SARS-CoV-2 Mpro inhibition by zinc ion: structural features and hints for drug design

ABSTRACT

SARS-CoV-2 main protease (SARS-CoV-2 Mpro) is a cysteine protease that hydrolyses the viral polyproteins at several sites with a preference for the Leu-Gln(Ser, Ala, Gly) sequences1. The enzyme represents one of the main drug-target candidates for covid-19 syndrome because the large and deep pocket at the active site and its crucial activity for viral replication2-5 Here, we provide X-ray structural data on SARS-CoV-2 Mpro in complex with the isolated Zn2+ ion. The comparison with the apo SARSCoV- 2 Mpro shows that residues involved in zinc binding are not affected by significant structural rearrangement upon zinc binding supporting the idea that the binding site is ready to accommodate the metal. The interaction of SARS-CoV-2 Mpro with Zn2+ ion was also investigated by NMR. Moreover, zinc binding is able to inhibit protein activity, demonstrating that the zinc ion is capable of an efficient binding also in solution. These findings provide a solid ground for designing potent and selective inhibitors of SARS-CoV-2 Mpro suggesting that a zinc ion incorporated into suitable ligands interacting with additional sites at the protein surface can modulate the binding energy.