Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

Sargsyan, Karen; Lin, Chien‐Chu; Chen, Ting; Grauffel, Cédric; Chen, Yiping; Yang, Wei‐Zen; Yuan, Hanna S.; Lim, Carmay

doi:10.1039/d0sc02646h

Cited by 83 publications

(111 citation statements)

References 30 publications

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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%

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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Section: Resultsmentioning

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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“…Of note, the replacement of zinc from zinc‐finger motifs and formation of so called gold‐fingers has been well documented [18] . Interestingly, a very recent paper reports on the dual activity of thiol‐reacting inhibitor Disulfiram as zinc removing agent as well as modifier of the catalytic cysteine of SARS‐CoV‐2 PLpro [19] . As Disulfiram displayed similar activity with the Au‐1 , Au‐2 and Au‐5 against both types of PLpro, it could be speculated that these compounds share such dual activity against the enzyme.…”

Section: Figurementioning

confidence: 99%

“…To determine if the inhibitors are Zn-ejecting agents the presence of the Zn 2 + cation in solution was measured according to arecently published preprint. [19] The inhibitor compounds were prepared as stock solutions in DMSO and diluted hundredfold with HEPES buffer (50 mm HEPES, pH 7.5) to 100 mm concentrations. Volumes of 50 mLo f1mm His 6 -SARS-CoV-1 PLpro (SouthBayBio) or SARS-CoV-2 PLpro (Elabscience) in HEPES buffer or blank HEPES buffer (control for false positive results) were added to the wells of a black 96-well microtiter plate (Nunclon, Nunc).…”

Section: Zn-ejection Assays With Sars-cov-1a Nd Sars-cov-2 Plpromentioning

confidence: 99%

“…To determine if the inhibitors are Zn‐ejecting agents the presence of the Zn 2+ cation in solution was measured according to a recently published preprint [19] . The inhibitor compounds were prepared as stock solutions in DMSO and diluted hundredfold with HEPES buffer (50 m m HEPES, pH 7.5) to 100 μ m concentrations.…”

Section: Figurementioning

confidence: 99%

“…[18] Interestingly, av ery recent paper reportso nt he dual activity of thiol-reacting inhibitor Disulfiram as zinc removing agent as well as modifier of the catalytic cysteine of SARS-CoV-2 PLpro. [19] As Disulfiram displayed similar activity with the Au-1, Au-2 and Au-5 against both types of PLpro, it could be speculated that these compounds share such dual activity against the enzyme. Thus we evaluated the ability of the inhibitors to replacez inc ions from PLpro by measuringt he released zinc with azinc selective fluorescent dye.…”

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confidence: 95%

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Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike‐ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**

Gil-Moles

Basu

Büssing

et al. 2020

Chemistry A European J

106

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Gold complexes have al ong tradition in medicine and for many examples antirheumatic, anticancer or anti-infective effectsh ave been confirmed. Herein,w e evaluated the lead compound Auranofin and five selected gold organometallics as inhibitors of two relevant drug targetso fs evere acute respiratory syndrome coronaviruses (SARS-CoV). The gold metallodrugsw ere effectivei nhibitorso ft he interaction of the SARS-CoV-2 spike protein with the angiotensin converting enzyme 2(ACE2) host receptor and might thusi nterfere with the viral entry process. The gold metallodrugsw ere also efficient inhibitors of the papain-like protease (PLpro) of SARS-CoV-1 and SARS-CoV-2, which is ak ey enzymei nt he viral replication. Regarding PLpro from SARS-CoV-2,t he here reportedi nhibitorsa re among the very first experimentally confirmed examples with activity against this target enzyme. Importantly,t he activity of the complexes against both PLpro enzymes correlated with the ability of the inhibitors to removez inc ions from the labile zinc center of the enzyme. Ta ken together,the results of this pilot study suggest further evaluation of gold complexes as SARS-CoV antiviral drugs.

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Metal Complexes as Antiviral Agents for SARS‐CoV‐2

Karges

Cohen

2021

ChemBioChem

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The severe acute respiratory syndrome – coronavirus 2 (SARS‐CoV‐2), the infectious agent responsible for COVID‐19 – has caused more than 2.5 million deaths worldwide and triggered a global pandemic. Even with successful vaccines being delivered, there is an urgent need for novel treatments to combat SARS‐CoV‐2, and other emerging viral diseases. While several organic small molecule drug candidates are in development, some effort has also been devoted towards the application of metal complexes as potential antiviral agents against SARS‐CoV‐2. Herein, the metal complexes that have been reported to show antiviral activity against SARS‐CoV‐2 or one of its target proteins are described and their proposed mechanisms of action are discussed.

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Multi-targeting of functional cysteines in multiple conserved SARS-CoV-2 domains by clinically safe Zn-ejectors

Abstract: By combining evolutionary and physico-chemical principles, previously unknown druggable Zn-sites in multiple conserved SARS-CoV-2 domains have been identified.

Cited by 83 publications

References 30 publications

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

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

Gold Metallodrugs to Target Coronavirus Proteins: Inhibitory Effects on the Spike‐ACE2 Interaction and on PLpro Protease Activity by Auranofin and Gold Organometallics**

Metal Complexes as Antiviral Agents for SARS‐CoV‐2

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