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Evaluation of SARS-CoV-2 Main Protease Inhibitors Using a Novel Cell-Based Assay
Wenyue Cao1, Chia-Chuan Dean Cho1, Zhi Zachary Geng1
1Texas A&M Drug Discovery Laboratory, Department of Chemistry, Texas A&M University, College Station, Texas 77843, United States.
ACS Central Science
|March 1, 2022
Summary
A new assay measures SARS-CoV-2 main protease (MPro) inhibition in cells. Several known inhibitors showed weak MPro activity, while MPI8 demonstrated high cellular and antiviral potency, suggesting its potential for COVID-19 treatment.
Area of Science:
- Virology
- Biochemistry
- Drug Discovery
Background:
- Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) main protease (MPro) is crucial for viral replication and causes host cell toxicity.
- MPro inhibitors are potential therapeutic agents for COVID-19, but their cellular activity needs precise assessment.
Purpose of the Study:
- To develop and validate a novel assay for bulk analysis of cellular MPro inhibitor potency.
- To evaluate the cellular MPro inhibition of 30 known MPro inhibitors and antiviral compounds.
Main Methods:
- A novel assay leveraging toxicity alleviation by MPro inhibitors for bulk cellular potency analysis.
- Screening of 30 known MPro inhibitors and antiviral compounds for cellular MPro inhibition.
Main Results:
- Eleven compounds, including chloroquine and hydroxychloroquine, exhibited weak or undetectable cellular MPro inhibition despite strong antiviral effects.
- MPI5, MPI6, MPI7, and MPI8 demonstrated high cellular and antiviral potency.
- MPI8 showed the highest potency with a cellular MPro inhibition IC50 of 31 nM and an antiviral EC50 of 30 nM.
Conclusions:
- The novel assay provides precise cellular MPro inhibition data, differentiating direct MPro inhibitors from compounds with other mechanisms.
- MPI8 is a promising candidate for further preclinical investigation as a COVID-19 therapeutic agent due to its potent cellular and antiviral activity.
