Targeting SARS-CoV-2 differently

Using X-ray crystallography, Sebastian Günther and colleagues screened more than 5,000 drug compounds, identified seven compounds that bind to Mpro, SARS-CoV-2’s main enzyme, and showed target-specific antiviral activity. Calpeptin and pelitinib were the two compounds with the most potent antiviral activity at nontoxic concentration. The findings could shape the search for drug treatments for COVID-19, by offering calpeptin and pelitinib as candidates for preclinical testing and by identifying different sites bound by inhibitors on the 3D protein structure of Mpro.

The enzyme is an attractive drug target because it performs an essential step in SARS-CoV-2 replication, by cleaving the initial viral polyprotein into functional proteins. To find suitable Mpro targets, Günther et al. examined 5,953 compounds that are either being studied in clinical trials or are already approved for use in people. Their analysis of 3D protein structure using X-ray crystallography identified 37 compounds that bind to Mpro, with seven of those showing significant antiviral activity. Calpeptin and most of the other promising compounds bind to the enzyme’s active site that catalyzes key biochemical action. Other compounds like pelitinib, however, bind to sites that alter the enzyme at the active site.