Inhibition of SARS-CoV-2 replication by zinc gluconate in combination with hinokitiol

Tao, Xiaoma; Zhang, Lu; Du, Liubing; Lǚ, Kai; Zhao, Zhennan; Xie, Yufang; Li, Xiaobo; Huang, Shuxiang; Wang, Pei‐Hui; Pan, Jing; Dai, Jun; Mao, Zong‐Wan

doi:10.1016/j.jinorgbio.2022.111777

Cited by 13 publications

(13 citation statements)

References 29 publications

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“…It is also important to consider that M pro is an enzyme with a high structural conservation of the main core among the various coronaviruses [ 13 , 14 ]; therefore, the discovery of high-affinity inhibitors for this protease may be an excellent starting point for selecting new antiviral compounds that are active against a broad spectrum of coronaviruses [ 15 ]. The recently solved 3D structures of SARS-CoV-2 M pro in complex with zinc ion [ 16 , 17 , 18 ] showed that the metal ion is bound to the catalytically relevant Cys145 and His 41 residues. Furthermore, a few recent works demonstrated that other metal ions or metal-based compounds, such as rhenium, gold and copper compounds, can be efficient inhibitors of viral proteases [ 19 , 20 , 21 ].…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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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 Mpro), a validated drug target for the COVID-19 disease. The investigational panel of gold compounds included Auranofin; three halido analogues, i.e., Au(PEt3)Cl, Au(PEt3)Br, and Au(PEt3)I; and two gold carbene complexes, i.e., Au(NHC)Cl and [Au(NHC)2]PF6. Notably, all these gold compounds, with the only exception of [Au(NHC)2]PF6, turned out to be potent inhibitors of the catalytic activity of SARS-CoV-2 Mpro: the measured Ki values were in the range 2.1–0.4 μM. The reactions of the various gold compounds with SARS-CoV-2 Mpro 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 Mpro, again with the only exception of [Au(NHC)2]PF6, The metal-protein stoichiometry was unambiguously determined for the resulting species. The crystal structures of the metallodrug- Mpro adducts were solved in the case of Au(PEt3)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(PEt3)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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Section: Introductionmentioning

confidence: 99%

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

et al. 2022

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“…This makes them attractive targets for potential therapies against COVID-19. Currently, some SARS-CoV-2 protease inhibitors are being studied, such as Lopinavir and Ritonavir, two already-approved Human Immunodeficiency Virus treatments ( Tao et al, 2022 ). In this regard, coordination compounds have emerged as new candidates for PL pro or M pro inhibitors, including Zn(II) ( DeLaney et al, 2021 ; Tao et al, 2022 ), Au(I) ( Gil-Moles et al, 2020 ), Bi(III) ( Yuan et al, 2020 ; Tao et al, 2021 ), Re(I) complexes ( Karges et al, 2021 ), and other metals ( Gandhimathi and Anbuselvi, 2022 ).…”

Section: Resultsmentioning

confidence: 99%

“…Currently, some SARS-CoV-2 protease inhibitors are being studied, such as Lopinavir and Ritonavir, two already-approved Human Immunodeficiency Virus treatments ( Tao et al, 2022 ). In this regard, coordination compounds have emerged as new candidates for PL pro or M pro inhibitors, including Zn(II) ( DeLaney et al, 2021 ; Tao et al, 2022 ), Au(I) ( Gil-Moles et al, 2020 ), Bi(III) ( Yuan et al, 2020 ; Tao et al, 2021 ), Re(I) complexes ( Karges et al, 2021 ), and other metals ( Gandhimathi and Anbuselvi, 2022 ). Other inhibitory studies on the host receptor ACE2 with transition metal-based compounds ( Al-Harbi, 2022 ) or against the spike protein with decavanadate ( Favre et al, 2022 ) have also been conducted.…”

Section: Resultsmentioning

confidence: 99%

Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19

et al. 2023

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SARS-CoV-2 is the virus responsible for the COVID-19 pandemic. For the virus to enter the host cell, its spike (S) protein binds to the ACE2 receptor, and the transmembrane protease serine 2 (TMPRSS2) cleaves the binding for the fusion. As part of the research on COVID-19 treatments, several Casiopeina-analogs presented here were looked at as TMPRSS2 inhibitors. Using the DFT and conceptual-DFT methods, it was found that the global reactivity indices of the optimized molecular structures of the inhibitors could be used to predict their pharmacological activity. In addition, molecular docking programs (AutoDock4, Molegro Virtual Docker, and GOLD) were used to find the best potential inhibitors by looking at how they interact with key amino acid residues (His296, Asp 345, and Ser441) in the catalytic triad. The results show that in many cases, at least one of the amino acids in the triad is involved in the interaction. In the best cases, Asp435 interacts with the terminal nitrogen atoms of the side chains in a similar way to inhibitors such as nafamostat, camostat, and gabexate. Since the copper compounds localize just above the catalytic triad, they could stop substrates from getting into it. The binding energies are in the range of other synthetic drugs already on the market. Because serine protease could be an excellent target to stop the virus from getting inside the cell, the analyzed complexes are an excellent place to start looking for new drugs to treat COVID-19.

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“…The interactome is consistent with the fact that zinc acts at multiple levels in cells to combat SARS-CoV-2, which makes it difficult to define a single cellular or biochemical mechanism of action. Recent studies have shown that different zinc salts possess antiviral activity against SARS-CoV-2 [74,75]. The antiviral activity of zinc reflects a series of effects on viral binding, penetration, uncoating, and replication [76].…”

Section: Intrinsic Relationship Between Metal Ions and Host-virus Int...mentioning

confidence: 99%

Therapeutic potential of metal ions for COVID-19: insights from the papain-like protease of SARS-CoV-2

Shetler

Ferreira

Cardoso³

et al. 2022

Biochemical Journal

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Coronaviruses have been responsible for multiple challenging global pandemics, including coronavirus disease 2019 (COVID-19), which is caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). Papain-like protease (PLpro), one of two cysteine proteases responsible for the maturation and infectivity of SARS-CoV-2, processes and liberates functional proteins from the viral polyproteins and cleaves ubiquitin and ISG15 modifications to inhibit innate immune sensing. Consequently, PLpro is an attractive target for developing COVID-19 therapies. PLpro contains a zinc-finger domain important for substrate binding and structural stability. However, the impact of metal ions on the activity and biophysical properties of SARS-CoV-2 PLpro has not been comprehensively studied. Here, we assessed the impacts of metal ions on the catalytic activity of PLpro. Zinc had the largest inhibitory effect on PLpro, followed by manganese. Calcium, magnesium, and iron had smaller or no effects on PLpro activity. EDTA at a concentration of 0.5 mM was essential for PLpro activity, likely by chelating trace metals that inhibit PLpro. IC50 values for ZnCl2, ZnSO4, and MnCl2 of 0.42 ± 0.02 mM, 0.35 ± 0.01 mM, and 2.6 ± 0.3 mM were obtained in the presence of 0.5 mM EDTA; in the absence of EDTA, the estimated IC50 of ZnCl2 was 14 µM. Tryptophan intrinsic fluorescence analysis confirmed the binding of zinc and manganese to PLpro, and differential scanning calorimetry revealed that zinc but not manganese reduced ΔHcal of PLpro. The results of this study provide a reference for further work targeting PLpro to prevent and treat COVID-19.

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Inhibition of SARS-CoV-2 replication by zinc gluconate in combination with hinokitiol

Cited by 13 publications

References 29 publications

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

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

Interaction of copper potential metallodrugs with TMPRSS2: A comparative study of docking tools and its implications on COVID-19

Therapeutic potential of metal ions for COVID-19: insights from the papain-like protease of SARS-CoV-2

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