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Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing


The emergence of the novel SARS coronavirus 2 (SARS-CoV-2) in 2019 has triggered an ongoing global pandemic of severe pneumonia-like disease designated as coronavirus disease 2019 (COVID-19)1. The development of a vaccine is likely to require at least 12-18 months, and the typical timeline for approval of a novel antiviral therapeutic can exceed 10 years. Thus, repurposing of known drugs could significantly accelerate the deployment of novel therapies for COVID-19. Towards this end, we profiled a library of known drugs encompassing approximately 12,000 clinical-stage or FDA-approved small molecules. We report the identification of 100 molecules that inhibit viral replication, including 21 known drugs that exhibit dose response relationships. Of these, thirteen were found to harbor effective concentrations likely commensurate with achievable therapeutic doses in patients, including the PIKfyve kinase inhibitor apilimod2–4, and the cysteine protease inhibitors MDL-28170, Z LVG CHN2, VBY-825, and ONO 5334. Notably, MDL-28170, ONO 5334, and apilimod were found to antagonize viral replication in human iPSC-derived pneumocyte-like cells, and the PIKfyve inhibitor also demonstrated antiviral efficacy in a primary human lung explant model. Since most of the molecules identified in this study have already advanced into the clinic, the known pharmacological and human safety profiles of these compounds will enable accelerated preclinical and clinical evaluation of these drugs for the treatment of COVID-19.

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Correspondence to Arnab K. Chatterjee or Kwok-Yung Yuen or Sumit K. Chanda.

Supplementary information

Supplementary Information

This file contains a Supplementary Discussion of the limitations and bias associated with the CPE-based primary screen performed in Vero E6 cells and its IF-based orthogonal validation. It also contains Supplementary Figure 1, a depiction of the gating strategy for flow cytometry analyses of iPSC-derived pneumocyte-like cells.

Reporting Summary

Enriched drug targets

Supplementary Table 1 . A list of drug targets enriched in GSEA analysis of HTS data.

RNAseq and GSEA analyses

Supplementary Table 2 . Processed RNAseq data from mock-infected and SARS-CoV-2 infected Vero E6 cells (MOI=0.3) collected 24 hpi (“RNAseq_Vero E6”). GSEA analysis of these RNAseq dataset (“GSEA_Vero E6”) and GSAE analysis of publicly available RNA-seq dataset of nasopharyngeal swab specimens collected from COVID-19 patients (“GSEA_Mason’s paper”). P-values were calculated as described in the materials and methods.

List of validated antiviral compounds

Supplementary Table 3 . A list of compounds confirmed to inhibit infection by 40 % or more at a single dose (1 or 2.5 µM) in Vero E6 cells.

List of the 21 most potent compounds validated in dose response across multiple cell lines

Supplementary Table 4 . Activities, reported mechanism of action (MOA), and clinical profiles of the most potent 21 compounds with dose-activity relationships listed in Figure 3. The target class and the likely antiviral mechanism are also indicated. NA- not available; QD- once daily; BID-twice daily. Information retrieved from CortellisTM (Clarivate Analytics) and

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Riva, L., Yuan, S., Yin, X. et al. Discovery of SARS-CoV-2 antiviral drugs through large-scale compound repurposing. Nature (2020).

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