Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. Beginning with carbohydrate-based lead molecules, we pursued an optimization strategy of reducing polar surface area to align the desired drug-like properties of potency, selectivity, high … 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. Inhibition of O-GlcNAcase (OGA), the enzyme responsible for the removal of O-GlcNAc modification, has been shown to reduce tau pathology in several transgenic models. Epub 2020 Jun 3. 2012;7(4):e35277. and you may need to create a new Wiley Online Library account. Increases O-GlcNAc-modified protein levels (EC 50 = 30 nM). The inhibitors goblin1 (OGT bisubstrate-linked inhibitor 1; Figure 1) and goblin2 have been created by connecting an acceptor peptide to a UDP through a short linker that replaces the GlcNAc moiety. Epub 2019 Sep 10. When applied at nanomolar concentrations on live cells, these cell-penetrant molecules shift the Working off-campus? Properties. Inhibition of O -GlcNAcase (OGA), the enzyme that removes O -GlcNAc moieties, is a novel strategy to attenuate the formation of pathologic tau. O-GlcNAcase Inhibitors as Tools to Study O-GlcNAc Signaling The elucidation of the OGA catalytic mechanism has enabled the development of potent and selective inhibitors that have subsequently been used to study O-GlcNAcylation in cells and organisms. USA.gov. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. Brain Res Bull. Bukke VN, Villani R, Archana M, Wawrzyniak A, Balawender K, Orkisz S, Ferraro L, Serviddio G, Cassano T. Int J Mol Sci. 4 Epub 2016 Aug 4. We found that … 2020 Sep 21;26(53):12086-12100. doi: 10.1002/chem.202000155. HHS Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. Wang X, Li W, Marcus J, Pearson M, Song L, Smith K, Terracina G, Lee J, Hong KK, Lu SX, Hyde L, Chen SC, Kinsley D, Melchor JP, Rubins DJ, Meng X, Hostetler E, Sur C, Zhang L, Schachter JB, Hess JF, Selnick HG, Vocadlo DJ, McEachern EJ, Uslaner JM, Duffy JL, Smith SM. If you do not receive an email within 10 minutes, your email address may not be registered, (2010) Inhibition of O-GlcNAcase using a potent and cell-permeable inhibitor does not induce insulin resistance in 3T3-L1 adipocytes. Request PDF | O-GlcNAcase inhibitors | O-GlcN Acylation is a newly discovered protein post-translational modification on Ser/Thr. NIH 88 Biochemical Society Transactions (2016) Volume 44, part 1 O-GlcNAc transferase inhibitors: current tools and future challenges Riccardo Trapannone*1, Karim Rafie*1 and Daan M.F. O-GlcNAcylation is an essential posttranslational modification in metazoa. Please enable it to take advantage of the complete set of features! Novel non-carbohydrate O-GlcNAcase inhibitors with CNS drug properties as potential treatment for Alzheimer’s disease and tauopathies. Consistent with this proposal, 1,2-dideoxy-2′-methyl-α-d-glucopyranoso-[2,1-d]-Δ2′-thiazoline, an inhibitor that mimics the oxazoline intermediate proposed in the catalytic mechanism of family 20 glycoside hydrolases, is shown to act as a potent competitive inhibitor of both O-GlcNAcase (K I I = 0.070 μ m) and β-hexosaminidase (K = 0.070 μ m). doi: 10.1371/journal.pone.0035277. The Glucose Metabolic Pathway as A Potential Target for Therapeutics: Crucial Role of Glycosylation in Alzheimer's Disease. Potent, selective O-GlcNAcase inhibitor (K i = 21 nM). CNS Neurosci Ther. PUGNAc (CAS 132489-69-1) is an O-GlcNAcase (O-GlcNAc-β-N-acetylglucosaminidase) and β-hexosaminidase inhibitor (K i =46 and 36 nM, respectively). Protein O-GlcNAcase is an enzyme with systematic name -3-O--L-serine/threonine N-acetylglucosaminyl hydrolase. Epub 2020 Jul 20. Epub 2014 Apr 24. Chemical name . The reagent su Molecular Interrogation to Crack the Case of O-GlcNAc. General description The β-N-acetylglucosaminidase (OGA) gene encodes two alternatively spliced isoforms that are widely expressed in mammalian tissues.OGA (also known as O-GlcNAcase, MGEA5, NCOAT) belongs to the family of 84 glycoside hydrolases.The longer OGA form is a bifunctional nuclear/cytoplasmic enzyme that contains two distinct domains, an O-GlcNAcase domain at the N … The mechanisms mediating the neuroprotective effects of OGA inhibitors, however, remain poorly understood. eCollection 2019. IDO1 INHIBITOR Cancer ERK INHIBITOR Cancer DACRA-089 Diabetes BAFF/IL-17 Immunology IL-23/CGRP Immunology IL-2 CONJUGATE Immunology AUTOMATED INSULIN DELIVERY SYS Diabetes IL-33 MAB Immunology BASAL INSULIN-FC Diabetes TIM-3 MAB Cancer OXYNTOMODULIN Diabetes CXCR1/2L MAB Immunology AUR A KIN INH Cancer ABEMACICLIB HR+/HER2+MBC … van Aalten*†2 *Medical Research Council Protein Phosphorylation and Ubiquitylation Unit, College of Life Sciences, University of Dundee, Dundee DD1 5EH, U.K. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. Modulation of O-GlcNAc levels with small molecule inhibitors of O-GlcNAc hydrolase (OGA) is a useful strategy to probe the role of this modification in a range of cellular processes. These results strongly suggest that OGA inhibitors act within brain through a mechanism involving enhancement of autophagy, which aids the brain in combatting the accumulation of toxic protein species. 3 Induces insulin resistance in rat skeletal muscle. We focus on the catalytic mechanism and substrate recognition by OGA. Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation. Our study supports OGA inhibition being a feasible therapeutic strategy for hindering the progression of AD and other neurodegenerative diseases. This site needs JavaScript to work properly. Orally active. O-GlcNAcylation is a post-translational modification consisting of the addition of a single N-acetyl-glucosamine residue (GlcNAc) to specific serine/threonine residues of proteins.The addition of GlcNAc has been compared to phosphorylation, and there may be significant interplay between the two … We have painstakingly mapped out these targets for your convenience, so that you may quickly and painlessly find and decide the right inhibitor for your work. Kuang H, Tan CY, Tian HZ, Liu LH, Yang MW, Hong FF, Yang SL. Can use p-nitrophenyl-beta-GlcNAc and 4-methylumbelliferone-GlcNAc as substrates but not p-nitrophenyl-beta-GalNAc or p-nitrophenyl-alpha-GlcNAc (in vitro) (PubMed:11148210). COVID-19 is an emerging, rapidly evolving situation. 2014 Oct 7;43(19):6839-58. doi: 10.1039/c4cs00038b. ABSTRACT: Inhibition of O-GlcNAcase (OGA) has emerged as a promising therapeutic approach to treat tau pathology in neurodegenerative diseases such as Alzheimer’s disease and progressive supranuclear palsy. These compounds exhibited low micromolar affinity for OGT and inhibited O-GlcNAcylation of peptides and protein substrates in vitro (IC 50 =18 μM for goblin1) [ 44 ]. Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds Helge C. Dorfmueller, Daan M.F. Beginning with carbohydrate-based lead molecules, we … Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice | springermedizin.de Skip to main content O-GLCNACASE Inhibitors The Biocompare Inhibitor Search lets researchers browse thousands of compounds by searching not only by inhibitor name, but also by its target enzyme. Alzheimer’s disease; O-GlcNAc; Thiamet-G; autophagy; glycosylation; neurodegeneration. Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Chemical structure. This review highlights recent insights into the structure of human O‐GlcNAcase and its isoforms. Learn about our remote access options, Center for Neuro-Medicine Brain Science Institute, Korea Institutes of Science and Technology, Seoul, 02792 (Republic of Korea, Division of Bio-Med KIST school, Korea University of Science and Technology (UST), Gajungro 217 Youseong-gu, Daejeon (Republic of, Korea, Daegu University, Department of Science Education-Chemistry, Gyeongsan-si, Gyeongsangbuk-do, Gyeongbuk, 38453 (Republic of Korea. NLM Hastings NB, Wang X, Song L, Butts BD, Grotz D, Hargreaves R, Fred Hess J, Hong KK, Huang CR, Hyde L, Laverty M, Lee J, Levitan D, Lu SX, Maguire M, Mahadomrongkul V, McEachern EJ, Ouyang X, Rosahl TW, Selnick H, Stanton M, Terracina G, Vocadlo DJ, Wang G, Duffy JL, Parker EM, Zhang L. Mol Neurodegener. 2017 Jul;133:80-87. doi: 10.1016/j.brainresbull.2016.08.002. For the biopharma industry investment, business development and competitive intelligence professionals who require information to support financing, partnering and licensing activities, BCIQ provides accurate information and context to support profitable and strategic decision making. Here we show, using a range of methods in neuroblastoma N2a cells, in primary rat neurons, and in mouse brain, that selective OGA inhibitors stimulate autophagy through an mTOR-independent pathway without obvious toxicity. Moreover, O-GlcNAc is implicated in various diseases including cancers, diabetes, cardiac dysfunction, and neurodegenerative diseases. Here, we show that Thiamet‐G, a highly selective pharmacological agent that inhibits the glycoside hydrolase O‐GlcNAcase (OGA), blunts the cellular uptake of α‐syn fibrils. 2 Protects cardiac function after trauma-hemorrhage which is mediated by increased protein O-GlcNAc levels. 108155 Ensembl ENSG00000147162 ENSMUSG00000034160 UniProt O15294 Q8CGY8 RefSeq (mRNA) NM_003605 NM_181672 NM_181673 NM_001290535 NM_139144 RefSeq (protein) NP_858058 NP_858059 NP_001277464 NP_631883 Location (UCSC) Chr X: 71.53 – 71.58 Mb Chr X: 101.64 – 101.68 Mb PubMed search Wikidata View/Edit Human View/Edit Mouse Protein O -GlcNAc … Inhibition of O-GlcNAcase leads to elevation of O-GlcNAc tau and reduction of tauopathy and cerebrospinal fluid tau in rTg4510 mice. Keywords: | CAS Number. Yu Y, Zhang L, Li X, Run X, Liang Z, Li Y, Liu Y, Lee MH, Grundke-Iqbal I, Iqbal K, Vocadlo DJ, Liu F, Gong CX. Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation … O-GlcNAc and neurodegeneration: biochemical mechanisms and potential roles in Alzheimer's disease and beyond. Macauley MS, He Y, Gloster TM, Stubbs KA, Davies GJ, et al. Does not bind acetyl-CoA and does not have histone acetyltransferase activity (PubMed:24088714). Modulation of O-GlcNAcylation Regulates Autophagy in Cortical Astrocytes. Irregular O‐GlcNAcylation is linked to several diseases including cancer, diabetes and neurodegeneration. Clarifying the underlying mechanism by which OGA inhibition leads to the reduction of pathological tau and identifying translatable measures to guide human dosing and efficacy determination would significantly facilitate … 1009816-48-1. 2020 Oct 19;21(20):7739. doi: 10.3390/ijms21207739. These data have stimulated interest in the possibility of using OGA-selective inhibitors as pharmaceuticals to alter the progression of AD. This enzyme catalyses the removal of the O-GlcNAc post-translational modification in the following chemical reaction: -3-O--L-serine + H2O ⇌ -L-serine + N-acetyl-D-glucosamine -3-O--L-threonine + H2O ⇌ -L-threonine + N-acetyl-D-glucosamine In vitro, this compound is a potent inhibitor of the human OGA enzyme with comparable activity against the corresponding … Cleaves GlcNAc but not GalNAc from O-glycosylated proteins. A widely used tool for increasing cellular levels of O-GlcNAc. We discuss inhibitor structures, binding modes, and selectivity towards the enzyme, and potential outcomes in probing O‐GlcNAcylation at cellular levels. 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. Blocks tau phosphorylation. Drug design targeting active posttranslational modification protein isoforms. | Accumulation of hyperphosphorylated tau, a microtubule-associated protein, plays an important role in the progression of Alzheimer disease. Chem Soc Rev. In this study, we injected thiamet-G into the lateral ventricle of mice to increase O-GlcNAcylation of proteins and investigated the resulting effects on site-specific tau phosphorylation. An O-GlcNAcase-specific inhibitor and substrate are engineered by the extension of the N-Acetyl Moiety of O-(2-acet-amido-2-deoxy-D-glucopyranosylidene)amino-N-phenylcarbamate (PUGNAc). European Journal of Pharmaceutical Sciences. Shows antitauopathic effects in vivo. O-GlcNAcase Inhibitor Alzheimer's Oxyntomodulin Diabetes PACAP38 Antibody Pain PD-1 Antibody Agonist Immunology ... Lilly defines First Human Dose as the date of the first dose administered in the initial clinical study of the molecule given to healthy volunteers. Blood-brain barrier permeable. Recently, the discovery of small‐molecule OGA inhibitors has enabled the physiological function of O‐GlcNAcylation to be investigated. O-GLCNACASE INH Alzheimer’s GGG TRI-AGONIST Diabetes CDK7 INHIBITOR Cancer CONNECTED CARE PREFILLED INSULIN PEN Diabetes GLP-1R NPA Diabetes TRPA1 ANTAGONIST Pain SSTR4 AGONIST Pain D1 PAM II Dementia ANGPTL3/8 MAB CVD SERD Cancer TIRZEPATIDE Obesity LEBRIKIZUMAB Atopic Dermatitis SELPERCATINIB 1L Med Thyroid Cancer SELPERCATINIB 1L … Would you like email updates of new search results? Here, we report the pharmacokinetics of … National Center for Biotechnology Information, Unable to load your collection due to an error, Unable to load your delegates due to an error. 2019 Nov 13;2019:6279313. doi: 10.1155/2019/6279313. Clipboard, Search History, and several other advanced features are temporarily unavailable. Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer’s disease (AD) mouse models manifesting either tau or amyloid pathology. Moreover, these data suggest more targeted strategies to stimulate autophagy in an mTOR-independent manner may be found within the O-GlcNAc pathway. Inhibitors of O-GlcNAcase, the enzyme removing O-GlcNAc, are useful tools for studying the role of O-GlcNAc in a range of cellular processes. Additionally, OGA inhibition significantly decreased the levels of toxic protein species associated with AD pathogenesis in the JNPL3 tauopathy mouse model as well as the 3×Tg-AD mouse model. Get the latest public health information from CDC: https://www.coronavirus.gov, Get the latest research information from NIH: https://www.nih.gov/coronavirus, Find NCBI SARS-CoV-2 literature, sequence, and clinical content: https://www.ncbi.nlm.nih.gov/sars-cov-2/. Number of times cited according to CrossRef: Biological evaluation and molecular modeling of peptidomimetic compounds as inhibitors for O-GlcNAc transferase (OGT). Use the link below to share a full-text version of this article with your friends and colleagues. O-GlcNAc is involved in diverse cellular processes ranging from the regulation of gene expression to stress response. These findings should aid the advancement of OGA inhibitors within the clinic. Thiamet-G is a recently synthesized potent OGA inhibitor, and initial studies suggest it can influence O-GlcNAc levels in the brain, allowing OGA inhibition to be a potential route to altering disease progression in AD. Animal studies suggest that one strategy for treating Alzheimer disease and related tauopathies may be inhibition of O -GlcNAcase (OGA), which may subsequently decrease pathologic tau phosphorylation. NCI CPTC Antibody Characterization Program. 2020 Feb;26(2):155-166. doi: 10.1111/cns.13216. For the biopharma industry investment, business development and competitive intelligence professionals who require information to support financing, partnering and licensing activities, BCIQ provides accurate information and context to support profitable and strategic decision making. 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. We find that short OGA, which possesses O-GlcNAcase catalysis machinery like that of long OGA, exhibits comparative resistance to previously described potent inhibitors of long OGA and lysosomal hexosaminidases, including PUGNAc and NAG-thiazoline, suggesting a role for the HAT domain in O-GlcNAcase catalysis. | Acutely elevated O-GlcNAcylation suppresses hippocampal activity by modulating both intrinsic and synaptic excitability factors. PLoS One. 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. van Aalten* Division of Molecular Microbiology, College of Life Sciences, University of Dundee, Dundee DD1 5EH, Scotland, UK article info Article history: Received 16 October 2009 Revised 1 December 2009 Accepted 13 December 2009 Available online 16 December 2009 Edited by Judit … Pharmacological inhibition of O-GlcNAcase (OGA), the sole enzyme that removes O-GlcNAc, reproducibly slows neurodegeneration in various Alzheimer's disease (AD) mouse models manifesting either tau or amyloid pathology. Learn more. Exploring the bi-directional relationship between autophagy and Alzheimer's disease. Here we described the in vitro and in vivo pharmacological properties of a novel and selective OGA inhibitor, MK-8719. OGA is encoded by the MGEA5 gene. Estevez A, Zhu D, Blankenship C, Jiang J. Chemistry. Chem Biol 17: 937–948. Epub 2012 Apr 19. 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. Wani WY, Chatham JC, Darley-Usmar V, McMahon LL, Zhang J. View Article Google Scholar 41. We report the discovery of nanomolar OGA inhibitors that are up to 900,000-fold selective over the related lysosomal hexosaminidases. This effect correlates with increased nucleocytoplasmic levels of O ‐linked N ‐acetylglucosamine ( O ‐GlcNAc)‐modified proteins, and genetic knockdown of OGA expression closely phenocopies both these effects. Please check your email for instructions on resetting your password. Sci Rep. 2019 May 13;9(1):7287. doi: 10.1038/s41598-019-43017-9. The mechanisms mediating the neuroprotective effects of OGA inhibitors, … Enter your email address below and we will send you your username, If the address matches an existing account you will receive an email with instructions to retrieve your username, orcid.org/http://orcid.org/0000-0001-6339-1190, I have read and accept the Wiley Online Library Terms and Conditions of Use. The glycosylation of nucleocytoplasmic proteins with O-linked N-acetylglucosamine residues (O-GlcNAc) is conserved among metazoans and is particularly abundant within brain. In addition, it presents an updated overview of small‐molecule OGA inhibitors, with either carbohydrate or noncarbohydrate scaffolds. J Pharmacol Exp Ther. Oxid Med Cell Longev. In order to identify new human O‐GlcNAcase inhibitors, a high‐throughput screening assay was performed based on the release of 4‐methylumbelliferol (4MU) from the pseudo substrate 4MU‐GlcNAc, initially using the bacterial OGA homologue from C. perfringens (CpOGA) which has recently been shown to be a good model of hOGA . 2020 Aug;374(2):252-263. doi: 10.1124/jpet.120.266122. 2017 May 18;12(1):39. doi: 10.1186/s13024-017-0181-0. The available inhibitors … O-GlcNAcylation: New Tools to Investigate this Important Post-Translational Modification. , Chatham JC, Darley-Usmar V, McMahon LL, Zhang J 53 ):12086-12100. doi: 10.1111/cns.13216 noncarbohydrate. After trauma-hemorrhage which is mediated by increased protein O-GlcNAc levels enzyme removing O-GlcNAc, are useful tools studying... Metazoans and is particularly abundant within brain findings should aid the advancement of OGA inhibitors, however, poorly!, diabetes and neurodegeneration of an O-GlcNAcase inhibitor scaffolds Helge C. 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