Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs

Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 M<sup>pro</sup>), a validated...

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Main Authors: Lara Massai, Deborah Grifagni, Alessia De Santis, Andrea Geri, Francesca Cantini, Vito Calderone, Lucia Banci, Luigi Messori
Format: Article
Language:English
Published: MDPI AG 2022-11-01
Series:Biomolecules
Subjects:
Online Access:https://www.mdpi.com/2218-273X/12/11/1675
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author Lara Massai
Deborah Grifagni
Alessia De Santis
Andrea Geri
Francesca Cantini
Vito Calderone
Lucia Banci
Luigi Messori
author_facet Lara Massai
Deborah Grifagni
Alessia De Santis
Andrea Geri
Francesca Cantini
Vito Calderone
Lucia Banci
Luigi Messori
author_sort Lara Massai
collection DOAJ
description Gold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 M<sup>pro</sup>), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt<sub>3</sub>)Cl, Au(PEt<sub>3</sub>)Br, and Au(PEt<sub>3</sub>)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)<sub>2</sub>]PF<sub>6</sub>. Notably, all these gold compounds, with the only exception of [Au(NHC)<sub>2</sub>]PF<sub>6</sub>, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 M<sup>pro</sup>: the measured K<sub>i</sub> values were in the range 2.1–0.4 μM. The reactions of the various gold compounds with SARS-CoV-2 M<sup>pro</sup> were subsequently investigated through electrospray ionization (ESI) mass spectrometry (MS) upon a careful optimization of the experimental conditions; the ESI MS spectra provided clear evidence for the formation of tight metallodrug-protein adducts and for the coordination of well defined gold-containing fragments to the SARS-CoV-2 M<sup>pro</sup>, again with the only exception of [Au(NHC)<sub>2</sub>]PF<sub>6</sub>, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- M<sup>pro</sup> adducts were solved in the case of Au(PEt<sub>3</sub>)Br and Au(NHC)Cl. These crystal structures show that gold coordination occurs at the level of catalytic Cys 145 in the case of Au(NHC)Cl and at the level of both Cys 145 and Cys 156 for Au(PEt<sub>3</sub>)Br. Tight coordination of gold atoms to functionally relevant cysteine residues is believed to represent the true molecular basis of strong enzyme inhibition.
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spelling doaj.art-a3ea0616ea5a4d1899af8596752ff6742023-11-24T07:47:36ZengMDPI AGBiomolecules2218-273X2022-11-011211167510.3390/biom12111675Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its AnalogsLara Massai0Deborah Grifagni1Alessia De Santis2Andrea Geri3Francesca Cantini4Vito Calderone5Lucia Banci6Luigi Messori7Department of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyDepartment of Chemistry “Ugo Schiff”, University of Florence, Via Della Lastruccia 3, 50019 Florence, ItalyGold compounds have a long tradition in medicine and offer many opportunities for new therapeutic applications. Herein, we evaluated the lead compound Auranofin and five related gold(I) complexes as possible inhibitors of SARS-CoV-2 Main Protease (SARS-CoV-2 M<sup>pro</sup>), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt<sub>3</sub>)Cl, Au(PEt<sub>3</sub>)Br, and Au(PEt<sub>3</sub>)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)<sub>2</sub>]PF<sub>6</sub>. Notably, all these gold compounds, with the only exception of [Au(NHC)<sub>2</sub>]PF<sub>6</sub>, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 M<sup>pro</sup>: the measured K<sub>i</sub> values were in the range 2.1–0.4 μM. The reactions of the various gold compounds with SARS-CoV-2 M<sup>pro</sup> were subsequently investigated through electrospray ionization (ESI) mass spectrometry (MS) upon a careful optimization of the experimental conditions; the ESI MS spectra provided clear evidence for the formation of tight metallodrug-protein adducts and for the coordination of well defined gold-containing fragments to the SARS-CoV-2 M<sup>pro</sup>, again with the only exception of [Au(NHC)<sub>2</sub>]PF<sub>6</sub>, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- M<sup>pro</sup> adducts were solved in the case of Au(PEt<sub>3</sub>)Br and Au(NHC)Cl. These crystal structures show that gold coordination occurs at the level of catalytic Cys 145 in the case of Au(NHC)Cl and at the level of both Cys 145 and Cys 156 for Au(PEt<sub>3</sub>)Br. Tight coordination of gold atoms to functionally relevant cysteine residues is believed to represent the true molecular basis of strong enzyme inhibition.https://www.mdpi.com/2218-273X/12/11/1675COVID-19nsp5M<sup>pro</sup>SARS-CoV-2Auranofingold compounds
spellingShingle Lara Massai
Deborah Grifagni
Alessia De Santis
Andrea Geri
Francesca Cantini
Vito Calderone
Lucia Banci
Luigi Messori
Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
Biomolecules
COVID-19
nsp5
M<sup>pro</sup>
SARS-CoV-2
Auranofin
gold compounds
title Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
title_full Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
title_fullStr Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
title_full_unstemmed Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
title_short Gold-Based Metal Drugs as Inhibitors of Coronavirus Proteins: The Inhibition of SARS-CoV-2 Main Protease by Auranofin and Its Analogs
title_sort gold based metal drugs as inhibitors of coronavirus proteins the inhibition of sars cov 2 main protease by auranofin and its analogs
topic COVID-19
nsp5
M<sup>pro</sup>
SARS-CoV-2
Auranofin
gold compounds
url https://www.mdpi.com/2218-273X/12/11/1675
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