Cell-Penetrant, Nanomolar O-GlcNAcase Inhibitors Selective against Lysosomal Hexosaminidases

Dorfmueller, Helge C.; Borodkin, Vladimir S.; Schimpl, M.; Zheng, Xiaowei; Kime, Robert; Read, Kevin D.; Aalten, Daan M. F. van

doi:10.1016/j.chembiol.2010.09.014

Cited by 52 publications

(73 citation statements)

References 25 publications

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“…Incorporation of the phenethyl group as an aglycon mimic and exploitation of the same active site pocket as NButGT have led to nanomolar and highly selective inhibitors of OGA including GlcNAcstatin C (27; Fig. 3c,d) 48,49 . In summary, bioavailable carbohydrate-based inhibitors of OGA are available, and class promiscuity is being addressed.…”

Section: Review Articlementioning

confidence: 99%

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

2012

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Glycoconjugates are ubiquitous biomolecules found in all kingdoms of life. These diverse structures are metabolically responsive and occur in a cell line- and protein-specific manner, conferring tissue type-specific properties. Glycans have essential roles in diverse processes, including, for example, intercellular signaling, inflammation, protein quality control, glucohomeostasis and cellular adhesion as well as cell differentiation and proliferation. Many mysteries remain in the field, however, and uncovering the physiological roles of various glycans remains a key pursuit. Realizing this aim necessitates the ability to subtly and selectively manipulate the series of different glycoconjugates both in cells and in vivo. Selective small-molecule inhibitors of glycan processing enzymes hold great potential for such manipulation as well as for determining the function of 'orphan' carbohydrate-processing enzymes. In this review, we discuss recent advances and existing inhibitors, the prospects for small-molecule inhibitors and the challenges associated with generating high-quality chemical probes for these families of enzymes. The coordinated efforts of chemists, biochemists and biologists will be crucial for creating and characterizing inhibitors that are useful tools both for advancing a basic understanding of glycobiology in mammals as well as for validating new potential therapeutic targets within this burgeoning field.

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Section: Review Articlementioning

confidence: 99%

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

2012

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“…GlcNAcstatins, following a similar structure to PUGNAc, were developed to have higher selectivity to human OGA 66 . These proved to penetrate the cell and increase global O-GlcNAcylation 2–3 fold but at the cost of low solubility in aqueous solutions 67 . Yuzwa et al mimicked electrostatic interactions that occur once the bicyclic oxazoline intermediate forms during the reaction mechanism of OGA with another inhibitor called Thiamet G 53, 68 .…”

Section: Regulation Of O-glcnacmentioning

confidence: 99%

O-GlcNAc and the cardiovascular system

Dassanayaka¹,

Jones²

2014

Pharmacology & Therapeutics

120

105

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The cardiovascular system is capable of robust changes in response to physiologic and pathologic stimuli through intricate signaling mechanisms. The area of metabolism has witnessed a veritable renaissance in the cardiovascular system. In particular, the post-translational β-O-linkage of N-acetylglucosamine (O-GlcNAc) to cellular proteins represents one such signaling pathway that has been implicated in the pathophysiology of cardiovascular disease. This highly dynamic protein modification may induce functional changes in proteins and regulate key cellular processes including translation, transcription, and cell death. In addition, its potential interplay with phosphorylation provides an additional layer of complexity to post-translational regulation. The hexosamine biosynthetic pathway generally requires glucose to form the nucleotide sugar, UDP-GlcNAc. Accordingly, O-GlcNAcylation may be altered in response to nutrient availability and cellular stress. Recent literature supports O-GlcNAcylation as an autoprotective response in models of acute stress (hypoxia, ischemia, oxidative stress). Models of sustained stress, such as pressure overload hypertrophy, and infarct-induced heart failure, may also require protein O-GlcNAcylation as a partial compensatory mechanism. Yet, in models of Type II diabetes, O-GlcNAcylation has been implicated in the subsequent development of vascular, and even cardiac, dysfunction. This review will address this apparent paradox and discuss the potential mechanisms of O-GlcNAc-mediated cardioprotection and cardiovascular dysfunction. This discussion will also address potential targets for pharmacologic interventions and the unique considerations related to such targets.

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“…Subsequent queries into the N-acetyl chemical space helped generate a highly specific hOGA inhibitor designated GlcNAcstatin G. This particular derivative showed a 9 × 10 5 fold increased selectivity towards the human isoform compared to Hex A/B with Ki of about 5 nM. 44 These derivatives were also shown to be cell-penetrant and increased overall cellular O-GlcNAcylation by 2 to 3-fold when treated for 6 hours.…”

Section: O-glcnac As a Chemical Modification – Chemistry Of The Camentioning

confidence: 99%

Chemical approaches to study O-GlcNAcylation

2013

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The enzymatic addition of a single β-D-N-acetylglucosamine sugar molecule on serine and/or threonine residues of protein chains is referred to as O-GlcNAcylation. This novel form of post-translational modification, first reported in 1984, is extremely abundant on nuclear and cytoplasmic proteins and has site specific cycling dynamics comparable to that of protein-phosphorylation. A nutrient and stress sensor, O-GlcNAc abnormalities underlie insulin resistance and glucose toxicity in diabetes, neurodegenerative disorders and dysregulation of tumor suppressors and oncogenic proteins in cancer. Recent advances have helped understand the biochemical mechanisms of GlcNAc addition and removal and have opened the door to developing key inhibitors towards this type of protein modification. Advanced methods in detecting and measuring O-GlcNAcylation have assisted in delineating its biological roles in a variety of cellular processes and diseased states. Availability of facile glycomic techniques are allowing for the exponential growth in the study of protein O-GlcNAacylation and are helping to elucidate key biological roles of this novel PTM.

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Cell-Penetrant, Nanomolar O-GlcNAcase Inhibitors Selective against Lysosomal Hexosaminidases

Cited by 52 publications

References 25 publications

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

O-GlcNAc and the cardiovascular system

Chemical approaches to study O-GlcNAcylation

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