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Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen

Jordi Rodon, Jordana Muñoz-Basagoiti, Daniel Perez-Zsolt, Marc Noguera-Julian, Roger Paredes, Lourdes Mateu, Carles Quiñones, Itziar Erkizia, Ignacio Blanco, Alfonso Valencia, Víctor Guallar, Jorge Carrillo, Julià Blanco, Joaquim Segalés, Bonaventura Clotet, Júlia Vergara-Alert, View ORCID ProfileNuria Izquierdo-Useros
doi: https://doi.org/10.1101/2020.04.23.055756
Jordi Rodon
1IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus de la UAB, 08193 Bellaterra (Cerdanyola del Vallès), Spain
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Jordana Muñoz-Basagoiti
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
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Daniel Perez-Zsolt
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
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Marc Noguera-Julian
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
7University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
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Roger Paredes
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
6Germans Trias i Pujol Hospital, Badalona, Catalonia, Spain
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Lourdes Mateu
6Germans Trias i Pujol Hospital, Badalona, Catalonia, Spain
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Carles Quiñones
6Germans Trias i Pujol Hospital, Badalona, Catalonia, Spain
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Itziar Erkizia
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
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Ignacio Blanco
5Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain
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Alfonso Valencia
3Barcelona Supercomputing Center
4Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
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Víctor Guallar
3Barcelona Supercomputing Center
4Catalan Institution for Research and Advanced Studies (ICREA), Barcelona, Spain
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Jorge Carrillo
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
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Julià Blanco
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
5Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain
7University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
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Joaquim Segalés
8UAB, CReSA (IRTA-UAB), Campus de la UAB, 08193 Bellaterra (Cerdanyola del Vallès), Spain
9Departament de Sanitat i Anatomia Animals, Facultat de Veterinària, UAB, 08193 Bellaterra (Cerdanyola del Vallès), Spain
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Bonaventura Clotet
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
5Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain
7University of Vic–Central University of Catalonia (UVic-UCC), Vic, Spain
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Júlia Vergara-Alert
1IRTA, Centre de Recerca en Sanitat Animal (CReSA, IRTA-UAB), Campus de la UAB, 08193 Bellaterra (Cerdanyola del Vallès), Spain
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  • For correspondence: julia.vergara@irta.cat nizquierdo@irsicaixa.es
Nuria Izquierdo-Useros
2IrsiCaixa AIDS Research Institute, 08916, Badalona, Spain
5Germans Trias i Pujol Research Institute (IGTP), Can Ruti Campus, 08916, Badalona, Spain
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  • ORCID record for Nuria Izquierdo-Useros
  • For correspondence: julia.vergara@irta.cat nizquierdo@irsicaixa.es
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ABSTRACT

There is an urgent need to identify therapeutics for the treatment of Coronavirus diseases 2019 (COVID-19). Although different antivirals are given for the clinical management of SARS-CoV-2 infection, their efficacy is still under evaluation. Here, we have screened existing drugs approved for human use in a variety of diseases, to compare how they counteract SARS-CoV-2-induced cytopathic effect and viral replication in vitro. Among the potential 72 antivirals tested herein that were previously proposed to inhibit SARS-CoV-2 infection, only 18% had an IC50 below 25 μM or 102 IU/mL. These included plitidepsin, novel cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate, camostat along the well-known remdesivir and chloroquine derivatives. Plitidepsin was the only clinically approved drug displaying nanomolar efficacy. Four of these families, including novel cathepsin inhibitors, blocked viral entry in a cell-type specific manner. Since the most effective antivirals usually combine therapies that tackle the virus at different steps of infection, we also assessed several drug combinations. Although no particular synergy was found, inhibitory combinations did not reduce their antiviral activity. Thus, these combinations could decrease the potential emergence of resistant viruses. Antivirals prioritized herein identify novel compounds and their mode of action, while independently replicating the activity of a reduced proportion of drugs which are mostly approved for clinical use. Combinations of these drugs should be tested in animal models to inform the design of fast track clinical trials.

Competing Interest Statement

A patent application based on this work has been filed (EP20382821.5). The authors declare that no other competing financial interests exist.

Footnotes

  • ↵+ Dual senior authorship

  • http://gisaid.org

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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Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen
Jordi Rodon, Jordana Muñoz-Basagoiti, Daniel Perez-Zsolt, Marc Noguera-Julian, Roger Paredes, Lourdes Mateu, Carles Quiñones, Itziar Erkizia, Ignacio Blanco, Alfonso Valencia, Víctor Guallar, Jorge Carrillo, Julià Blanco, Joaquim Segalés, Bonaventura Clotet, Júlia Vergara-Alert, Nuria Izquierdo-Useros
bioRxiv 2020.04.23.055756; doi: https://doi.org/10.1101/2020.04.23.055756
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Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen
Jordi Rodon, Jordana Muñoz-Basagoiti, Daniel Perez-Zsolt, Marc Noguera-Julian, Roger Paredes, Lourdes Mateu, Carles Quiñones, Itziar Erkizia, Ignacio Blanco, Alfonso Valencia, Víctor Guallar, Jorge Carrillo, Julià Blanco, Joaquim Segalés, Bonaventura Clotet, Júlia Vergara-Alert, Nuria Izquierdo-Useros
bioRxiv 2020.04.23.055756; doi: https://doi.org/10.1101/2020.04.23.055756

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