Monitoring glycosidase activity for clustered sugar substrates, a study on β-glucuronidase

Brissonnet, Yoan; Compain, Guillaume; Renoux, Brigitte; Krammer, Eva-Maria; Daligault, Franck; Deniaud, David; Papot, Sébastien; Gouin, Sébastien G.

doi:10.1039/c9ra08847d

Cited by 5 publications

(3 citation statements)

References 43 publications

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“…The increasing awareness of the multilateral character of (hetero)multivalency, with additional reports expanding the range of MEI responsive glycosidases 235,236 and extending the generalized multivalent effect to the glycosyltransferase enzyme category [237][238][239] and anti-carbohydrate antigen antibodies, 240 will likely fuel research in carbohydrate supramolecular chemistry with a new perspective. The current embodiments exploiting the heteromultivalent effect to reach optimal cell targeting in vivo 76 and multivalent inhibitors to regulate the activity of diseaseassociated enzymes, e.g.…”

Section: Conclusion and Future Outlookmentioning

confidence: 99%

Carbohydrate supramolecular chemistry: beyond the multivalent effect

2020

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It has been amply constated that sugar ligand multivalency increases lectin-binding avidities dramatically, thereby modulating the capacity of carbohydrates to participate in supramolecular recognition processes involving transfer of biological information. The importance of this concept, the multivalent or glycoside cluster effect, in cell biology in general and in the glycosciences in particular is reflected in the ever-growing number of papers in the field. An impressive range of glycoarchitectures has been conceived to imitate the glycan coating of cells (the glycocalyx) in order to target complementary lectin receptors. However, these models rarely address the heterogeneity and the fluidity of the densely glycosylated cell membrane. They also disregard the impact that high-density nanosized arrangements could have in their interactions with the whole spectrum of carbohydrate-interacting proteins, among which glycosidases are notable representatives. For many years it has been tacitly assumed that:(i) efficient recognition by lectins generally requires high densities of the putative primary ligand and (ii) the mechanisms governing binding of a carbohydrate motif by a lectin or a glycosidase are totally disparate.Notwithstanding, an increasing amount of evidence seriously questions this paradigm. First, it was shown that secondary ''innocent'' ligands can play important roles in the recognition of heteroglycocluster constructs by lectins through synergistic or antagonistic contributions, a phenomenon termed the heterocluster effect. Second, the existence of multivalent effects in the inhibition of certain glycosidases by glycomimetic-and, even more disturbing, glyco-coated architectures (multivalent enzyme inhibition) was demonstrated. These observations call for a generalized multivalent effect governing the supramolecular chemistry of carbohydrate or glycomimetic structures in a biological context, with (hetero)multivalency acting as a multimodal switcher to drive the encoded information through different pathways. In this Feature Article we review the advancements made in the last few years in our understanding of the mechanisms underpinning the generalized multivalent effect, with an emphasis on the potential risks and opportunities derived from (hetero)multivalency-elicited promiscuity.

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Section: Conclusion and Future Outlookmentioning

confidence: 99%

Carbohydrate supramolecular chemistry: beyond the multivalent effect

2020

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“…FimH LEctPROFILE kit assays from GLYcoDiag (Orléans, France) were performed according to GlycoDiag’s protocol already described [ 60 , 61 , 62 ]. Briefly, the interaction profiles of each compound were determined through a competitive inhibition assay based on the inhibition by the compounds of the interaction between FimH lectin coated onto the microplate surface and a biotinylated neoglycoprotein NeoM (Man-BSA) as a tracer.…”

Section: Methodsmentioning

confidence: 99%

Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists

et al. 2023

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Selective antiadhesion antagonists of Uropathogenic Escherichia coli (UPEC) type-1 Fimbrial adhesin (FimH) are attractive alternatives for antibiotic therapies and prophylaxes against acute or recurrent urinary tract infections (UTIs) caused by UPECs. A rational small library of FimH antagonists based on previously described C-linked allyl α-D-mannopyranoside was synthesized using Heck cross-coupling reaction using a series of iodoaryl derivatives. This work reports two new members of FimH antagonist amongst the above family with sub nanomolar affinity. The resulting hydrophobic aglycones, including constrained alkene and aryl groups, were designed to provide additional favorable binding interactions with the so-called FimH “tyrosine gate”. The newly synthesized C-linked glycomimetic antagonists, having a hydrolytically stable anomeric linkage, exhibited improved binding when compared to previously published analogs, as demonstrated by affinity measurement through interactions by FimH lectin. The crystal structure of FimH co-crystallized with one of the nanomolar antagonists revealed the binding mode of this inhibitor into the active site of the tyrosine gate. In addition, selected mannopyranoside constructs neither affected bacterial growth or cell viability nor interfered with antibiotic activity. C-linked mannoside antagonists were effective in decreasing bacterial adhesion to human bladder epithelial cells (HTB-9). Therefore, these molecules constituted additional therapeutic candidates’ worth further development in the search for potent anti-adhesive drugs against infections caused by UPEC.

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“…β-Glucuronidase (GLU), lysosomal glycosidase, is an important biologically active protease that exists in the human body. − GLU is mainly involved in the degradation of glycosaminoglycans containing glucuronides and is related to a variety of pathophysiological conditions in the organism. , In addition, GLU is also a tumor biomarker, and the active expression of GLU is closely related to tumor cell invasion, apoptosis, metastasis, and proliferation. − Studies have shown that, compared with normal liver cells when liver cells become cancerous, the activity of GLU in liver tissues is significantly enhanced. − In the normal liver detoxification process, toxic substances are combined with glucuronides under the action of uridine 5′-diphospho-glucuronosyltransferase to form hydrophilic substances that are eliminated from the body. − In contrast, in cancerous liver cells, the overexpression of GLU will cause glucuronides to be overly decomposed and lose their ability to bind to harmful substances. , In the end, it is difficult for the organism to exclude the hydrophobic harmful substances from the body and the long-term accumulation of toxic substances in the organism results in the body’s pathological changes. ,,− This is also an important reason why GLU has become a target for real-time monitoring and the early diagnosis of liver cancer. Therefore, developing a method to accurately detect and analyze GLU is the problem that researchers must solve.…”

Section: Introductionmentioning

confidence: 99%

A Novel Fluorescent Probe Strategy Activated by β-Glucuronidase for Assisting Surgical Resection of Liver Cancer

Wang

Zhang

et al. 2022

Anal. Chem.

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Liver cancer is a primary malignant tumor with a very high fatality rate, which has seriously threatened human health and life. In normal hepatocellular lesions, β-glucuronidase (GLU) activity in liver cancer tissues is significantly increased. Therefore, GLU has become one of the important biomarkers of primary liver cancer. Here, a series of fluorescent probes (DCDH, DCDCH 3 , DCDOCH 3 , and DCDNO 2 ) for early diagnosis of liver cancer and auxiliary surgical resection were successfully synthesized. Since the electron-withdrawing group −NO 2 connected to the probe DCDNO 2 accelerates the rapid cleavage of the glycosidic bond, DCDNO 2 exhibits superior fluorescence properties that are more sensitive and rapid than the other three probes DCDH, DCDCH 3 , and DCDOCH 3 when detecting GLU. DCDNO 2 has been well-applied in real-time fluorescent visualization imaging for the detection of GLU activity in liver cancer cells and tumor tissues. In addition, DCDNO 2 has also been successfully used in the early diagnosis of liver cancer and real-time imaging to guide the surgical resection of liver cancer tumors. Therefore, DCDNO 2 has great potential for development in bioclinical medicine for the early detection and treatment of liver cancer.

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Monitoring glycosidase activity for clustered sugar substrates, a study on β-glucuronidase

Abstract: Enzymatically-triggered probes to determine glucuronidase hydrolysis kinetics for clustered substrates.

Cited by 5 publications

References 43 publications

Carbohydrate supramolecular chemistry: beyond the multivalent effect

Carbohydrate supramolecular chemistry: beyond the multivalent effect

Insightful Improvement in the Design of Potent Uropathogenic E. coli FimH Antagonists

A Novel Fluorescent Probe Strategy Activated by β-Glucuronidase for Assisting Surgical Resection of Liver Cancer

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