15.296228

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