Identification of Potent and Safe Antiviral Therapeutic Candidates Against SARS-CoV-2.

Xia Xiao,De Chang,Tao Jiao,Charles S Dela Cruz,Zhendong Zhao,Ying Wang,Xiaojing Dong,Xiaobo Lei,Lokesh Sharma,Lili Ren,Conghui Wang,Jianwei Wang

doi:10.3389/fimmu.2020.586572

Abstract

COVID-19 pandemic has infected millions of people with mortality exceeding >1 million. There is an urgent need to find therapeutic agents that can help clear the virus to prevent severe disease and death. Identifying effective and safer drugs can provide more options to treat COVID-19 infections either alone or in combination. Here, we performed a high throughput screening of approximately 1,700 US FDA-approved compounds to identify novel therapeutic agents that can effectively inhibit replication of coronaviruses including SARS-CoV-2. Our two-step screen first used a human coronavirus strain OC43 to identify compounds with anti-coronaviral activities. The effective compounds were then screened for their effectiveness in inhibiting SARS-CoV-2. These screens have identified 20 anti-SARS-CoV-2 drugs including previously reported compounds such as hydroxychloroquine, amlodipine besylate, arbidol hydrochloride, tilorone 2HCl, dronedarone hydrochloride, mefloquine, and thioridazine hydrochloride. Five of the newly identified drugs had a safety index (cytotoxic/effective concentration) of >600, indicating a wide therapeutic window compared to hydroxychloroquine which had a safety index of 22 in similar experiments. Mechanistically, five of the effective compounds (fendiline HCl, monensin sodium salt, vortioxetine, sertraline HCl, and salifungin) were found to block SARS-CoV-2 S protein-mediated cell fusion. These FDA-approved compounds can provide much needed therapeutic options that we urgently need during the midst of the pandemic.

Highlights

Novel coronavirus (CoV)–mediated disease (COVID-19) emerged as a major pandemic and has spread across the world in such a short period since December 2019
While most respiratory viral infection research has been focused on influenza viruses that cause a huge burden of seasonal flu and occasionally pandemic outbreaks, CoV is likely to emerge as a similar or more severe pathogen than flu in long term
The experimental therapies being used with known antiviral agents either show limited efficacy or have high systemic toxicity, limiting their usefulness [22,23,24]

Summary

Introduction

Novel coronavirus (CoV)–mediated disease (COVID-19) emerged as a major pandemic and has spread across the world in such a short period since December 2019. As of October 5, 2020, more than 35.1 million confirmed infections have been reported with approximately 1 million deaths (WHO, https:// covid19.who.int/). These numbers may be a vast underestimation as many of the infected patients may. The disease is caused by a novel CoV termed SARSCoV-2 which belongs to the Coronaviridae family and is the third major CoV pandemic in the last 20 years after Severe Acute Respiratory Syndrome (SARS) and Middle East Respiratory Syndrome (MERS) [2,3,4,5,6,7]. The lack of available therapeutic options is a major limiting factor in treating these infections, leading to excessive mortality

Methods

Results

Conclusion