OGA inhibition by GlcNAc-selenazoline

Kim, Sang Hyun; Love, Dona C.; Darout, Etzer; Abdo, Mohannad; Rempel, Brian P.; Withers, Stephen G.; Rablen, Paul R.; Hanover, John A.; Knapp, Spencer

doi:10.1016/j.bmc.2010.08.010

Cited by 18 publications

(8 citation statements)

References 49 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…In summary, tetravalent S - and Se -galactoclusters synthesized by click-chemistry were found to be suitable ligands of the lectin PA-IL in vitro, with significant, about 64 times better inhibitory activity than simple d -galactose. We can also conclude that enzymatically stable S - [ 32 ] and Se -interglycosidic linkages [ 17 , 18 ] do not influence the potency of ligands compared with the appropriate O -glycosides [ 12 ]. We could prove using STD-NMR techniques that the multivalent ligands compete with the natural ligand for the binding sites of the protein.…”

Section: Resultsmentioning

confidence: 99%

“…Selenium could be also potentially used as a trace for the selective detection of compounds in the biofluids [24]. A further advantage of the Se-interglycosidic linkage is its higher stability towards hydrolases [17,18].…”

Section: Synthesismentioning

confidence: 99%

“…They were synthesized for various purposes [ 13 ], exploiting the inherent potential of the selenium nucleus [ 14 ]. Selenoglycosides were used as glycosyl donors [ 15 ], for protein glycoconjugation in site-selective glycosylation by Se-S-mediated ligation [ 16 ], as enzyme inhibitors ( O -GlcNAcase [ 17 ] and as novel glycosidase inhibitors [ 18 ]). Mono- and divalent selenogalactosides and diselenide digalactosides proved to be potential ligands to biomedically relevant galactophilic lectins [ 19 ]; non-glycosidically linked Se -containing pseudodisaccharides were also synthesized as BanLec and ConA lectin ligands [ 20 ].…”

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Synthesis of Tetravalent Thio- and Selenogalactoside-Presenting Galactoclusters and Their Interactions with Bacterial Lectin PA-IL from Pseudomonas aeruginosa

et al. 2021

View full text Add to dashboard Cite

Synthesis of tetravalent thio- and selenogalactopyranoside-containing glycoclusters using azide-alkyne click strategy is presented. Prepared compounds are potential ligands of Pseudomonas aeruginosa lectin PA-IL. P. aeruginosa is an opportunistic human pathogen associated with cystic fibrosis, and PA-IL is one of its virulence factors. The interactions of PA-IL and tetravalent glycoconjugates were investigated using hemagglutination inhibition assay and compared with mono- and divalent galactosides (propargyl 1-thio- and 1-seleno-β-d-galactopyranoside, digalactosyl diselenide and digalactosyl disulfide). The lectin-carbohydrate interactions were also studied by saturation transfer difference NMR technique. Both thio- and seleno-tetravalent glycoconjugates were able to inhibit PA-IL significantly better than simple d-galactose or their intermediate compounds from the synthesis.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Synthesismentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Synthesis of Tetravalent Thio- and Selenogalactoside-Presenting Galactoclusters and Their Interactions with Bacterial Lectin PA-IL from Pseudomonas aeruginosa

et al. 2021

View full text Add to dashboard Cite

show abstract

“…[86] The selenium analogue of NGT, GlcNAc-selenazoline (8) demonstrated a 70-fold decrease in inhibitory activity for OGA due to steric clashes with the substrate carbonyl oxygen in the OGA active site. [87] The protonated form of NButGT has a pK a of 3.4. [81] As a result, in solution at a physiological pH of 7.4, NButGT is mostly present in a deprotonated form, thus weakening ionic interaction with the key catalytic Asp174 that facilitates the attack of the neighboring anomeric acetamido group.…”

Section: Pugnac and Other Related Derivativesmentioning

confidence: 99%

O‐GlcNAcase: Emerging Mechanism, Substrate Recognition and Small‐Molecule Inhibitors

2020

Self Cite

View full text Add to dashboard Cite

O‐GlcNAcylation is the dynamic and ubiquitous post‐translational glycosylation of nucleocytoplasmic proteins on serine/threonine residues; it is implicated in regulation of the cell cycle. This protein modification is mainly governed by a pair of enzymes: O‐GlcNAc transferase (OGT) adds the N‐acetylglucosamine moiety to acceptor proteins, and O‐GlcNAcase (OGA) hydrolyses the sugar moiety from protein acceptors. Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation to be investigated. However, the design of highly potent and selective inhibitors faces several challenges as no full structural data of human OGA has been discovered to date. Moreover, there are a number of mechanistically similar related enzymes such as β‐hexosaminidases (Hex), and the concomitant inhibition of these enzymes leads to undesirable lysosomal‐storage disorders. This review highlights recent insights into the structure of human O‐GlcNAcase and its isoforms. We focus on the catalytic mechanism and substrate recognition by OGA. In addition, it presents an updated overview of small‐molecule OGA inhibitors, with either carbohydrate or noncarbohydrate scaffolds. We discuss inhibitor structures, binding modes, and selectivity towards the enzyme, and potential outcomes in probing O‐GlcNAcylation at cellular levels.

show abstract

“…Zhang et al4 recently reported the chemical synthesis of selenazole-containing cyclic peptides (e.g., 3 ) and their application in X-ray diffraction studies of P-glycoprotein. 1,3-Selenazolines1a have also received attention in recent years,5 for example, Withers et al5a have reported the synthesis of a GlcNAc-derived 1,3-selenazole that was evaluated as a potential O -GlcNAcase inhibitor. Most synthetic routes to 1,3-selenazoles are based on the Hantzsch synthesis,1a, 5c, 6 although other methods have been investigated 7…”

mentioning

confidence: 99%