Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen

There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 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 u...

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Autores: Rodon, Jordi, Muñoz-Basagoiti, Jordana, Perez, Carles, Valencia, Alfonso|||0000-0002-8937-6789, Guallar, Víctor|||0000-0002-4580-1114
Tipo de recurso: artículo
Fecha de publicación:2021
País:España
Institución:Universitat Politècnica de Catalunya (UPC)
Repositorio:UPCommons. Portal del coneixement obert de la UPC
Idioma:inglés
OAI Identifier:oai:upcommons.upc.edu:2117/345471
Acceso en línea:https://hdl.handle.net/2117/345471
https://dx.doi.org/10.3389/fphar.2021.646676
Access Level:acceso abierto
Palabra clave:COVID-19 (Disease)
Antivirals
Drugs
Viral entry
SARS-CoV-2
Plitidepsin
Synergy
COVID-19 (Malaltia)
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
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repository_id_str
spelling Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screenRodon, JordiMuñoz-Basagoiti, JordanaPerez, CarlesValencia, Alfonso|||0000-0002-8937-6789Guallar, Víctor|||0000-0002-4580-1114COVID-19 (Disease)AntiviralsDrugsViral entrySARS-CoV-2AntiviralsPlitidepsinSynergyCOVID-19 (Malaltia)Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::BioinformàticaThere is an urgent need to identify therapeutics for the treatment of Coronavirus disease 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.We are grateful to patients at the Hospital Germans Trias i Pujol that donated their samples for research. For his excellent assistance and advice, we thank Jordi Puig from Fundació Lluita contra la SIDA. We are most grateful to Lidia Ruiz and the Clinical Sample Management Team of IrsiCaixa for their outstanding sample processing and management, and to M. Pilar Armengol and the translational genomics platform team at the Institut de Recerca Germans Trias i Pujol. We truly thank B. Trinité for generating the Spike expression plasmid construct used in this study. We thank Pharma Mar, Rubió Laboratories, Janssen and Drs. Cabrera and Ballana form IrsiCaixa; Pascual-Figal, Lax and Asensio-Lopez MC from “Instituto de Investigación Biosanitaria IMIB-Arrixaca” of Murcia; and Fernández-Real and Barretina from the “Institut d'Investigació Biomèdica de Girona Dr Josep Trueta” for providing some of the reagents tested.Peer Reviewed"Article signat per 18 autors/es: Jordi Rodon, Jordana Muñoz-Basagoiti, Daniel Perez-Zsolt, Marc Noguera-Julian, Roger Paredes, Lourdes Mateu, Carles Quiñones, Carles Perez, Itziar Erkizia, Ignacio Blanco, Alfonso Valencia, Víctor Guallar, Jorge Carrillo, Julià Blanco, Joaquim Segalés, Bonaventura Clotet, Júlia Vergara-Alert, Nuria Izquierdo-Useros"Frontiers Media20212021-01-0120212021-05-11journal articlehttp://purl.org/coar/resource_type/c_6501VoRhttp://purl.org/coar/version/c_970fb48d4fbd8a85info:eu-repo/semantics/articleapplication/pdfhttps://hdl.handle.net/2117/345471https://dx.doi.org/10.3389/fphar.2021.646676reponame:UPCommons. Portal del coneixement obert de la UPCinstname:Universitat Politècnica de Catalunya (UPC)Inglésengopen accesshttp://purl.org/coar/access_right/c_abf2Attribution 3.0 Spainhttp://creativecommons.org/licenses/by/3.0/es/Attribution 3.0 Spainhttps://creativecommons.org/licenses/by/4.0/info:eu-repo/semantics/openAccessoai:upcommons.upc.edu:2117/3454712026-05-27T15:37:01Z
dc.title.none.fl_str_mv Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
title Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
spellingShingle Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
Rodon, Jordi
COVID-19 (Disease)
Antivirals
Drugs
Viral entry
SARS-CoV-2
Antivirals
Plitidepsin
Synergy
COVID-19 (Malaltia)
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
title_short Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
title_full Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
title_fullStr Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
title_full_unstemmed Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
title_sort Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen
dc.creator.none.fl_str_mv Rodon, Jordi
Muñoz-Basagoiti, Jordana
Perez, Carles
Valencia, Alfonso|||0000-0002-8937-6789
Guallar, Víctor|||0000-0002-4580-1114
author Rodon, Jordi
author_facet Rodon, Jordi
Muñoz-Basagoiti, Jordana
Perez, Carles
Valencia, Alfonso|||0000-0002-8937-6789
Guallar, Víctor|||0000-0002-4580-1114
author_role author
author2 Muñoz-Basagoiti, Jordana
Perez, Carles
Valencia, Alfonso|||0000-0002-8937-6789
Guallar, Víctor|||0000-0002-4580-1114
author2_role author
author
author
author
dc.subject.none.fl_str_mv COVID-19 (Disease)
Antivirals
Drugs
Viral entry
SARS-CoV-2
Antivirals
Plitidepsin
Synergy
COVID-19 (Malaltia)
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
topic COVID-19 (Disease)
Antivirals
Drugs
Viral entry
SARS-CoV-2
Antivirals
Plitidepsin
Synergy
COVID-19 (Malaltia)
Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica
description There is an urgent need to identify therapeutics for the treatment of Coronavirus disease 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.
publishDate 2021
dc.date.none.fl_str_mv 2021
2021-01-01
2021
2021-05-11
dc.type.none.fl_str_mv journal article
http://purl.org/coar/resource_type/c_6501
VoR
http://purl.org/coar/version/c_970fb48d4fbd8a85
dc.type.openaire.fl_str_mv info:eu-repo/semantics/article
format article
dc.identifier.none.fl_str_mv https://hdl.handle.net/2117/345471
https://dx.doi.org/10.3389/fphar.2021.646676
url https://hdl.handle.net/2117/345471
https://dx.doi.org/10.3389/fphar.2021.646676
dc.language.none.fl_str_mv Inglés
eng
language_invalid_str_mv Inglés
language eng
dc.rights.none.fl_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 3.0 Spain
http://creativecommons.org/licenses/by/3.0/es/
Attribution 3.0 Spain
https://creativecommons.org/licenses/by/4.0/
dc.rights.openaire.fl_str_mv info:eu-repo/semantics/openAccess
rights_invalid_str_mv open access
http://purl.org/coar/access_right/c_abf2
Attribution 3.0 Spain
http://creativecommons.org/licenses/by/3.0/es/
https://creativecommons.org/licenses/by/4.0/
eu_rights_str_mv openAccess
dc.format.none.fl_str_mv application/pdf
dc.publisher.none.fl_str_mv Frontiers Media
publisher.none.fl_str_mv Frontiers Media
dc.source.none.fl_str_mv reponame:UPCommons. Portal del coneixement obert de la UPC
instname:Universitat Politècnica de Catalunya (UPC)
instname_str Universitat Politècnica de Catalunya (UPC)
reponame_str UPCommons. Portal del coneixement obert de la UPC
collection UPCommons. Portal del coneixement obert de la UPC
repository.name.fl_str_mv
repository.mail.fl_str_mv
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score 15,300724

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