Screening of ~5500 FDA-approved drugs and clinical candidates for anti-SARS-CoV-2 activity
Ellen Van Damme
At the end of 2019, a cluster of pneumonia cases with unknown origin was reported in Wuhan, China. The main symptoms of this disease were fever and coughing but in some cases the disease pattern evolved to severe pneumonia and even death (1). Early 2020, a novel coronavirus was found to be responsible for this outbreak which was designated SARS-CoV-2 (2). The World Health Organization has named the disease caused by the SARS-CoV-2 coronavirus disease 2019 (COVID-19). After SARS-1 (2002-2003) and MERS (2012), SARS-CoV-2 is the third coronavirus that causes significant international concerns in less than two decades. Due to globalization and international travel, SARS-CoV-2 spread around the globe, infected over 125 million people and caused at least 2,7 million people to die by March 2021. SARS-CoV-2, like SARS-1, OC43, HKU and MERS, is a betacoronavirus with a 30kB genome divided into 14 open reading frames (ORFs). The first two ORFs, 1a and 1ab, (67% of the genome) code for 16 non-structural proteins (NSP), while the remaining part of the genome encodes accessory proteins and structural proteins (3). The main viral drug targets in SARS-CoV-2 are the spike protein (structural), the Main protease (Mpro), the Papain-like protease (PLpro), the RNA-dependent RNA polymerase and the exonuclease, although other accessory proteins may prove to be valuable targets in the future. As part of an immediate response strategy to COVID-19, a drug repurposing library consisting of ~5500 FDA-approved drugs and clinical candidates that have passed phase I studies was screened in a stable GFP-expressing VeroE6 cell line infected with SARS-CoV-2. This assay system provides a positive readout: when cells are intact, they express GFP which can be detected with a GFP plate reader or microscope; when cells succumb to CPE caused by the virus (or toxicity), the GFP signal disappears.