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Published on: January 9, 2019
Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness
David T Barkan1, Keira Garland2, Lei Zhang2
1Discovery Sciences, Novartis Biomedical Research, Cambridge, Massachusetts 02139, United States.
Abstract:
The COVID-19 pandemic highlights the ongoing risk of zoonotic transmission of coronaviruses to global health. To prepare for future pandemics, it is essential to develop effective antivirals targeting a broad range of coronaviruses. Targeting the essential and clinically validated coronavirus main protease (Mpro), we constructed a structurally diverse Mpro panel by clustering all known coronavirus sequences by Mpro active site sequence similarity. Through screening, we identified a potent covalent inhibitor that engaged the catalytic cysteine of SARS-CoV-2 Mpro and used structure-based medicinal chemistry to develop compounds in the pyrazolopyrimidine sulfone series that exhibit submicromolar activity against multiple Mpro homologues. Additionally, we solved the first X-ray cocrystal structure of Mpro from the human-infecting OC43 coronavirus, providing insights into potency differences among compound-target pairs. Overall, the chemical compounds described in this study serve as starting points for the development of antivirals with broad-spectrum activity, enhancing our preparedness for emerging human-infecting coronaviruses.
Insights
Researchers developed broad-spectrum antiviral compounds targeting the coronavirus main protease (Mpro). This work enhances preparedness for future pandemics by providing starting points for new antiviral drugs against emerging coronaviruses.
Area of Science:
- Virology
- Medicinal Chemistry
- Drug Discovery
Background:
- The COVID-19 pandemic underscores the threat of zoonotic coronavirus transmission.
- Developing broad-spectrum antivirals is crucial for pandemic preparedness.
- The coronavirus main protease (Mpro) is an essential and validated drug target.
Purpose of the Study:
- To identify and develop novel antiviral compounds targeting the Mpro of various coronaviruses.
- To create a diverse panel of Mpro sequences for inhibitor screening.
- To gain structural insights into Mpro-inhibitor interactions.
Main Methods:
- Clustering of coronavirus sequences based on Mpro active site similarity.
- Screening for potent Mpro inhibitors.
- Structure-based medicinal chemistry for compound optimization.
- X-ray crystallography of Mpro from OC43 coronavirus.
Main Results:
- Identification of a potent covalent inhibitor targeting SARS-CoV-2 Mpro.
- Development of pyrazolopyrimidine sulfone compounds with submicromolar activity against multiple Mpro homologues.
- Obtained the first X-ray cocrystal structure of OC43 coronavirus Mpro.
Conclusions:
- The identified compounds are promising starting points for broad-spectrum antiviral drug development.
- Structural insights aid in understanding potency variations.
- This research strengthens global readiness against emerging coronaviruses.
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