Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial

Kil, Jonathan; Lobariñas, Edward; Spankovich, Christopher; Griffiths, Scott; Antonelli, Patrick J.; Lynch, Eric D.; Prell, Colleen G. Le

doi:10.1016/s0140-6736(17)31791-9

Cited by 230 publications

(167 citation statements)

References 24 publications

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“…Ebselen is an organoselenium compound with anti-inflammatory, anti-oxidant and cytoprotective properties. This compound has been investigated for the treatment of multiple diseases, such as bipolar disorders 25 and hearing loss 26,27 . Ebselen has extremely low cytotoxicity (LD 50 in rats > 4,600 mg/kg, per os) 28 and its safety in humans has been evaluated in a number of clinical trials 26,27,29 .…”

Section: Antiviral Activity Assaymentioning

confidence: 99%

Structure of M^profrom COVID-19 virus and discovery of its inhibitors

Jin

et al. 2020

Preprint

384

625

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SUMMARYA new coronavirus (CoV) identified as COVID-19 virus is the etiological agent responsible for the 2019-2020 viral pneumonia outbreak that commenced in Wuhan1–4. Currently there is no targeted therapeutics and effective treatment options remain very limited. In order to rapidly discover lead compounds for clinical use, we initiated a program of combined structure-assisted drug design, virtual drug screening and high-throughput screening to identify new drug leads that target the COVID-19 virus main protease (Mpro). Mpro is a key CoV enzyme, which plays a pivotal role in mediating viral replication and transcription, making it an attractive drug target for this virus5,6. Here, we identified a mechanism-based inhibitor, N3, by computer-aided drug design and subsequently determined the crystal structure of COVID-19 virus Mpro in complex with this compound. Next, through a combination of structure-based virtual and high-throughput screening, we assayed over 10,000 compounds including approved drugs, drug candidates in clinical trials, and other pharmacologically active compounds as inhibitors of Mpro. Six of these inhibit Mpro with IC50 values ranging from 0.67 to 21.4 μM. Ebselen also exhibited promising antiviral activity in cell-based assays. Our results demonstrate the efficacy of this screening strategy, which can lead to the rapid discovery of drug leads with clinical potential in response to new infectious diseases where no specific drugs or vaccines are available.

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Section: Antiviral Activity Assaymentioning

confidence: 99%

Structure of M^profrom COVID-19 virus and discovery of its inhibitors

Jin

et al. 2020

Preprint

384

625

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“…Their chemical synthesis is well established and is not expensive. Moreover, ebselen has been already used in clinical trials, including acute ischaemic stroke, aneurysmal subarachnoid haemorrhage, cerebral ischaemia, bipolar disorders and hearing loss found to be non‐toxic (Kil et al, ; Masaki et al, ; Ogawa et al, ; M. Parnham & Sies, ; M. J. Parnham & Sies, ; Saito et al, ; Yamaguchi et al, ). In these studies, ebselen was used at doses comparable to those used in mice (Pirazzini et al, ; Zanetti et al, ).…”

Section: Trxr‐trx Inhibitors In the Treatment Of Infant Botulism And mentioning

confidence: 99%

“…Moreover, ebselen has been already used in clinical trials, including acute ischaemic stroke, aneurysmal subarachnoid haemorrhage, cerebral ischaemia, bipolar disorders and hearing loss found to be nontoxic (Kil et al, 2017;Masaki et al, 2016;Ogawa et al, 1999;M. Parnham & Sies, 2000;M.…”

Section: Trxr-trx Inhibitors In the Treatment Of Infant Botulism Anmentioning

confidence: 99%

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

Rossetto

Pirazzini

Lista

et al. 2019

Cellular Microbiology

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A large number of bacterial toxins consist of active and cell binding protomers linked by an interchain disulfide bridge. The largest family of such disulfide‐bridged exotoxins is that of the clostridial neurotoxins that consist of two chains and comprise the tetanus neurotoxins causing tetanus and the botulinum neurotoxins causing botulism. Reduction of the interchain disulfide abolishes toxicity, and we discuss the experiments that revealed the role of this structural element in neuronal intoxication. The redox couple thioredoxin reductase–thioredoxin (TrxR‐Trx) was identified as the responsible for reduction of this disulfide occurring on the cytosolic surface of synaptic vesicles. We then discuss the very relevant finding that drugs that inhibit TrxR‐Trx also prevent botulism. On this basis, we propose that ebselen and PX‐12, two TrxR‐Trx specific drugs previously used in clinical trials in humans, satisfy all the requirements for clinical tests aiming at evaluating their capacity to effectively counteract human and animal botulism arising from intestinal toxaemias such as infant botulism.

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“…The aromatic nature of ebselen likely contributes to its observed lack of acutetoxicity in humans. [14] Unfortunately,a ni nitial investigation of aromatic seleninate esters 9 and 10 a (R = H), revealed almostn o activity (t 1/2 = 252 and 162 h, respectively)w ith TBHP. [26,27] However,f urthers tudy of para-substituted (relative to Se) derivatives of 10 with hydrogen peroxide as the oxidant showeda correlation between electron-donating and withdrawing properties of the substituents with catalytic activity.AHammett plot produced ar eaction constant with an egative slope (1 = À0.45), indicating that the transitions tate of the rate-determining step incurred an increase in positive character that was mesomerically stabilized by an electron-donating para-substituent.…”

Section: Cyclic Seleninate Estersmentioning

confidence: 99%

“…Its peroxidedestroying catalytic activity is only moderate and its poor aqueous solubility makes intravenous administration problematic, an especially important consideration for the mitigation of oxidative stress in acute conditions such as those associated with ischemic reperfusion of heart attack and stroke patients, where timely intervention is crucial. On the other hand, clinical trials of ebselen have demonstrated ar emarkable absence of toxicity [14] that cannot be assumed for newer,l ess rigorously tested organoselenium compounds. This has contributed to the popularity of ebselena sapotential drug candidate.W hile numerous mechanistic and optimization studies of ebselen and its analogues have been reported, [10] other types of compounds possessing covalent NÀSe bonds, [2e, 15] or pendant amino groups capable of coordination with the selenium center, [16] have also been investigated.…”

Section: Introductionmentioning

confidence: 99%

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

Sands

Tuck

Back

2018

Chemistry A European J

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Selenium compounds play an important role in redox homeostasis in living organisms. One of their major functions is to suppress the harmful effects of hydrogen peroxide, hydroperoxides and downstream reactive oxygen species that lead to oxidative stress, which has in turn been implicated in many diseases and degenerative conditions. The glutathione peroxidase (GPx) family of selenoenzymes plays a key protective role by catalyzing the reduction of peroxides with glutathione. Considerable effort has been expended toward the discovery of small-molecule selenium compounds that mimic GPx. To date, ebselen has been the most widely studied such compound, including in several clinical trials. However, despite its proven lack of significant toxicity, it displays only moderate catalytic activity and very poor aqueous solubility. The cyclic seleninate esters and spirodioxyselenuranes have recently been investigated as potential next generation GPx mimetics, along with structurally related selenenate esters, diazaselenuranes and pincer selenuranes. Their catalytic activities, redox mechanisms and structure-activity relationships are described in this Review, along with a description and discussion of the relative merits of assays for measuring their activities.

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Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 230 publications

References 24 publications

Structure of M^profrom COVID-19 virus and discovery of its inhibitors

Structure of M^profrom COVID-19 virus and discovery of its inhibitors

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

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Safety and efficacy of ebselen for the prevention of noise-induced hearing loss: a randomised, double-blind, placebo-controlled, phase 2 trial

Cited by 230 publications

References 24 publications

Structure of Mprofrom COVID-19 virus and discovery of its inhibitors

Structure of Mprofrom COVID-19 virus and discovery of its inhibitors

The role of the single interchains disulfide bond in tetanus and botulinum neurotoxins and the development of antitetanus and antibotulism drugs

Cyclic Seleninate Esters, Spirodioxyselenuranes and Related Compounds: New Classes of Biological Antioxidants That Emulate Glutathione Peroxidase

Contact Info

Product

Resources

About

Structure of M^profrom COVID-19 virus and discovery of its inhibitors

Structure of M^profrom COVID-19 virus and discovery of its inhibitors