The current pandemic of multiple variants has created an urgent need for effective inhibitors of SARS-CoV-2 to complement vaccine strategies. PF-07321332, developed by Pfizer, is the first orally administered coronavirus-specific main protease inhibitor approved by the FDA.
Over the past 20 years, Severe acute respiratory syndrome CoV (SARS-CoV), Middle East respiratory syndrome CoV (MERS-CoV) and severe acute respiratory syndrome-coronavirus-2 (SARS-CoV-2), have all emerged, causing severe epidemic human respiratory diseases throughout the globe. Developing broad spectrum drugs would be invaluable in responding to new emerging coronaviruses of the future and could address unmet urgent clinical needs. Main protease (M
pro
, also known as 3CL
pro
) has a major role in the replication of a coronavirus life cycle and is one of the most important drug targets for anticoronavirus agents. We show that a natural product, noncovalent inhibitor shikonin, can pan-main protease inhibitor of SARS-CoV-2, SARS-CoV, MERS-CoV, HCoV-HKU1, HCoV-NL63 and HCoV-229E with micromolar IC
50
values. Structures of the main protease of different coronavirus genus, SARS-CoV from betacoronaviruses and HCoV-NL63 from alphacoronaviruses, were determined by X-ray crystallography and reveals that the inhibitor interacts with key active-site residues in a unique mode. The structure of the main protease inhibitor complex presents an opportunity to discover a novel series of broad-spectrum inhibitors. These data provide substantial evidence that shikonin and its derivatives may be effective against most coronaviruses, as well as emerging coronaviruses in the future. Given the importance of main protease for the coronavirus therapeutic indication, insights from these studies should accelerate the development and design of safer and more effective antiviral agents.
Importance
The current pandemic has created an urgent need for broad spectrum inhibitors of SARS-CoV-2. Main protease is relatively conservative compared with the spike protein and thus is one of the most promising drug targets for developing anticoronavirus agents. We have solved crystal structures of main protease of SARS-CoV and HCoV-NL63 bound to shikonin. The structures provide important insights that have broad implications for understanding the structural basis underlying enzyme activity, and can facilitate rational design of broad spectrum anticoronavirus ligands as new therapeutic agents.
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