Search for SARS-CoV-2 inhibitors in currently approved drugs to tackle COVID-19 pandemia

Rodon, Jordi; Munoz-Basagoiti, Jordana; Perez-Zsolt, Daniel; Noguera-Julian, Marc; Paredes, Roger; Mateu, Lourdes; Quinones, Carles; Erkizia, Itziar; Blanco, Ignacio; Valencia, Alfonso; Guallar, Víctor; Carrillo, Jorge; Blanco, JuliÃ; Segalés, Joaquim; Clotet, Bonaventura; Vergara-Alert, Júlia; Izquierdo-Useros, Nuria

There is an urgent need to identify novel drugs against the new coronavirus. 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 in vitro antiviral activity. Moreover, only eight families had an IC50 below 25 {micro}M or 102 IU/mL. These include chloroquine derivatives and remdesivir, along with plitidepsin, cathepsin inhibitors, nelfinavir mesylate hydrate, interferon 2-alpha, interferon-gamma, fenofibrate and camostat. 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.