SARS-CoV-2 Enzyme Structure Reveals Potential Inhibitors


X-ray macromolecular crystallography helped identify compounds that inhibit SARS-CoV-2 replication in a line of kidney epithelial cells (called Vero E6) extracted from the African green monkey. In this set of images, researchers conducted a whole cell assay to determine the effectiveness of “compound 4” at inhibiting viral replication. The bottom row of images shows that 70-90% of cells in the three control replicates (0 uM compound 4) were positive for the SARS-CoV-2 spike protein, suggesting viral replication proceeded unchecked. With increasing concentrations of compound 4 (0.1 uM, 1 uM, 10 uM), the percentage of cells with replicating virus decreased. The top row of images shows that a 10uM concentration of compound 4 prevented viral replication in all cells. [Reprinted under a Creative Commons CC BY license ( from J. Osipiuk et al. "Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors." Nat Commun 12, 743 (2021). DOI: 10.1038/s41467-021-21060-3]

Research at the U.S. Department of Energy’s Advanced Photon Source (APS) published in Nature Communications reports a high-resolution structure of Papain-like protease (PLpro), one of at least 29 different proteins encoded by SARS-CoV-2, the virus that causes COVID-19. PLpro is an enzyme responsible for releasing other proteins from a large protein complex and plays an important role in disrupting the host immune response.

Structural, biochemical, and virus replication studies identified a set of chemical compounds capable of blocking PLpro activity in vitro. A subset of the compounds further demonstrated an ability to block SARS-CoV-2 from replicating in cell culture assays.

Such inhibitors will need to undergo in vivo testing in animal models before being tested in human clinical trials, but the findings accelerate structure-based drug design efforts targeting PLpro to identify high-affinity inhibitors of clinical value.

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Osipiuk, J., Azizi, SA., Dvorkin, S. et al. “Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors.” Nat Commun 12, 743 (2021). [DOI: 10.1038/s41467-021-21060-3]