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...
| Autores: | ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; ; |
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| Tipo de documento: | Artículo |
| Fecha de publicación: | 2021 |
| País: | España |
| Institución: | Universitat Autònoma de Barcelona |
| Repositorio: | Dipòsit Digital de Documents de la UAB |
| Lenguaje: | Inglés |
| OAI Identifier: | oai:ddd.uab.cat:255454 |
| Acceso en línea: | https://ddd.uab.cat/record/255454 https://dx.doi.org/urn:doi:10.3389/fphar.2021.646676 |
| Nivel de acceso: | Acceso abierto |
| Palabra clave: | SARS-CoV-2 Antivirals Plitidepsin Synergy Viral entry |
| _version_ | 1878739519284445184 |
|---|---|
| author | Rodon, Jordi|||0000-0002-1032-9091 |
| author2 | Muñoz-Basagoiti, Jordana|||0000-0002-0384-5928 Perez-Zsolt, Daniel|||0000-0003-4192-7622 Noguera-Julian, Marc|||0000-0002-6194-1395 Paredes, Roger|||0000-0002-6553-691X Mateu, Lourdes|||0000-0001-7223-7611 Quiñones Ribas, Carles|||0000-0003-2974-2086 Perez, Carles Erkizia, Itziar|||0000-0003-1244-8972 Blanco Guillermo, Ignacio|||0000-0002-7414-7481 Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Victor|||0000-0002-4580-1114 Carrillo, Jorge|||0000-0003-0221-5948 Blanco, Julià|||0000-0002-2225-0217 Segalés Coma, Joaquim|||0000-0002-1539-7261 Clotet Sala, Bonaventura|||0000-0003-3232-4598 Vergara-Alert, Júlia|||0000-0001-7484-444X Izquierdo Useros, Nuria|||0000-0002-1039-1821 |
| author2_role | author author author author author author author author author author author author author author author author author |
| author_browse | Blanco Guillermo, Ignacio|||0000-0002-7414-7481 Blanco, Julià|||0000-0002-2225-0217 Carrillo, Jorge|||0000-0003-0221-5948 Clotet Sala, Bonaventura|||0000-0003-3232-4598 Erkizia, Itziar|||0000-0003-1244-8972 Guallar, Victor|||0000-0002-4580-1114 Izquierdo Useros, Nuria|||0000-0002-1039-1821 Mateu, Lourdes|||0000-0001-7223-7611 Muñoz-Basagoiti, Jordana|||0000-0002-0384-5928 Noguera-Julian, Marc|||0000-0002-6194-1395 Paredes, Roger|||0000-0002-6553-691X Perez, Carles Perez-Zsolt, Daniel|||0000-0003-4192-7622 Quiñones Ribas, Carles|||0000-0003-2974-2086 Rodon, Jordi|||0000-0002-1032-9091 Segalés Coma, Joaquim|||0000-0002-1539-7261 Valencia, Alfonso|||0000-0002-8937-6789 Vergara-Alert, Júlia|||0000-0001-7484-444X |
| author_facet | Rodon, Jordi|||0000-0002-1032-9091 Muñoz-Basagoiti, Jordana|||0000-0002-0384-5928 Perez-Zsolt, Daniel|||0000-0003-4192-7622 Noguera-Julian, Marc|||0000-0002-6194-1395 Paredes, Roger|||0000-0002-6553-691X Mateu, Lourdes|||0000-0001-7223-7611 Quiñones Ribas, Carles|||0000-0003-2974-2086 Perez, Carles Erkizia, Itziar|||0000-0003-1244-8972 Blanco Guillermo, Ignacio|||0000-0002-7414-7481 Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Victor|||0000-0002-4580-1114 Carrillo, Jorge|||0000-0003-0221-5948 Blanco, Julià|||0000-0002-2225-0217 Segalés Coma, Joaquim|||0000-0002-1539-7261 Clotet Sala, Bonaventura|||0000-0003-3232-4598 Vergara-Alert, Júlia|||0000-0001-7484-444X Izquierdo Useros, Nuria|||0000-0002-1039-1821 |
| author_role | author |
| collection | Dipòsit Digital de Documents de la UAB |
| 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 IC below 25 µM or 10 2 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_c308232ce09dc1a531b8d6d59edcbb8c |
| institution | Universitat Autònoma de Barcelona |
| instname_str | Universitat Autònoma de Barcelona |
| language | eng |
| network_acronym_str | ES |
| network_name_str | España |
| oai_identifier_str | oai:ddd.uab.cat:255454 |
| publishDate | 2021 |
| publishDateSort | 2021 |
| reponame_str | Dipòsit Digital de Documents de la UAB |
| spelling | Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen Rodon, Jordi|||0000-0002-1032-9091 Muñoz-Basagoiti, Jordana|||0000-0002-0384-5928 Perez-Zsolt, Daniel|||0000-0003-4192-7622 Noguera-Julian, Marc|||0000-0002-6194-1395 Paredes, Roger|||0000-0002-6553-691X Mateu, Lourdes|||0000-0001-7223-7611 Quiñones Ribas, Carles|||0000-0003-2974-2086 Perez, Carles Erkizia, Itziar|||0000-0003-1244-8972 Blanco Guillermo, Ignacio|||0000-0002-7414-7481 Valencia, Alfonso|||0000-0002-8937-6789 Guallar, Victor|||0000-0002-4580-1114 Carrillo, Jorge|||0000-0003-0221-5948 Blanco, Julià|||0000-0002-2225-0217 Segalés Coma, Joaquim|||0000-0002-1539-7261 Clotet Sala, Bonaventura|||0000-0003-3232-4598 Vergara-Alert, Júlia|||0000-0001-7484-444X Izquierdo Useros, Nuria|||0000-0002-1039-1821 SARS-CoV-2 Antivirals Plitidepsin Synergy Viral entry 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 IC below 25 µM or 10 2 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. https://ddd.uab.cat/record/255454 https://dx.doi.org/urn:doi: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|||0000-0002-1032-9091 SARS-CoV-2 Antivirals Plitidepsin Synergy Viral entry |
| 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 | SARS-CoV-2 Antivirals Plitidepsin Synergy Viral entry |
| topic_facet | SARS-CoV-2 Antivirals Plitidepsin Synergy Viral entry |
| url | https://ddd.uab.cat/record/255454 https://dx.doi.org/urn:doi:10.3389/fphar.2021.646676 |