Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro

Virol Sin. 2020 Dec;35(6):776-784. doi: 10.1007/s12250-020-00288-1. Epub 2020 Sep 10.


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. Virus-encoded 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 Kaletra®, 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: COVID-19; Protease inhibitor; Respiratory pharmacology; SARS-CoV-2.

MeSH terms

  • Animals
  • Antiviral Agents / chemistry
  • Antiviral Agents / pharmacology*
  • COVID-19 / blood
  • COVID-19 / virology
  • COVID-19 Drug Treatment*
  • Cell Line
  • Chlorocebus aethiops
  • Coronavirus 3C Proteases / antagonists & inhibitors*
  • Coronavirus 3C Proteases / chemistry
  • Coronavirus 3C Proteases / metabolism
  • Drug Combinations
  • Humans
  • Lopinavir / blood
  • Lopinavir / pharmacology*
  • Male
  • Molecular Docking Simulation
  • Ritonavir / blood
  • Ritonavir / pharmacology*
  • SARS-CoV-2 / drug effects*
  • SARS-CoV-2 / enzymology*
  • Vero Cells
  • Viral Protease Inhibitors / chemistry
  • Viral Protease Inhibitors / pharmacology*


  • Antiviral Agents
  • Drug Combinations
  • Viral Protease Inhibitors
  • lopinavir-ritonavir drug combination
  • Lopinavir
  • Coronavirus 3C Proteases
  • Ritonavir