Identification of Potent, Broad-Spectrum Coronavirus Main Protease Inhibitors for Pandemic Preparedness

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.