Ethacridine inhibits SARS-CoV-2 by inactivating viral particles.

Junjiao Yang,Xiaokun Shu,Tsuguhisa Nakayama,Jayakar V Nayak,Raul Andino,Chien-Ting Wu,Peter V Lidsky,Xiaoquan Li,Peter K Jackson,Miguel Garcia-Knight,Kanta Subbarao,Yinghong Xiao

doi:10.1371/journal.ppat.1009898

Abstract

The respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2. Here we report the discovery of ethacridine as a potent drug against SARS-CoV-2 (EC50 ~ 0.08 μM). Ethacridine was identified via high-throughput screening of an FDA-approved drug library in living cells using a fluorescence assay. Plaque assays, RT-PCR and immunofluorescence imaging at various stages of viral infection demonstrate that the main mode of action of ethacridine is through inactivation of viral particles, preventing their binding to the host cells. Consistently, ethacridine is effective in various cell types, including primary human nasal epithelial cells that are cultured in an air-liquid interface. Taken together, our work identifies a promising, potent, and new use of the old drug via a distinct mode of action for inhibiting SARS-CoV-2.

Highlights

The worldwide outbreak of the respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2
We examined viral RNA accumulation in infected cells. qRT-PCR measurement revealed no change of viral RNA levels when the drug was added after viral binding and cell entry (DMSO + Eth.) in both the supernatant and the cells (Fig 4A, lower middle and right panels), compared with the control (DMSO + DMSO)
Several small molecule-based inhibitors have been identified to interfere with major targets involved in the viral lifecycle of SARS-CoV-2, including the main protease Mpro and the SARS-CoV-2 replicase RdRp

Summary

Introduction

The worldwide outbreak of the respiratory disease COVID-19 is caused by the coronavirus SARS-CoV-2 (severe acute respiratory syndrome coronavirus 2). SARS-CoV-2 is an RNA betacoronavirus of the family Coronaviridae. It contains a single-stranded positive-sense RNA genome encapsulated within a membrane envelope [1,2,3,4]. The genome of SARS-CoV-2 can be split into two main regions that contain as many as 14 open reading frames (ORFs) [5]. The pp1a polyprotein is translated from ORF1a and the pp1ab polyprotein comes from a -1 ribosomal frameshift between ORF1a and ORF1b. Both pp1a and pp1ab are mainly processed by a 3-chymotrypsinlike protease (3CLpro, referred as the main protease, Mpro). The membrane-bound RTC synthesizes a full-length negative-strand RNA template for the positivestrand viral genomic RNA

Methods

Results

Conclusion