SARS-CoV-2 Mpro inhibitors and activity-based probes for patient-sample imaging

In December 2019, the first cases of infection with a novel coronavirus, SARS-CoV-2, were diagnosed. Currently, there is no effective antiviral treatment for COVID-19. To address this emerging problem, we focused on the SARS-CoV-2 main protease that constitutes one of the most attractive antiviral drug targets. We have synthesized a combinatorial library of fluorogenic substrates with glutamine in the P1 position. We used it to determine the substrate preferences of the SARS-CoV and SARS-CoV-2 main proteases. On the basis of these findings, we designed and synthesized a potent SARS-CoV-2 inhibitor (Ac-Abu-dTyr-Leu-Gln-VS, half-maximal effective concentration of 3.7 mu M) and two activity-based probes, for one of which we determined the crystal structure of its complex with the SARS-CoV-2 M-pro. We visualized active SARS-CoV-2 M-pro in nasopharyngeal epithelial cells of patients suffering from COVID-19 infection. The results of our work provide a structural framework for the design of inhibitors as antiviral agents and/or diagnostic tests.

Automated summary

A team of researchers synthesized a new type of antiviral agent, demonstrating through experiments its high efficacy in inhibiting SARS-CoV-2 with a low effective concentration, providing new insights for antiviral treatment. By observing the active SARS-CoV-2 M-pro in the cells of patients infected with COVID-19, important clues were provided for the design of antiviral drugs and diagnostic tests.