Ebselen is a potent non-competitive inhibitor of extracellular nucleoside diphosphokinase

Lucia, Semianrio-Vidal,; Catharina, van Hesuden,; Mugesh, Govindasamy; Lazarowski, Eduardo R.

doi:10.1007/s11302-010-9203-x

Cited by 14 publications

(7 citation statements)

References 51 publications

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“…3A) showed that ebselen inhibited DOXol formation by a noncompetitive mechanism (K i = 5.586 6 0.254 mM). The same inhibition behavior has previously been observed for other enzymes treated with ebselen (Schewe et al, 1994;Semianrio-Vidal et al, 2010). Moreover, the inhibition was irreversible because ultrafiltration or long-term dialysis of ebselen-treated heart cytosolic fractions failed to restore anthracycline reductase activity (activity recovery was less than 5%).…”

Section: Resultssupporting

confidence: 78%

Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

Mordente¹,

Silvestrini²,

Martorana³

et al. 2015

Drug Metab Dispos

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The clinical efficacy of anthracyclines (e.g., doxorubicin and daunorubicin) in cancer therapy is limited by their severe cardiotoxicity, the etiology of which is still not fully understood. The development of anthracycline-induced cardiomyopathy has been found to correlate with myocardial formation and accumulation of anthracycline secondary alcohol metabolites (e.g., doxorubicinol and daunorubicinol) that are produced by distinct cytosolic NADPH-dependent reductases. The aim of the current study is to identify chemical compounds capable of inhibiting myocardial reductases implied in anthracycline reductive metabolism in an attempt to decrease the production of cardiotoxic C-13 alcohol metabolites. Among the variety of tested compounds (metal chelators, radical scavengers, antioxidants, b-blockers, nitrone spin traps, and lipid-lowering drugs), ebselen, cyclopentenone prostaglandins, nitric oxide donors, and short-chain coenzyme Q analogs resulted in being effective inhibitors of both doxorubicinol and daunorubicinol formation. In particular, ebselen (as well as ebselen diselenide, its storage form in the cells) was the most potent inhibitor of cardiotoxic anthracycline alcohol metabolites with 50% inhibition of doxorubicinol formation at 0.2 mol Eq of ebselen with respect to doxorubicin concentration. The high efficacy, together with its favorable pharmacological profile (low toxicity, lack of adverse effects, and metabolic stability) portends ebselen as a promising cardioprotective agent against anthracycline-induced cardiotoxicity.

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Section: Resultssupporting

confidence: 78%

Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

Mordente¹,

Silvestrini²,

Martorana³

et al. 2015

Drug Metab Dispos

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“…The data are supportive of a complex link between the activities of AMPK and NDPK-A which co-localize 23 (see below). This is compatible with our early data on chloride as a signal to phosphohistidine generation and perhaps there exists a latent functional inter-regulation between NDPK, that is part of an epithelial, chloride-sensitive, membranedelimited phosphorylation system working with membranebound AMPK 76 in association with CFTR.…”

Section: Regulation Of Cftr Activity By the 5′-amp-acti-vated Proteinsupporting

confidence: 91%

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

Muimo

Alothaid

Mehta

2018

Laboratory Investigation

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“…There has been considerable interest in applications of selenolate compounds because of their broad therapeutic spectrum and low toxicity. The organoselenium compound ebselen [2-phenyl-1,2-benzisoselenazol-3(2H)-one] an anti-inflammatory and general antioxidant, is also a potent inhibitor of extracellular nucleoside diphosphokinase [ 26 ]. Furthermore, Achillion Pharmaceuticals (New Haven, CT, USA) has recently developed a selenophene inhibitor of bacterial topoisomerases that shows promise as an antibiotic [ 27 ].…”

Section: Discussionmentioning

confidence: 99%

Structural characterization of angiotensin I‐converting enzyme in complex with a selenium analogue of captopril

et al. 2011

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Human somatic angiotensin I-converting enzyme (ACE), a zinc-dependent dipeptidyl carboxypeptidase, is central to the regulation of the renin–angiotensin aldosterone system. It is a well-known target for combating hypertension and related cardiovascular diseases. In a recent study by Bhuyan and Mugesh [Org. Biomol. Chem. (2011) 9, 1356–1365], it was shown that the selenium analogues of captopril (a well-known clinical inhibitor of ACE) not only inhibit ACE, but also protect against peroxynitrite-mediated nitration of peptides and proteins. Here, we report the crystal structures of human testis ACE (tACE) and a homologue of ACE, known as AnCE, from Drosophila melanogaster in complex with the most promising selenium analogue of captopril (SeCap) determined at 2.4 and 2.35 Å resolution, respectively. The inhibitor binds at the active site of tACE and AnCE in an analogous fashion to that observed for captopril and provide the first examples of a protein–selenolate interaction. These new structures of tACE–SeCap and AnCE–SeCap inhibitor complexes presented here provide important information for further exploration of zinc coordinating selenium-based ACE inhibitor pharmacophores with significant antioxidant activity.DatabaseStructural data for the two SeCap complexes with ACE and AnCE have been deposited with the RCSB Protein Data Bank under the codes 2YDM and 3ZQZ, respectively.

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Ebselen is a potent non-competitive inhibitor of extracellular nucleoside diphosphokinase

Cited by 14 publications

References 51 publications

Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

Inhibition of Anthracycline Alcohol Metabolite Formation in Human Heart Cytosol: A Potential Role for Several Promising Drugs

NM23 proteins: innocent bystanders or local energy boosters for CFTR?

Structural characterization of angiotensin I‐converting enzyme in complex with a selenium analogue of captopril

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