Related Experiment Video
Updated: Aug 13, 2025
10:29
Quantitative Structure-Activity Relationship, Activity Prediction, and Molecular Dynamics of Non-nucleotide Reverse Transcriptase Inhibitors
Published on: May 9, 2025
1.4K
Ensitrelvir is effective against SARS-CoV-2 3CL protease mutants circulating globally
Sho Kawashima1, Yuki Matsui2, Takumi Adachi2
1Laboratory for Drug Discovery and Disease Research, Shionogi & Co., Ltd., 1-1, Futaba-cho 3-chome, Toyonaka, Osaka, 561-0825, Japan.
Biochemical and Biophysical Research Communications
|January 23, 2023
Summary
Ensitrelvir effectively targets SARS-CoV-2 3C-like protease (3CLpro) in emerging variants and common mutations. This antiviral maintains efficacy against diverse COVID-19 strains, including Omicron variants with 3CLpro changes.
Area of Science:
- Virology
- Drug Discovery
- Molecular Biology
Background:
- The COVID-19 pandemic, caused by SARS-CoV-2, necessitates continuous development of effective antiviral treatments.
- Emergence of SARS-CoV-2 variants and mutations poses challenges to existing therapies.
- Ensitrelvir targets the SARS-CoV-2 3C-like protease (3CLpro), a crucial enzyme for viral replication.
Purpose of the Study:
- To evaluate the efficacy of ensitrelvir against newly emerging SARS-CoV-2 variants.
- To assess the impact of globally prevalent 3CLpro mutations on ensitrelvir's antiviral activity.
- To confirm ensitrelvir's effectiveness against variants carrying specific 3CLpro mutations.
Main Methods:
- In vitro antiviral activity assays against various SARS-CoV-2 variants.
- Genetic surveillance of SARS-CoV-2 3CLpro using public databases to identify prevalent mutations.
- Enzyme kinetic assays to determine the activity of mutated 3CLpro compared to wild type (WT).
- In vitro assessment of ensitrelvir's inhibitory effect on mutated 3CLpro.
Main Results:
- Ensitrelvir demonstrated comparable antiviral activity against a wide range of SARS-CoV-2 variants, including Omicron sublineages (BA.1.1, BA.2, BA.2.75, BA.4, BA.5, BQ.1.1, XBB.1, XE), mu, lambda, and theta.
- Genetic surveillance identified 11 major globally circulating 3CLpro mutations, with P132H being highly prevalent (99.69%) in Omicron variants.
- Mutated 3CLpro enzymes exhibited comparable enzymatic activity to WT.
- Ensitrelvir effectively inhibited mutated 3CLpro, showing similar inhibitory effects as against WT.
Conclusions:
- Ensitrelvir maintains antiviral efficacy against diverse and emerging SARS-CoV-2 variants, including those with significant 3CLpro mutations.
- The drug's consistent performance against mutated viral proteases suggests its potential as a broad-spectrum therapeutic for COVID-19.
- These findings support ensitrelvir's utility in combating current and future SARS-CoV-2 strains, including those with potential resistance mutations.
