(Peer-Reviewed) Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo
Haoran Peng 彭浩然 ¹, Cuiling Ding 丁翠玲 ¹, Liangliang Jiang 江亮亮 ¹, Wanda Tang ¹, Yan Liu 刘燕 ¹, Lanjuan Zhao 赵兰娟 ¹, Zhigang Yi 易志刚 ², Hao Ren 任浩 ¹, Chong Li ³, Yanhua He 何燕华 ¹, Xu Zheng ¹, Hailin Tang 唐海琳 ¹, Zhihui Chen 陈志辉 ⁴, Zhongtian Qi 戚中田 ¹, Ping Zhao 赵平 ¹
¹ Department of Microbiology, Second Military Medical University, Shanghai Key Laboratory of Medical Biodefense, Shanghai, 200433, China
中国 上海 第二军医大学微生物学教研室 上海市医学生物防护重点实验室
² Key Laboratory of Medical Molecular Virology (MOE/NHC/CAMS), School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, 200032, China
中国 上海 复旦大学上海医学院基础医学院 医学分子病毒学教育部/卫生部/医科院重点实验室
³ Cancer Institute, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200000, China
中国 上海 复旦大学上海医学院肿瘤学系 复旦大学附属肿瘤医院 肿瘤研究所
⁴ Department of Infectious Disease, Changhai Hospital, Shanghai, 200433, China
中国 上海 长海医院感染科
Abstract
The coronavirus disease 2019 (COVID-19) pandemic caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is a global crisis. Clinical candidates with high efficacy, ready availability, and that do not develop resistance are in urgent need. Despite that screening to repurpose clinically approved drugs has provided a variety of hits shown to be effective against SARS-CoV-2 infection in cell culture, there are few confirmed antiviral candidates in vivo.
In this study, 94 compounds showing high antiviral activity against SARS-CoV-2 in Vero E6 cells were identified from 2,580 FDA-approved small-molecule drugs. Among them, 24 compounds with low cytotoxicity were selected, and of these, 17 compounds also effectively suppressed SARS-CoV-2 infection in HeLa cells transduced with human ACE2. Six compounds disturb multiple processes of the SARS-CoV-2 life cycle. Their prophylactic efficacies were determined in vivo using Syrian hamsters challenged with SARS-CoV-2 infection. Seven compounds reduced weight loss and promoted weight regain of hamsters infected not only with the original strain but also the D614G variant.
Except for cisatracurium, six compounds reduced hamster pulmonary viral load, and IL-6 and TNF-α mRNA when assayed at 4 d postinfection. In particular, sertraline, salinomycin, and gilteritinib showed similar protective effects as remdesivir in vivo and did not induce antiviral drug resistance after 10 serial passages of SARS-CoV-2 in vitro, suggesting promising application for COVID-19 treatment.
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