Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2

Gil-Moles, María; O’Beirne, Cillian; Esarev, Igor V.; Lippmann, Petra; Tacke, Matthias; Cinatl, Jindrich; Bojkova, Denisa; Ott, Ingo

doi:10.1039/d3md00067b

Cited by 11 publications

(5 citation statements)

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“…However, the iodide complexes did not trigger any cytotoxic effects up to the highest applied concentration of 100 μM (Figures and S15). This result is in good agreement with our previous report on various silver NHC complexes and might indicate that the observed nontoxicity of (NHC)AgI complexes could be of general validity …”

Section: Resultssupporting

confidence: 93%

“…As the biological effects of silver are attributed to the release of Ag + ions, the identification of robustly coordinated ligands is crucial for silver metallodrug development, in order to enhance bioavailability, improve targeting, and optimize binding to molecular drug targets. N-heterocyclic carbenes (NHCs) are ligands that form highly stable organometallic complexes with many transition metals and are therefore nowadays widely employed in bioinorganic medicinal chemistry. , Youngs and co-workers have pioneered the field of antibacterial silver NHC complexes and confirmed the antibacterial efficacy of this type of complexes in vitro and in vivo (see Figure for 1 as a representative example). − The rapidly increasing number of reported silver NHC complexes with antibacterial activity confirms the recognized potential of such complexes for drug discovery. − For example, complex 2 , developed by Tacke and colleagues, represents a promising example of a silver drug candidate, for which detailed proteomic responses have been recorded, and the inhibition of bacterial thioredoxin reductase was demonstrated. ,− Notably, silver NHC complexes have also been described as antiviral and cytotoxic agents. − …”

mentioning

confidence: 96%

“…This result is in good agreement with our previous report on various silver NHC complexes and might indicate that the observed nontoxicity of (NHC)AgI complexes could be of general validity. 33 ■…”

mentioning

confidence: 99%

“… 21 , 30 − 32 Notably, silver NHC complexes have also been described as antiviral and cytotoxic agents. 33 − 36 …”

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confidence: 99%

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Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects

Esarev,

Karge,

Zeng

et al. 2024

ACS Infect. Dis.

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The antibacterial activity of silver species is wellestablished; however, their mechanism of action has not been adequately explored. Furthermore, issues of low-molecular silver compounds with cytotoxicity, stability, and solubility hamper their progress to drug leads. We have investigated silver N-heterocyclic carbene (NHC) halido complexes [(NHC)AgX, X = Cl, Br, and I] as a promising new type of antibacterial silver organometallics. Spectroscopic studies and conductometry established a higher stability for the complexes with iodide ligands, and nephelometry indicated that the complexes could be administered in solutions with physiological chloride levels. The complexes showed a broad spectrum of strong activity against pathogenic Gram-negative bacteria. However, there was no significant activity against Gram-positive strains. Further studies clarified that tryptone and yeast extract, as components of the culture media, were responsible for this lack of activity. The reduction of biofilm formation and a strong inhibition of both glutathione and thioredoxin reductases with IC 50 values in the nanomolar range were confirmed for selected compounds. In addition to their improved physicochemical properties, the compounds with iodide ligands did not display cytotoxic effects, unlike the other silver complexes. In summary, silver NHC complexes with iodide secondary ligands represent a useful scaffold for nontoxic silver organometallics with improved physicochemical properties and a distinct mechanism of action that is based on inhibition of thioredoxin and glutathione reductases.

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Section: Resultssupporting

confidence: 93%

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confidence: 96%

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Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects

Esarev,

Karge,

Zeng

et al. 2024

ACS Infect. Dis.

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“…For this reason, biological data on Cu( i )(NHC) complexes are very restricted, while Ag( i )(NHC) shows interesting biological activity when bound to volumous NHC ligands, as they decrease ligand scrambling and photounstability of Ag(NHC) complexes. 37–39…”

Section: Introductionmentioning

confidence: 99%

Unraveling ligand exchange reactions in linear neutral Au(i) and Cu(i) N-heterocyclic carbene complexes for biological applications

Rodrigues,

Barrionuevo,

San-Miguel

et al. 2024

New J. Chem.

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The first evaluation of the in vitro effects of silver(I)-N-heterocyclic carbene complexes on Encephalitozoon intestinalis and Leishmania major promastigotes

Ataş,

Akın-Polat,

Gülpınar

et al. 2024

J Biol Inorg Chem

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Encephalitozoon intestinalis is an opportunistic microsporidian parasite that primarily infects immunocompromised individuals, such as those with HIV/AIDS or undergoing organ transplantation. Leishmaniasis is responsible for parasitic infections, particularly in developing countries. The disease has not been effectively controlled due to the lack of an effective vaccine and affordable treatment options. Current treatment options for E. intestinalis infection and leishmaniasis are limited and often associated with adverse side effects. There is no previous study in the literature on the antimicrosporidial activities of Ag(I)-N-heterocyclic carbene compounds. In this study, the in vitro antimicrosporidial activities of previously synthesized Ag(I)-N-heterocyclic carbene complexes were evaluated using E. intestinalis spores cultured in human renal epithelial cell lines (HEK-293). Inhibition of microsporidian replication was determined by spore counting. In addition, the effects of the compounds on Leishmania major promastigotes were assessed by measuring metabolic activity or cell viability using a tetrazolium reaction. Statistical analysis was performed to determine significant differences between treated and control groups. Our results showed that the growth of E. intestinalis and L. major promastigotes was inhibited by the tested compounds in a concentration-dependent manner. A significant decrease in parasite viability was observed at the highest concentrations. These results suggest that the compounds have potential anti-microsporidial and anti-leishmanial activity. Further research is required to elucidate the underlying mechanisms of action and to evaluate the efficacy of the compounds in animal models or clinical trials. Graphical abstract

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Silver N-heterocyclic carbene complexes are potent uncompetitive inhibitors of the papain-like protease with antiviral activity against SARS-CoV-2

Abstract: The ongoing SARS-CoV-2 pandemic has caused a high demand for novel innovative antiviral drug candidates. Despite first promising results, metal complexes have been relatively unexplored as antiviral agents in general...

Cited by 11 publications

References 67 publications

Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects

Silver Organometallics that are Highly Potent Thioredoxin and Glutathione Reductase Inhibitors: Exploring the Correlations of Solution Chemistry with the Strong Antibacterial Effects

Unraveling ligand exchange reactions in linear neutral Au(i) and Cu(i) N-heterocyclic carbene complexes for biological applications

The first evaluation of the in vitro effects of silver(I)-N-heterocyclic carbene complexes on Encephalitozoon intestinalis and Leishmania major promastigotes

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