Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen
Rodon, Jordi (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Muñoz-Basagoiti, Jordana (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Perez-Zsolt, Daniel (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Noguera-Julian, Marc (Universitat de Vic - Universitat Central de Catalunya)
Paredes, Roger (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Mateu, Lourdes (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Quiñones Ribas, Carles (Institut Germans Trias i Pujol. Hospital Universitari Germans Trias i Pujol)
Perez, Carles (Barcelona Supercomputing Center)
Erkizia, Itziar (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Blanco Guillermo, Ignacio (Institut Germans Trias i Pujol)
Valencia, Alfonso (Institució Catalana de Recerca i Estudis Avançats)
Guallar, Victor (Institució Catalana de Recerca i Estudis Avançats)
Carrillo, Jorge (Institut Germans Trias i Pujol. Institut de Recerca de la Sida IrsiCaixa)
Blanco, Julià (Institut Germans Trias i Pujol)
Segalés Coma, Joaquim (Universitat Autònoma de Barcelona. Departament de Sanitat i d'Anatomia Animals)
Clotet Sala, Bonaventura (Institut Germans Trias i Pujol)
Vergara-Alert, Júlia (Institut de Recerca i Tecnologia Agroalimentàries. Centre de Recerca en Sanitat Animal)
Izquierdo Useros, Nuria (Institut Germans Trias i Pujol)
Universitat Autònoma de Barcelona

Data:	2021
Resum:	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.
Drets:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Llengua:	Anglès
Document:	Article ; recerca ; Versió publicada
Matèria:	SARS-CoV-2 ; Antivirals ; Plitidepsin ; Synergy ; Viral entry
Publicat a:	Frontiers in Pharmacology, Vol. 12 (march 2021) , ISSN 1663-9812

DOI: 10.3389/fphar.2021.646676
DOI: 10.3389/fphar.2021.64667
PMID: 33841165

12 p, 1.8 MB

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Documents de recerca > Documents dels grups de recerca de la UAB > Centres i grups de recerca (producció científica) > Ciències de la salut i biociències > Institut d'Investigació en Ciencies de la Salut Germans Trias i Pujol (IGTP)
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