Nsp14/nsp10 complex serves as an important target for antivirals against SARS-CoV-2: discovery of metallo-antiviral agents

Abstract

<p>Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has posed an unprecedented threat to public health globally. SARS-CoV-2 open reading frames (ORF) 1a and 1b encode 16 non-structural proteins (nsps) which are closely related to virus replication and transcription¹. Among them, nsp14 (a Zn(II)/Mg(II) enzyme) functions as an exoribonuclease (ExoN) and S-adenosyl methionine-dependent (guanine-N7) methyl transferase (MTase), and the ExoN activity of nsp14 was stimulated by its critical co-factor nsp10². Nsp14/nsp10 complex was believed to be an attractive target for anti-SARS-CoV-2 drugs.</p><p>The diversity geometries, coordination numbers, and redox properties of metal complexes make them quite distinguish from organic compounds, resulting in a unique role in disease diagnosis and treatment^3,4,5. Herein, we found that certain metal complexes including those clinically used metallodrugs, effectively inhibit both MTase activity and ExoN activity of nsp14, especially bismuth(III)- and gold(I)-based compounds. The inhibition mechanism of bismuth(III) and gold(I) compounds was found to displace Zn(II) ions from nsp14 and nsp10 by bismuth(III) or gold(I) ions, leading to change on stability and quaternary structure of the protein. Our study demonstrates a high potential of bismuth(III) and gold(I) compounds as anti-SARS-CoV-2 agents.</p><p><em>This work was supported by the Research Grants Council (RGC, 17318322, 2122-7S04), ITF (ITS/278/20) of Hong Kong SAR and the University of Hong Kong (URC and Norman & Cecilia Foundation)</em>.</p><p><br></p><p><strong>References</strong></p><p>(1) Zhou, P. et al. A pneumonia outbreak associated with a new coronavirus of probable bat origin. <em>Nature </em><strong>2020</strong>, <em>579</em> (7798), 270-273.</p><p>(2) Lin, S. et al. Crystal structure of SARS-CoV-2 nsp10 bound to nsp14-ExoN domain reveals an exoribonuclease with both structural and functional integrity. <em>Nucleic Acids Res. </em><strong>2021</strong>, <em>49</em> (9), 5382-5392.</p><p>(3) Griffith, D. M.; Li, H.; Sun, H. et al. Medicinal chemistry and biomedical applications of bismuth-based compounds and nanoparticles. <em>Chem. Soc. Rev. </em><strong>2021</strong>, <em>50</em> (21), 12037-12069.</p><p>(4) Li H.Y.; Sun H. Recent advances in bioinorganic chemistry of bismuth. <em>Curr. Opin. Chem. Biol. </em><strong>2012</strong>, <em>16 </em>(1), 74-83</p><p>(5) Wang, Y.; Li, H.; Sun, H. Metalloproteomics for Unveiling the Mechanism of Action of Metallodrugs. <em>Inorg. Chem. </em><strong>2019</strong>, <em>58</em> (20), 13673-13685.</p>