Target discovery of ebselen with a biotinylated probe

Chen, Zhenzhen; Jiang, Zhongyao; Chen, Nan; Shi, Qian; Tong, Lili; Kong, Fanming; Cheng, Xiu‐Fen; Chen, Hao; Wang, Chu; Tang, Bo

doi:10.1039/c8cc04258f

Cited by 43 publications

(40 citation statements)

References 28 publications

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“…When Cys6 is present, however, a population of SOD1 molecules appear receptive to ligand binding within the β-barrel. This highlights the promiscuity of ebselen; an assessment of stable ebselen binding within cells indicated over 400 protein targets [86]. Furthermore, the selenylsulphide bond is prone to cleavage by cytoplasmic reductants unless it is protected.…”

Section: Ebselenmentioning

confidence: 99%

“…Furthermore, the selenylsulphide bond is prone to cleavage by cytoplasmic reductants unless it is protected. As a consequence stable cytoplasmic binding to SOD1 Cys111 has not been observed [84,86]. However, ebselen is a thiol oxidase and was able to catalyse formation of the SOD1 intra-subunit disulphide bond within cells in the absence of overexpressed hCCS [84].…”

Section: Ebselenmentioning

confidence: 99%

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Molecular and pharmacological chaperones for SOD1

Wright

2020

Biochemical Society Transactions

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The efficacy of superoxide dismutase-1 (SOD1) folding impacts neuronal loss in motor system neurodegenerative diseases. Mutations can prevent SOD1 post-translational processing leading to misfolding and cytoplasmic aggregation in familial amyotrophic lateral sclerosis (ALS). Evidence of immature, wild-type SOD1 misfolding has also been observed in sporadic ALS, non-SOD1 familial ALS and Parkinson's disease. The copper chaperone for SOD1 (hCCS) is a dedicated and specific chaperone that assists SOD1 folding and maturation to produce the active enzyme. Misfolded or misfolding prone SOD1 also interacts with heat shock proteins and macrophage migration inhibitory factor to aid folding, refolding or degradation. Recognition of specific SOD1 structures by the molecular chaperone network and timely dissociation of SOD1-chaperone complexes are, therefore, important steps in SOD1 processing. Harnessing these interactions for therapeutic benefit is actively pursued as is the modulation of SOD1 behaviour with pharmacological and peptide chaperones. This review highlights the structural and mechanistic aspects of a selection of SOD1-chaperone interactions together with their impact on disease models.

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Section: Ebselenmentioning

confidence: 99%

Section: Ebselenmentioning

confidence: 99%

Molecular and pharmacological chaperones for SOD1

Wright

2020

Biochemical Society Transactions

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“…The recent introduction of drug-derivatized xylosides is a development of this idea. Ebselen is a small molecule seleno-compound that interacts with several enzymes some of which are involved in GAG biosynthesis and is cytotoxic at elevated concentrations [74,88]. In a proof-of-concept study, the cytotoxicity in cancer cells of Ebselen-β-D-xyloside was found to exceed that of Ebselen alone.…”

Section: Gag Metabolic Enzymes As Targetmentioning

confidence: 99%

Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends

Ghiselli¹

2019

Medicines

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The polyanionic nature and the ability to interact with proteins with different affinities are properties of sulfated glycosaminoglycans (GAGs) that determine their biological function. In designing drugs affecting the interaction of proteins with GAGs the challenge has been to generate agents with high binding specificity. The example to emulated has been a heparin-derived pentasaccharide that binds to antithrombin-III with high affinity. However, the portability of this model to other biological situations is questioned on several accounts. Because of their structural flexibility, oligosaccharides with different sulfation and uronic acid conformation can display the same binding proficiency to different proteins and produce comparable biological effects. This circumstance represents a formidable obstacle to the design of drugs based on the heparin scaffold. The conceptual framework discussed in this article is that through a direct intervention on the heparin-binding functionality of proteins is possible to achieve a high degree of action specificity. This objective is currently pursued through two strategies. The first makes use of small molecules for which in the text we provide examples from past and present literature concerning angiogenic factors and enzymes. The second approach entails the mutagenesis of the GAG-binding site of proteins as a means to generate a new class of biologics of therapeutic interest.

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“…Considering the great demand for a simple and efficient method for both off‐ and on‐DNA C−H selenylation, and in continuation of our research program in DELs, we were interested in developing a new and versatile selenide reagent, and especially one that would allow introduction of multiple functional groups for diversification beyond selenylation. We envisaged that benzoselenazolone could meet these demands in that the N−Se bond is polarized and can be cleaved via nucleophilic attack by sulfhydryl and Grignard reagents . Moreover, the nucleophilic character of C(sp 2 )−Rh III species suggested a good probability of success .…”

Section: Introductionmentioning

confidence: 99%

A Chemistry for Incorporation of Selenium into DNA‐Encoded Libraries

Zhang

et al. 2020

Angewandte Chemie

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Conventional direct C−H selenylation suffers from simple selenation with limited atom economy and complicated reaction system. In this work, we designed benzoselenazolone as a novel bifunctional selenide reagent for both off‐ and on‐DNA C−H selenylation under rhodium(III) catalysis. We show that using benzoselenazolone allowed production of a series of selenylation products containing an adjacent aminoacyl group in a fast and efficient way, with high atom economy. The synthetic application of this method was demonstrated by taking advantage of the amide functionality as a nucleophile, directing group, and amide coupling partner. This work shows great potential in facilitating rapid construction of selenium‐containing DNA‐encoded chemical libraries (SeDELs), and lays the foundation for the development of selenium‐containing drugs.

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Target discovery of ebselen with a biotinylated probe

Cited by 43 publications

References 28 publications

Molecular and pharmacological chaperones for SOD1

Molecular and pharmacological chaperones for SOD1

Heparin Binding Proteins as Therapeutic Target: An Historical Account and Current Trends

A Chemistry for Incorporation of Selenium into DNA‐Encoded Libraries

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