RT Journal Article
SR Electronic
T1 Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect after a Drug Repurposing Screen
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 2020.04.23.055756
DO 10.1101/2020.04.23.055756
A1 Jordi Rodon
A1 Jordana Muñoz-Basagoiti
A1 Daniel Perez-Zsolt
A1 Marc Noguera-Julian
A1 Roger Paredes
A1 Lourdes Mateu
A1 Carles Quiñones
A1 Itziar Erkizia
A1 Ignacio Blanco
A1 Alfonso Valencia
A1 Víctor Guallar
A1 Jorge Carrillo
A1 Julià Blanco
A1 Joaquim Segalés
A1 Bonaventura Clotet
A1 Júlia Vergara-Alert
A1 Nuria Izquierdo-Useros
YR 2021
UL http://biorxiv.org/content/early/2021/01/04/2020.04.23.055756.abstract
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.