Sci China Life Sci . Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo

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Sci China Life Sci


. 2021 Dec 24.
doi: 10.1007/s11427-021-2031-7. Online ahead of print.
Discovery of potential anti-SARS-CoV-2 drugs based on large-scale screening in vitro and effect evaluation in vivo


Haoran Peng ^{# 1} , Cuiling Ding ^{# 1} , Liangliang Jiang ^{# 1} , Wanda Tang ¹ , Yan Liu ¹ , Lanjuan Zhao ¹ , Zhigang Yi ² , Hao Ren ¹ , Chong Li ³ , Yanhua He ¹ , Xu Zheng ¹ , Hailin Tang ¹ , Zhihui Chen ⁴ , Zhongtian Qi ⁵ , Ping Zhao ⁶



Affiliations

• PMID: 34962614
• DOI: 10.1007/s11427-021-2031-7

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.

Keywords: D614G variant; SARS-CoV-2; drug repurposing; drug resistance; drug screening; hamster model.