Drug Repurposing Screen for Compounds Inhibiting the Cytopathic Effect of SARS-CoV-2

Abstract

Drug repurposing is a rapid approach to identifying therapeutics for the treatment of emerging infectious diseases such as COVID-19. To address the urgent need for treatment options, we carried out a quantitative high-throughput screen using a SARS-CoV-2 cytopathic assay with a compound collection of 8,810 approved and investigational drugs, mechanism-based bioactive compounds, and natural products. Three hundred and nineteen compounds with anti-SARS-CoV-2 activities were identified and confirmed, including 91 approved drug and 49 investigational drugs. Among these confirmed compounds, the anti-SARS-CoV-2 activities of 230 compounds, including 38 approved drugs, have not been previously reported. Chlorprothixene, methotrimeprazine, and piperacetazine were the three most potent FDA approved drugs with anti-SARS-CoV-2 activities. These three compounds have not been previously reported to have anti-SARS-CoV-2 activities, although their antiviral activities against SARS-CoV and Ebola virus have been reported. These results demonstrate that this comprehensive data set of drug repurposing screen for SARS-CoV-2 is useful for drug repurposing efforts including design of new drug combinations for clinical trials.

Ambroxol Hydrochloride Inhibits the Interaction between Severe Acute Respiratory Syndrome Coronavirus 2 Spike Protein’s Receptor Binding Domain and Recombinant Human ACE2

“…However, the IC 50 of Aloxistatin (21.78 µM) was similar to that of BHH (21.72 µM) ( Table 1 and 2). The IC 50 values that we observed for the reference compounds are consistent with earlier reports [44][45][46][47] . While writing this manuscript, we found that other cellular studies tested BHH and AMB at certain or single concentrations [48][49][50] ; however, this is the first study to our knowledge to conduct the IC 50 evaluation for BHH and AMB against the novel SARS-CoV-2 infection induced CPE.…”

The SARS-CoV-2 RNA interactome

“…Thus, redefining antiviral strategies should be contemplated beyond expeditious drug repurposing efforts. So far, collective large and multidisciplinary datasets from viral transcriptome (Kim et al, 2020a), host transcriptional response (Blanco-Melo et al, 2020), ribosome profiling (Finkel et al, 2020), whole proteomics (Bojkova et al, 2020), protein-protein interactions by co-IP (Gordon et al, 2020) and proximity labeling (St-Germain et al, 2020), phosphoproteomics (Bouhaddou et al, 2020), RNA structure (Lan et al, 2020), genome-wide CRISPR screen (Wei et al, 2020), and off-label drug screening (Chen et al, 2020) have all provided invaluable insights of the underlying biology of this novel human coronavirus.…”

DrugCentral 2021 supports drug discovery and repositioning

“…It currently consists of six ML models that represent six assays using data from the NCATS (National Center for Advancing Translational Sciences) COVID19 portal ( 43 ). These assays are: the SARS-CoV-2 cytopathic effect, CPE (LVI) ( 44 ); Vero E6 host cell cytotoxicity (LVI counterscreen); Spike-ACE2 protein-protein interaction (AlphaLISA; VE) ( 45 ), TruHit (VE) counterscreen; angiotensin-converting enzyme 2 (ACE2; VE) inhibition; and 3C-like proteinase (3CL or Mpro; VR) inhibition ( 46 ). These models use chemical structures (or drug names; or PubChem CIDs) as input; a similarity search retrieves similar compounds in the NCATS dataset, and sorts them according to the Tanimoto similarity score.…”