Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro
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RESEARCH ARTICLE
Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro Leike Zhang1 • Jia Liu1 • Ruiyuan Cao2 • Mingyue Xu1 • Yan Wu1 • Weijuan Shang1 • Xi Wang1 • Huanyu Zhang1 • Xiaming Jiang1 • Yuan Sun1 • Hengrui Hu1 • Yufeng Li1 • Gang Zou3 • Min Zhang2 Lei Zhao2 • Wei Li2 • Xiaojia Guo2 • Xiaomei Zhuang2 • Xing-Lou Yang1 • Zheng-Li Shi1 • Fei Deng1 • Zhihong Hu1 • Gengfu Xiao1 • Manli Wang1 • Wu Zhong2
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Received: 4 August 2020 / Accepted: 14 August 2020 Ó Wuhan Institute of Virology, CAS 2020
Abstract The recent outbreak of novel coronavirus pneumonia (COVID-19) caused by a new coronavirus has posed a great threat to public health. Identifying safe and effective antivirals is of urgent demand to cure the huge number of patients. Virusencoded proteases are considered potential drug targets. The human immunodeficiency virus protease inhibitors (lopinavir/ ritonavir) has been recommended in the global Solidarity Trial in March launched by World Health Organization. However, there is currently no experimental evidence to support or against its clinical use. We evaluated the antiviral efficacy of lopinavir/ritonavir along with other two viral protease inhibitors in vitro, and discussed the possible inhibitory mechanism in silico. The in vitro to in vivo extrapolation was carried out to assess whether lopinavir/ritonavir could be effective in clinical. Among the four tested compounds, lopinavir showed the best inhibitory effect against the novel coronavirus infection. However, further in vitro to in vivo extrapolation of pharmacokinetics suggested that lopinavir/ ritonavir could not reach effective concentration under standard dosing regimen [marketed as KaletraÒ, contained lopinavir/ritonavir (200 mg/50 mg) tablets, recommended dosage is 400 mg/10 mg (2 tablets) twice daily]. This research concluded that lopinavir/ritonavir should be stopped for clinical use due to the huge gap between in vitro IC50 and free plasma concentration. Nevertheless, the structure–activity relationship analysis of the four inhibitors provided further information for de novel design of future viral protease inhibitors of SARS-CoV-2. Keywords Respiratory pharmacology COVID-19 SARS-CoV-2 Protease inhibitor
Leike Zhang, Jia Liu, and Ruiyuan Cao contributed equally to this work. & Wu Zhong [email protected] & Manli Wang [email protected] & Gengfu Xiao [email protected] 1
State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan 430071, China
2
National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology, Beijing 100850, China
3
CAS Key Laboratory of Molecular Virology and Immunology, Institute Pasteur of Shanghai, Chinese Academy of Sciences, Shanghai 200031, China
Introduction The emerging coronavirus disease (COVID-19) is caused by an infection of severe acute respiratory syndr
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