4.7 Article

Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro

Journal

CHEMICAL COMMUNICATIONS
Volume 57, Issue 78, Pages 10083-10086

Publisher

ROYAL SOC CHEMISTRY
DOI: 10.1039/d1cc03563k

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Research shows that zinc can inhibit the SARS-CoV-2 main protease and viral replication, increasing antiviral potency. The crystal structure of the complex formed by zinc and Mpro provides important structural basis for further study of viral replication.
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-Zn2+ complex at 1.9 angstrom and provide the structural basis of viral replication inhibition. We show that Zn2+ coordinates 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-Zn2+ complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn2+. As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn2+ mediated inhibition of Mpro may have wider implications.

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