Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy

Chantadul, Varunya; Wright, Gareth S. A.; Amporndanai, K.; Shahid, Munazza; Antonyuk, S.V.; Washbourn, Gina; Rogers, Michael S.; Roberts, N. B.; Pye, Matthew; O’Neill, Paul M.; Hasnain, S.S.

doi:10.1038/s42003-020-0826-3

Cited by 39 publications

(41 citation statements)

References 52 publications

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“…Ebselen is a low-molecular-weight organoselenium drug that shows pleiotropic mode of action and due to its very low toxicity there are no barriers to using it in humans [15]. It is a well-known agent with therapeutic activity in neurological disorders [16] and cancers [17]. It also showed an antiviral effect on neurotropic viruses [18] and hepatitis C virus [19].…”

Section: Introductionmentioning

confidence: 99%

“…Another recently published work proposed via virtual screening ebselen as a possible inhibitor of M pro from SARS-CoV-2 [21]. Several lines of evidence demonstrated the biological effects of ebselen is mainly due to its antioxidant properties and capability of forming selenenyl-sulfide bonds with the cysteine residues in proteins [16,[22][23][24][25].…”

Section: Introductionmentioning

confidence: 99%

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Ebselen as a highly active inhibitor of PL^ProCoV2

Węglarz-Tomczak

Talma

et al. 2020

Preprint

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Since December 2019 a novel a coronavirus identified as SARS-CoV-2 or COV2 has been spreading around the world. On the 16th of May around 4.5 million people got infected and over 300,000 died due to the infection of COV2. The effective treatment remains a challenge. Targeted therapeutics are still under investigation. The papain-like protease (PL Pro ) from the human SARS-CoV-2 coronavirus is a cysteine protease that plays a critical role in virus replication. Its activity is required to process the viral polyprotein into functional, mature subunits. Moreover, COV2 uses this enzyme to modulate the host's immune system to its own benefit. Therefore, it represents a highly promising target for the development of antiviral drugs. In this work, we discovered that ebselen, a synthetic organoselenium drug molecule with anti-inflammatory, anti-oxidant and cytoprotective activity in mammalian cells and cytotoxicity in lower organisms, is a highly active inhibitor of PL Pro CoV2. We proved that ebselen is a covalent, fast-binding inhibitor of PL Pro CoV2 exhibiting a low micromolar potency. Furthermore, we identified a difference between PL Pro from SARS-CoV-1 (the corona virus which caused the 2002-2004 outbreak, SARS) and SARS-CoV-2 that allows to explain the difference in dynamics of the replication, and, thus, the disease progression. Namely, we present that they show differences in the binding affinity of substrates that we observed through kinetics and molecular docking studies. Using a novel Approximate Bayesian Computation method we were able to find kinetic constants for both enzymes. Molecular modeling study on the structure of the active site and binding mode of the ebselen with SARS and COV2 showed also significant differences that could explain our observation that ebselen is less active and slower bounding with SARS than COV2. In conclusion, we show that ebselen inhibits the activity of the essential viral enzyme papain-like protease (PLpro) from SARS-COV-2 in low micromolar range.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ebselen as a highly active inhibitor of PL^ProCoV2

Węglarz-Tomczak

Talma

et al. 2020

Preprint

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“…Ebselen is a seleno-organic drug with well-known anti-inflammatory, anti-atherosclerotic, cytoprotective properties and low toxicity in humans [13]. It has been proven to be an effective therapeutic agent in multiple diseases like cancer and hepatitis C virus [14][15][16][17][18].…”

Section: Introductionmentioning

confidence: 99%

Discovery of potent inhibitors of PL^proCoV2 by screening a library of selenium-containing compounds

Węglarz-Tomczak

Tomczak

Giurg

et al. 2020

Preprint

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A collection of twelve organoselenium compounds, structural analogues of antioxidant drug ebselen were screened for inhibition of the papain-like protease (PL pro ) from the acute respiratory syndrome coronavirus 2 (SARS-CoV-2, CoV2). This cysteine protease, being responsible for the hydrolysis of peptide bonds between specific amino acids, plays a critical role in CoV2 replication and in assembly of new viral particles within human cells. The activity of the PL pro CoV2 is essential for the progression of coronavirus disease 2019 (COVID-19) and it constitutes a key target for the development of anti-COVID-19 drugs. Here, we identified four strong inhibitors that bind favorably to the PL pro CoV2 with the IC 50 in the nanomolar range.

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“…Ebselen is known to bind to several proteins; crystal structures show ebselen covalently bound to cysteine residues of proteins including SOD1 (Capper et al, 2018;Chantadul et al, 2020) and the transpeptidase LdtMt2 from Mycobacterium tuberculosis (de Munnik et al, 2019). Ebselen has also been reported to inhibit the main protease from SARS-CoV-2 (Jin et al, 2020).…”

Section: Introductionmentioning

confidence: 99%

Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase

Fenn

Waller-Evans

Atack

et al. 2020

Acta Crystallogr F Struct Biol Commun

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Inositol monophosphatase (IMPase) is inhibited by lithium, which is the most efficacious treatment for bipolar disorder. Several therapies have been approved, or are going through clinical trials, aimed at the replacement of lithium in the treatment of bipolar disorder. One candidate small molecule is ebselen, a selenium-containing antioxidant, which has been demonstrated to produce lithium-like effects both in a murine model and in clinical trials. Here, the crystallization and the first structure of human IMPase covalently complexed with ebselen, a 1.47 Å resolution crystal structure (PDB entry 6zk0), are presented. In the complex with human IMPase, ebselen in a ring-opened conformation is covalently attached to Cys141, a residue located away from the active site. IMPase is a dimeric enzyme and in the crystal structure two adjacent dimers share four ebselen molecules, creating a tetramer with approximate 222 symmetry. In the crystal structure presented in this publication, the active site in the tetramer is still accessible, suggesting that ebselen may function as an allosteric inhibitor or may block the binding of partner proteins.

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Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy

Cited by 39 publications

References 52 publications

Ebselen as a highly active inhibitor of PL^ProCoV2

Ebselen as a highly active inhibitor of PL^ProCoV2

Discovery of potent inhibitors of PL^proCoV2 by screening a library of selenium-containing compounds

Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase

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Ebselen as template for stabilization of A4V mutant dimer for motor neuron disease therapy

Cited by 39 publications

References 52 publications

Ebselen as a highly active inhibitor of PLProCoV2

Ebselen as a highly active inhibitor of PLProCoV2

Discovery of potent inhibitors of PLproCoV2 by screening a library of selenium-containing compounds

Crystallization and structure of ebselen bound to Cys141 of human inositol monophosphatase

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Ebselen as a highly active inhibitor of PL^ProCoV2

Ebselen as a highly active inhibitor of PL^ProCoV2

Discovery of potent inhibitors of PL^proCoV2 by screening a library of selenium-containing compounds