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Published on: November 5, 2021
Efficacy of ensitrelvir against SARS-CoV-2 in a delayed-treatment mouse model
Haruaki Nobori1, Keita Fukao1, Takayuki Kuroda1
1Pharmaceutical Research Division, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka 561-0825, Japan.
Objectives:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the aetiological agent of coronavirus disease 2019 (COVID-19) and a devastating worldwide health concern. Development of safe and effective treatments is not only important for interventions during the current pandemic, but also for providing general treatment options moving forward. We have developed ensitrelvir, an antiviral compound that targets the 3C-like protease of SARS-CoV-2. In this study, a delayed-treatment mouse model was used to clarify the potential in vivo efficacy of ensitrelvir.
Methods:
Female BALB/cAJcl mice of different ages were infected with the SARS-CoV-2 gamma strain (hCoV-19/Japan/TY7-501/2021) or mouse-adapted SARS-CoV-2 MA-P10 and then 24 h post-infection orally administered various doses of ensitrelvir or vehicle. Viral titres and RNA levels in the lungs were quantified using VeroE6/TMPRSS2 cells and RT-qPCR, respectively. Body weight loss, survival, lung weight, cytokine/chemokine production, nucleocapsid protein expression and lung pathology were evaluated to investigate the in vivo efficacy of ensitrelvir.
Results:
Based on infectious viral titres and viral RNA levels in the lungs of infected mice, ensitrelvir reduced viral loads in a dose-dependent manner. The antiviral efficacy correlated with increased survival, reduced body weight loss, reduced pulmonary lesions and suppression of inflammatory cytokine/chemokine levels.
Conclusions:
This was the first evaluation of the in vivo anti-SARS-CoV-2 efficacy of ensitrelvir in a delayed-treatment mouse model. In this model, ensitrelvir demonstrated high antiviral potential and suppressed lung inflammation and lethality caused by SARS-CoV-2 infection. The findings support the continued clinical development of ensitrelvir as an antiviral agent to treat patients with COVID-19.
Insights
Ensitrelvir effectively reduced viral loads and improved survival in a delayed-treatment mouse model of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. This antiviral compound demonstrated significant potential for treating coronavirus disease 2019 (COVID-19).
Area of Science:
- Virology
- Immunology
- Pharmacology
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes coronavirus disease 2019 (COVID-19), a significant global health threat.
- Effective antiviral treatments are crucial for managing the current pandemic and future outbreaks.
- Ensitrelvir is a novel antiviral compound designed to inhibit the SARS-CoV-2 3C-like protease.
Purpose of the Study:
- To evaluate the in vivo efficacy of ensitrelvir in a delayed-treatment mouse model of SARS-CoV-2 infection.
- To assess the dose-dependent antiviral activity and impact on disease progression.
Main Methods:
- Female BALB/cAJcl mice of varying ages were infected with SARS-CoV-2.
- Mice received oral ensitrelvir or vehicle 24 hours post-infection.
- Viral load, body weight, survival, lung pathology, and inflammatory markers were assessed.
Main Results:
- Ensitrelvir demonstrated dose-dependent reduction in viral loads (infectious virus and RNA) in mouse lungs.
- Antiviral efficacy correlated with improved survival rates and reduced body weight loss.
- Treatment suppressed lung inflammation, characterized by reduced pulmonary lesions and inflammatory cytokine/chemokine levels.
Conclusions:
- Ensitrelvir exhibits significant in vivo antiviral potential against SARS-CoV-2 in a delayed-treatment model.
- The compound effectively mitigated lung inflammation and lethality associated with SARS-CoV-2 infection.
- Findings support the ongoing clinical development of ensitrelvir for treating COVID-19 patients.
