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Comparative Antiviral Efficacy of Viral Protease Inhibitors against the Novel SARS-CoV-2 In Vitro
Leike Zhang1, Jia Liu1, Ruiyuan Cao2
1State Key Laboratory of Virology, Wuhan Institute of Virology, Center for Biosafety Mega-Science, Chinese Academy of Sciences, Wuhan, 430071, China.
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. 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.
Insights
Lopinavir/ritonavir showed in vitro efficacy against SARS-CoV-2 but failed to reach effective plasma concentrations in clinical simulations. This antiviral is not recommended for COVID-19 treatment due to insufficient drug levels.
Area of Science:
- Virology
- Pharmacology
- Drug Discovery
Background:
- The COVID-19 pandemic necessitates urgent identification of effective antiviral treatments.
- Virus-encoded proteases are key targets for antiviral drug development.
- Lopinavir/ritonavir, an HIV protease inhibitor, was investigated for SARS-CoV-2.
Purpose of the Study:
- To evaluate the in vitro antiviral efficacy of lopinavir/ritonavir and other protease inhibitors against SARS-CoV-2.
- To assess the potential clinical effectiveness of lopinavir/ritonavir through in vitro to in vivo extrapolation.
- To provide insights for the de novo design of novel SARS-CoV-2 protease inhibitors.
Main Methods:
- In vitro antiviral assays were performed on four viral protease inhibitors.
- In silico analysis was used to explore potential inhibitory mechanisms.
- In vitro to in vivo pharmacokinetic extrapolation was conducted to predict clinical efficacy.
Main Results:
- Lopinavir demonstrated the most significant in vitro inhibitory effect against SARS-CoV-2.
- Pharmacokinetic analysis indicated that lopinavir/ritonavir does not achieve effective concentrations at standard dosages.
- A substantial gap exists between the in vitro IC50 and predicted free plasma concentrations.
Conclusions:
- Lopinavir/ritonavir should not be used clinically for COVID-19 due to inadequate pharmacokinetic properties.
- Structure-activity relationship analysis offers a basis for designing improved SARS-CoV-2 protease inhibitors.
- Further research is needed to develop effective antivirals targeting SARS-CoV-2 proteases.
