Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PL<sup>pro</sup>and M<sup>pro</sup>in in vitro studies

Żmudziński, Mikołaj; Rut, Wioletta; Olech, Kamila; Granda, Jarosław M.; Giurg, Mirosław; Burda-Grabowska, Małgorzata; Zhang, Linlin; Sun, Xinyuanyuan; Lv, Zhuo; Nayak, Digant; Kęsik-Brodacka, Małgorzata; Olsen, Shaun K.; Hilgenfeld, Rolf; Drąg, Marcin

doi:10.1101/2020.08.30.273979

Cited by 35 publications

(60 citation statements)

References 48 publications

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“…[39] Experimental and in silico studies have been carried out to find new Mpro and PLpro inhibitors, as well as, to explain the mechanisms of enzyme inhibition at the molecular and atomic level. [23,[40][41][42][43] Recent studies have suggested that EbSe interacts in the active site of the Mpro and PLpro and could react with the Cys145 and Cys111, respectively, leading to a Se-S bond formation, inhibiting the proteases, as previously demonstrated in vitro. [9,22] In addition, an in silico study has indicated that EbSe can bind with high probability to a second binding site of Mpro, located between the II and III domains (residues: Gln107, Pro108, Ile200, Val202, His246, Phe294), besides the catalytic site.…”

Section: Introductionmentioning

confidence: 62%

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

Nogara

Omage

Bolzan

et al. 2021

Molecular Informatics

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The COVID‐19 pandemic caused by the SARS‐CoV‐2 has mobilized scientific attention in search of a treatment. The cysteine‐proteases, main protease (Mpro) and papain‐like protease (PLpro) are important targets for antiviral drugs. In this work, we simulate the interactions between the Mpro and PLpro with Ebselen, its metabolites and derivatives with the aim of finding molecules that can potentially inhibit these enzymes. The docking data demonstrate that there are two main interactions between the thiol (−SH) group of Cys (from the protease active sites) and the electrophilic centers of the organoselenium molecules, i. e. the interaction with the carbonyl group (O=C … SH) and the interaction with the Se moiety (Se … SH). Both interactions may lead to an adduct formation and enzyme inhibition. Density Functional Theory (DFT) calculations with Ebselen indicate that the energetics of the thiol nucleophilic attack is more favorable on Se than on the carbonyl group, which is in accordance with experimental data (Jin et al. Nature , 2020, 582 , 289–293). Therefore, organoselenium molecules should be further explored as inhibitors of the SARS‐CoV‐2 proteases. Furthermore, we suggest that some metabolites of Ebselen (e. g. Ebselen diselenide and methylebselenoxide) and derivatives ethaselen and ebsulfur should be tested in vitro as inhibitors of virus replication and its proteases.

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Section: Introductionmentioning

confidence: 62%

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

Nogara

Omage

Bolzan

et al. 2021

Molecular Informatics

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“…However, within our assay we did not observe activity for ebselen, a small molecule with demonstrated in vitro activity against purified SARSpg. 6 reports showing that ebselen is highly reactive and readily forms selenosulfide bonds with numerous proteins including the SARS-CoV-2 papain-like protease (PLP) [19,[31][32][33].…”

Section: Compound Rescue Of Transfected 3clpro Cytotoxicity Mimics the Results Obtained With Live Virusmentioning

confidence: 99%

Inhibitors of Coronavirus 3CL Proteases Protect Cells from Protease-Mediated Cytotoxicity

Resnick

Iketani

Hong

et al. 2021

J Virol

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We describe a mammalian cell-based assay to identify coronavirus 3CL protease (3CLpro) inhibitors. This assay is based on rescuing protease-mediated cytotoxicity and does not require live virus. By enabling the facile testing of compounds across a range of 15 distantly related coronavirus 3CLpro enzymes, we identify compounds with broad 3CLpro inhibitory activity. We also adapt the assay for use in compound screening and in doing so uncover additional SARS-CoV-2 3CLpro inhibitors. We observe strong concordance between data emerging from this assay and those obtained from live virus testing. The reported approach democratizes the testing of 3CLpro inhibitors by developing a simplified method for identifying coronavirus 3CLpro inhibitors that can be used by the majority of laboratories, rather than the few with extensive biosafety infrastructure. We identify two lead compounds, GC376 and compound 4, with broad activity against all 3CL proteases tested including 3CLpro enzymes from understudied zoonotic coronaviruses. Importance Multiple coronavirus pandemics have occurred over the last two decades. This has highlighted a need to be proactive in the development of therapeutics that can be readily deployed in the case of future coronavirus pandemics. We develop and validate a simplified cell-based assay for the identification of chemical inhibitors of 3CL proteases encoded by a wide range of coronaviruses. This assay is reporter-free, does not require specialized biocontainment, and is optimized for performance in high-throughput screening. By testing reported 3CL protease inhibitors against a large collection of 3CL proteases with variable sequence similarity, we identify compounds with broad activity against 3CL proteases and uncover structural insights that contribute to their broad activity. Furthermore, we demonstrate this assay is suitable for identifying chemical inhibitors of proteases from families other than 3CL proteases.

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“…In this group, the main direction seems to be focused on the peptide scaffolds [30]. There are also other proposals for nonpeptide, covalent inhibitors, such as ebselen [37], its derivatives [31], and disulfiram [38]. In the case of the peptide inhibitors, the covalent bond is formed with one of the amino acids of the catalytic triad-Cys111.…”

Section: Resultsmentioning

confidence: 99%

“…The search for PLpro inhibitors has already begun. So far, most studies focus on trying to utilize previously developed noncovalent SARS-CoV inhibitors or their derivatives [7,24,29] or to design specific, covalent inhibitors [30,31]. However, covalent protease inhibitors come with risks of toxicity due to high reactivity and, in some cases, low selectivity and nonspecific binding off the target [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

Stasiulewicz

Maksymiuk

Nguyen

et al. 2021

IJMS

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Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) encodes the papain-like protease (PLpro). The protein not only plays an essential role in viral replication but also cleaves ubiquitin and ubiquitin-like interferon-stimulated gene 15 protein (ISG15) from host proteins, making it an important target for developing new antiviral drugs. In this study, we searched for novel, noncovalent potential PLpro inhibitors by employing a multistep in silico screening of a 15 million compound library. The selectivity of the best-scored compounds was evaluated by checking their binding affinity to the human ubiquitin carboxy-terminal hydrolase L1 (UCH-L1), which, as a deubiquitylating enzyme, exhibits structural and functional similarities to the PLpro. As a result, we identified 387 potential, selective PLpro inhibitors, from which we retrieved the 20 best compounds according to their IC50 values toward PLpro estimated by a multiple linear regression model. The selected candidates display potential activity against the protein with IC50 values in the nanomolar range from approximately 159 to 505 nM and mostly adopt a similar binding mode to the known, noncovalent SARS-CoV-2 PLpro inhibitors. We further propose the six most promising compounds for future in vitro evaluation. The results for the top potential PLpro inhibitors are deposited in the database prepared to facilitate research on anti-SARS-CoV-2 drugs.

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Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PL^proand M^proin in vitro studies

Cited by 35 publications

References 48 publications

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

Inhibitors of Coronavirus 3CL Proteases Protect Cells from Protease-Mediated Cytotoxicity

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

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Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PLproand Mproin in vitro studies

Cited by 35 publications

References 48 publications

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

In silico Studies on the Interaction between Mpro and PLpro From SARS‐CoV‐2 and Ebselen, its Metabolites and Derivatives

Inhibitors of Coronavirus 3CL Proteases Protect Cells from Protease-Mediated Cytotoxicity

SARS-CoV-2 Papain-Like Protease Potential Inhibitors—In Silico Quantitative Assessment

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Ebselen derivatives are very potent dual inhibitors of SARS-CoV-2 proteases - PL^proand M^proin in vitro studies