Identification of FDA-Approved Drugs That Inhibit SARS-CoV-2 and Human Norovirus Replication

Abstract

In this study, to identify novel compounds that inhibit severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) replication by targeting its protease, we screened an U.S. Food and Drug Administration (FDA)-approved drug library to determine their effects on SARS-CoV-2 3CL protease (3CL^pro) activity using a cellular- and green fluorescent protein (GFP) reporter-based 3CL^pro assay, called the FlipGFP-3CL^pro assay. Among the hit compounds, 5 compounds (auranofin, endoxifen, netupitant, pimozide, and regorafenib) were selected for further analysis. We found that 3 compounds (auranofin, endoxifen, and pimozide) showed dose-dependent inhibition of 3CL^pro activity using both the FlipGFP-3CL^pro assay and fluorescence-based in vitro 3CL^pro assays. We then tested the effect of these compounds on SARS-CoV-2 replication in cultured cells and found that all 5 compounds inhibited viral replication in a dose-dependent manner. Interestingly, 4 of them, except for auranofin, significantly suppressed human norovirus (HuNoV) replication in human intestinal organoids. In brief, we identified several FDA-approved drugs that inhibit SARS-CoV-2 and HuNoV replication, which warrant further investigation.

Keywords: FlipGFP assay; compound screen; human norovirus; severe acute respiratory syndrome coronavirus 2; viral protease.