PT  - JOURNAL ARTICLE
AU  - Jordi Rodon
AU  - Jordana Muñoz-Basagoiti
AU  - Daniel Perez-Zsolt
AU  - Marc Noguera-Julian
AU  - Roger Paredes
AU  - Lourdes Mateu
AU  - Carles Quiñones
AU  - Itziar Erkizia
AU  - Ignacio Blanco
AU  - Alfonso Valencia
AU  - Víctor Guallar
AU  - Jorge Carrillo
AU  - Julià Blanco
AU  - Joaquim Segalés
AU  - Bonaventura Clotet
AU  - Júlia Vergara-Alert
AU  - Nuria Izquierdo-Useros
TI  - Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen
AID  - 10.1101/2020.04.23.055756
DP  - 2021 Jan 01
TA  - bioRxiv
PG  - 2020.04.23.055756
4099  - http://biorxiv.org/content/early/2021/01/04/2020.04.23.055756.short
4100  - http://biorxiv.org/content/early/2021/01/04/2020.04.23.055756.full
AB  - 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 StatementA patent application based on this work has been filed (EP20382821.5). The authors declare that no other competing financial interests exist.