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...
| Authors: | ; ; ; ; |
|---|---|
| Format: | Article |
| Publication date: | 2021 |
| Country: | España |
| Institution: | Universitat Politècnica de Catalunya (UPC) |
| Repository: | UPCommons. Portal del coneixement obert de la UPC |
| Language: | English |
| OAI Identifier: | oai:upcommons.upc.edu:2117/345471 |
| Online Access: | https://hdl.handle.net/2117/345471 https://dx.doi.org/10.3389/fphar.2021.646676 |
| Access Level: | Open access |
| Keyword: | 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 |
| _version_ | 1878741128262451200 |
|---|---|
| author | Rodon, Jordi |
| author2 | Muñoz-Basagoiti, Jordana Perez, Carles Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Víctor|||0000-0002-4580-1114 |
| author2_role | author author author author |
| author_browse | Guallar, Víctor|||0000-0002-4580-1114 Muñoz-Basagoiti, Jordana Perez, Carles Rodon, Jordi Valencia, Alfonso|||0000-0002-8937-6789 |
| author_facet | Rodon, Jordi Muñoz-Basagoiti, Jordana Perez, Carles Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Víctor|||0000-0002-4580-1114 |
| author_role | author |
| collection | UPCommons. Portal del coneixement obert de la UPC |
| 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. |
| eu_rights_str_mv | openAccess |
| format | article |
| id | ES_dfa1b6fc89c2b94d2c55495c831d091a |
| institution | Universitat Politècnica de Catalunya (UPC) |
| instname_str | Universitat Politècnica de Catalunya (UPC) |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:upcommons.upc.edu:2117/345471 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| publisher | Frontiers Media |
| publisherStr | Frontiers Media |
| reponame_str | UPCommons. Portal del coneixement obert de la UPC |
| spelling | Identification of plitidepsin as potent inhibitor of SARS-CoV-2-induced cytopathic effect after a drug repurposing screen Rodon, Jordi Muñoz-Basagoiti, Jordana Perez, Carles Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Víctor|||0000-0002-4580-1114 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 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. 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 Media https://hdl.handle.net/2117/345471 https://dx.doi.org/10.3389/fphar.2021.646676 |
| 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 Plitidepsin Synergy COVID-19 (Malaltia) Àrees temàtiques de la UPC::Informàtica::Aplicacions de la informàtica::Bioinformàtica |
| title | 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_short | 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 |
| topic | 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 |
| topic_facet | 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 |
| url | https://hdl.handle.net/2117/345471 https://dx.doi.org/10.3389/fphar.2021.646676 |