Drug repurposing screens for inhibitors of SARS-CoV-2 replication identify fenofibrate as one of six promising treatments.

Key Messages

This laboratory study assessed the SARS-CoV-2 antiviral activity of 72 clinically approved drugs that may have antiviral effects alone or in combination.

SARS-CoV-2-infected cells were treated with 72 drugs and 28 combinations of drugs to determine their antiviral activities.

Six currently approved drugs, including fenofibrate, were identified as promising potential treatments due to their ability to prevent SARS-CoV-2 viral replication in cells.

Frontiers in Pharmacology

Publication Date: May 25, 2021
Peer Reviewed: Yes
Publication Type: Original | Preclinical
DOI: https://www.doi.org/10.3389/fphar.2021.646676

Identification of Plitidepsin as Potent Inhibitor of SARS-CoV-2-Induced Cytopathic Effect After a Drug Repurposing Screen

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

Abstract

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.