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

Panchariya, L.; Khan, W. A.; Kuila, S.; Sonkar, K.; Sahoo, S.; Ghoshal, A.; Kumar, A.; Verma, D. K.; Hasan, A.; Das, S.; Thakur, J. K.; Halder, R.; Sunil, S.; Arulandu, A.

doi:10.1101/2021.06.15.448551

bioRxiv · 10.1101/2021.06.15.448551

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

Panchariya, L.·Khan, W. A.·Kuila, S.·Sonkar, K.·Sahoo, S.·Ghoshal, A.·Kumar, A.·Verma, D. K.·Hasan, A.·Das, S.·Thakur, J. K.·Halder, R.·Sunil, S.·Arulandu, A.

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Abstract

Zinc deficiency is linked to poor prognosis in COVID-19 patients while clinical trials with Zinc demonstrate better clinical outcome. The molecular target and mechanistic details of anti-coronaviral activity of Zinc remain obscure. We show that ionic Zinc not only inhibits SARS-CoV-2 main protease (Mpro) with nanomolar affinity, but also viral replication. We present the first crystal structure of Mpro-Zn2+ complex at 1.9 [A] 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, 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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Panchariya, L., Khan, W. A., Kuila, S., Sonkar, K., Sahoo, S., Ghoshal, A., Kumar, A., Verma, D. K., Hasan, A., Das, S., Thakur, J. K., Halder, R., Sunil, S., Arulandu, A.. 2021-06-15. Zinc2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro.. https://doi.org/10.1101/2021.06.15.448551

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