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Updated: Aug 10, 2025
Analysis of Group IV Viral SSHHPS Using In Vitro and In Silico Methods
Published on: December 21, 2019
SS148 and WZ16 inhibit the activities of nsp10-nsp16 complexes from all seven human pathogenic coronaviruses
Fengling Li1, Pegah Ghiabi1, Taraneh Hajian2
1Structural Genomics Consortium, University of Toronto, Toronto, Ontario M5G 1L7, Canada.
Abstract:
Seven coronaviruses have infected humans (HCoVs) to-date. SARS-CoV-2 caused the current COVID-19 pandemic with the well-known high mortality and severe socioeconomic consequences. MERS-CoV and SARS-CoV caused epidemic of MERS and SARS, respectively, with severe respiratory symptoms and significant fatality. However, HCoV-229E, HCoV-NL63, HCoV-HKU1, and HCoV-OC43 cause respiratory illnesses with less severe symptoms in most cases. All coronaviruses use RNA capping to evade the immune systems of humans. Two viral methyltransferases, nsp14 and nsp16, play key roles in RNA capping and are considered valuable targets for development of anti-coronavirus therapeutics. But little is known about the kinetics of nsp10-nsp16 methyltransferase activities of most HCoVs, and reliable assays for screening are not available. Here, we report the expression, purification, and kinetic characterization of nsp10-nsp16 complexes from six HCoVs in parallel with previously characterized SARS-CoV-2. Probing the active sites of all seven by SS148 and WZ16, the two recently reported dual nsp14 / nsp10-nsp16 inhibitors, revealed pan-inhibition. Overall, our study show feasibility of developing broad-spectrum dual nsp14 / nsp10-nsp16-inhibitor therapeutics.
Insights
This study characterized methyltransferase activities in seven human coronaviruses (HCoVs), revealing potential for broad-spectrum antiviral drugs targeting nsp14 and nsp10-nsp16 complexes.
Area of Science:
- Virology
- Structural Biology
- Drug Discovery
Background:
- Seven human coronaviruses (HCoVs) cause infections, ranging from mild to severe respiratory illnesses.
- SARS-CoV-2, MERS-CoV, and SARS-CoV are notable for high mortality and significant outbreaks.
- All HCoVs utilize RNA capping, involving nsp14 and nsp16 methyltransferases, to evade host immune responses.
Purpose of the Study:
- To investigate the kinetics of nsp10-nsp16 methyltransferase activities across six HCoVs.
- To establish reliable assays for screening potential anti-coronavirus therapeutics.
- To evaluate the efficacy of dual nsp14 / nsp10-nsp16 inhibitors against various HCoVs.
Main Methods:
- Expression and purification of nsp10-nsp16 complexes from six HCoVs.
- Kinetic characterization of the purified methyltransferase complexes.
- Inhibition assays using SS148 and WZ16, dual nsp14 / nsp10-nsp16 inhibitors.
Main Results:
- Successfully expressed and purified nsp10-nsp16 complexes from six HCoVs.
- Characterized the kinetic properties of these methyltransferase activities.
- Demonstrated pan-inhibition of all seven HCoVs by dual nsp14 / nsp10-nsp16 inhibitors.
Conclusions:
- The study highlights the feasibility of developing broad-spectrum therapeutics targeting conserved nsp14 and nsp10-nsp16 methyltransferases.
- These findings provide a foundation for designing novel antiviral strategies against a wide range of human coronaviruses.
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