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Zinc 2+ ion inhibits SARS-CoV-2 main protease and viral replication in vitro .
- Source :
-
Chemical communications (Cambridge, England) [Chem Commun (Camb)] 2021 Sep 30; Vol. 57 (78), pp. 10083-10086. Date of Electronic Publication: 2021 Sep 30. - Publication Year :
- 2021
-
Abstract
- 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-Zn <superscript>2+</superscript> complex at 1.9 Å and provide the structural basis of viral replication inhibition. We show that Zn <superscript>2+</superscript> 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-Zn <superscript>2+</superscript> complex. Further, the natural ionophore quercetin increases the anti-viral potency of Zn <superscript>2+</superscript> . As the catalytic dyad is highly conserved across SARS-CoV, MERS-CoV and all variants of SARS-CoV-2, Zn <superscript>2+</superscript> mediated inhibition of Mpro may have wider implications.
- Subjects :
- Animals
Binding Sites
COVID-19 pathology
Catalytic Domain
Chlorocebus aethiops
Coordination Complexes chemistry
Coordination Complexes metabolism
Coronavirus 3C Proteases metabolism
Crystallography, X-Ray
Humans
Ions chemistry
Kinetics
Molecular Dynamics Simulation
Protease Inhibitors metabolism
Protease Inhibitors pharmacology
SARS-CoV-2 isolation & purification
Surface Plasmon Resonance
Thermodynamics
Vero Cells
Virus Replication drug effects
Coronavirus 3C Proteases antagonists & inhibitors
Protease Inhibitors chemistry
SARS-CoV-2 enzymology
Zinc chemistry
Subjects
Details
- Language :
- English
- ISSN :
- 1364-548X
- Volume :
- 57
- Issue :
- 78
- Database :
- MEDLINE
- Journal :
- Chemical communications (Cambridge, England)
- Publication Type :
- Academic Journal
- Accession number :
- 34514483
- Full Text :
- https://doi.org/10.1039/d1cc03563k