Zinc 2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro. - GreenMedInfo Summary

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with zinc demonstrate better clinical outcomes. The molecular targets and mechanistic details of the anti-coronaviral activity of zinc remain obscure. We show that zinc not only inhibits the SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of the Mpro-Zncomplex at 1.9Å and provide the structural basis of viral replication inhibition. We show that Zncoordinates with the catalytic dyad at the enzyme active site along with two previously unknown water molecules in a tetrahedral geometry to form a stable inhibited Mpro-Zncomplex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Znmediated inhibition of Mpro may have wider implications.