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Published on: October 11, 2013
Identification and Evaluation of Non-Nucleosidic MTase Inhibitors against SARS-CoV-2 nsp14 with Lower-Micromolar
Yuanmei Wen1, Jun Zhou1, Fan Pan1
1Shenzhen Key Laboratory of Small Molecule Drug Discovery and Synthesis, Department of Chemistry, Shenzhen Grubbs Institute and Medi-X Pingshan, Southern University of Science and Technology, Shenzhen 518000, China.
Abstract:
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) causes respiratory infections ranging from mild to severe, posing significant public health risks. The emergence of new variants highlights the need for inhibitors targeting conserved nonstructural proteins like nsp14, a key N7-methyltransferase (MTase) critical for viral RNA capping, immune evasion, and replication. Here, we screened 131 compounds using a drug repurposing approach and identified five candidates that inhibit MTase activity. Bobcat339 showed significant inhibition (IC50 = 21.6 μM) and binding affinity (ΔTm = +3.9 °C). It also reduced the replication of HCoV-229E and SARS-CoV-2 in infected Huh7 cells (EC50 = 29.8 and 28.4 μM, respectively). Molecular docking suggested Bobcat339 binds the SAM-binding pocket of nsp14 MTase. These results identify Bobcat339 as a promising lead for developing selective, non-nucleoside nsp14 inhibitors, supporting further structural optimization and preclinical evaluation.
Insights
Researchers identified Bobcat339 as a potential inhibitor of SARS-CoV-2 nsp14, a key protein for viral replication and immune evasion. This compound shows promise for developing new antiviral therapies against SARS-CoV-2 variants.
Area of Science:
- Virology
- Drug Discovery
- Biochemistry
Background:
- Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) poses a significant global health threat.
- Viral RNA capping, essential for replication and immune evasion, is mediated by nonstructural protein 14 (nsp14) N7-methyltransferase (MTase).
- The emergence of SARS-CoV-2 variants necessitates the development of novel antiviral strategies targeting conserved viral proteins.
Purpose of the Study:
- To identify potential inhibitors of the SARS-CoV-2 nsp14 MTase using a drug repurposing approach.
- To evaluate the antiviral activity of identified compounds against SARS-CoV-2 and other human coronaviruses.
- To elucidate the binding mechanism of promising inhibitors to the nsp14 MTase.
Main Methods:
- Screening of 131 compounds for nsp14 MTase inhibitory activity.
- Biochemical assays to determine IC50 and binding affinity (ΔTm) of lead compounds.
- Cell-based assays to assess the efficacy of compounds in reducing viral replication.
- Molecular docking simulations to predict the binding mode of inhibitors within the nsp14 MTase active site.
Main Results:
- Five compounds demonstrated nsp14 MTase inhibitory activity.
- Bobcat339 exhibited significant inhibition (IC50 = 21.6 μM) and binding affinity (ΔTm = +3.9 °C).
- Bobcat339 effectively reduced HCoV-229E and SARS-CoV-2 replication in cell culture (EC50 = 29.8 and 28.4 μM, respectively).
- Molecular docking indicated Bobcat339 binds to the SAM-binding pocket of nsp14 MTase.
Conclusions:
- Bobcat339 is a promising non-nucleoside inhibitor of the SARS-CoV-2 nsp14 MTase.
- The findings support Bobcat339 as a lead compound for further development of selective antiviral agents.
- Further structural optimization and preclinical studies are warranted for Bobcat339 as a potential therapeutic candidate.
