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

被引:67
作者
Xiao, Xia [1 ,2 ,3 ]
Wang, Conghui [1 ,2 ,3 ]
Chang, De [4 ]
Wang, Ying [1 ,2 ,3 ]
Dong, Xiaojing [1 ,2 ,3 ]
Jiao, Tao [1 ,2 ,3 ]
Zhao, Zhendong [1 ]
Ren, Lili [1 ,2 ,3 ]
Dela Cruz, Charles S. [5 ]
Sharma, Lokesh [5 ]
Lei, Xiaobo [1 ,2 ,3 ]
Wang, Jianwei [1 ,2 ,3 ]
机构
[1] Chinese Acad Med Sci & Peking Union Med Coll, Inst Pathogen Biol, NHC Key Lab Syst Biol Pathogens, Beijing, Peoples R China
[2] Chinese Acad Med Sci, Key Lab Resp Pathogen, Beijing, Peoples R China
[3] Chinese Acad Med Sci & Peking Union Med Coll, Inst Pathogen Biol, Christophe Merieux Lab, Beijing, Peoples R China
[4] Chinese Peoples Liberat Army Gen Hosp, Dept Pulm & Crit Care Med, Med Ctr 3, Beijing, Peoples R China
[5] Yale Univ, Sch Med, Dept Med, Sect Pulm & Crit Care & Sleep Med, New Haven, CT 06510 USA
来源
FRONTIERS IN IMMUNOLOGY | 2020年 / 11卷
基金
中国国家自然科学基金; 国家重点研发计划;
关键词
SARS-CoV-2; COVID-19; antiviral; therapy; US Food and Drug Administration-approved compounds; CORONAVIRUS;
D O I
10.3389/fimmu.2020.586572
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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.
引用
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页数:11
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