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Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology

Nature Chemical Biology volume 8, pages 683–694 (2012)Cite this article

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Abstract

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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Figure 1: Glycoside hydrolases have distinctive active site topologies that contain hydrophobic patches and in most cases use well-characterized mechanisms.
Figure 2: The proposed transition state structure for cleavage catalyzed by glycoside hydrolases is mimicked by various classes of carbohydrate-based inhibitors.
Figure 3: Exo- and endo-acting glycoside hydrolases can be inhibited by carbohydrate-based and medicinal chemistry–based inhibitors.
Figure 4: Proposed mechanisms for metal-independent glycosyltransferases, inhibitors of glycosyltransferases and the different approaches used to inhibit these enzymes in cells.
Figure 5: The active site structures of glycosyltransferases have complex topologies and can show structural rearrangement on binding of ligands.

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References

  1. Feizi, T. Demonstration by monoclonal antibodies that carbohydrate structures of glycoproteins and glycolipids are onco-developmental antigens. Nature 314, 53–57 (1985).

    Article  CAS  PubMed  Google Scholar 

  2. Partridge, E.A. et al. Regulation of cytokine receptors by Golgi N-glycan processing and endocytosis. Science 306, 120–124 (2004).

    Article  CAS  PubMed  Google Scholar 

  3. Da Silva, J.S., Hasegawa, T., Miyagi, T., Dotti, C.G. & Abad-Rodriguez, J. Asymmetric membrane ganglioside sialidase activity specifies axonal fate. Nat. Neurosci. 8, 606–615 (2005).

    Article  CAS  PubMed  Google Scholar 

  4. Sackstein, R. et al. Ex vivo glycan engineering of CD44 programs human multipotent mesenchymal stromal cell trafficking to bone. Nat. Med. 14, 181–187 (2008).

    Article  CAS  PubMed  Google Scholar 

  5. Reichner, J.S., Helgemo, S.L. & Hart, G.W. Recycling cell surface glycoproteins undergo limited oligosaccharide reprocessing in LEC1 mutant Chinese hamster ovary cells. Glycobiology 8, 1173–1182 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Määttänen, P., Gehring, K., Bergeron, J.J. & Thomas, D.Y. Protein quality control in the ER: the recognition of misfolded proteins. Semin. Cell Dev. Biol. 21, 500–511 (2010).

    Article  PubMed  CAS  Google Scholar 

  7. Kornfeld, S. Trafficking of lysosomal enzymes. FASEB J. 1, 462–468 (1987).

    Article  CAS  PubMed  Google Scholar 

  8. Moloney, D.J. et al. Fringe is a glycosyltransferase that modifies Notch. Nature 406, 369–375 (2000).

    Article  CAS  PubMed  Google Scholar 

  9. Phillips, M.L. et al. ELAM-1 mediates cell adhesion by recognition of a carbohydrate ligand, sialyl-LeX. Science 250, 1130–1132 (1990).

    Article  CAS  PubMed  Google Scholar 

  10. Ohtsubo, K. et al. Dietary and genetic control of glucose transporter 2 glycosylation promotes insulin secretion in suppressing diabetes. Cell 123, 1307–1321 (2005).

    Article  CAS  PubMed  Google Scholar 

  11. Frye, S.V. The art of the chemical probe. Nat. Chem. Biol. 6, 159–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  12. Abad-Zapatero, C. Ligand efficiency indices for effective drug discovery. Expert Opin. Drug Discov. 2, 469–488 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Leeson, P.D. & Springthorpe, B. The influence of drug-like concepts on decision-making in medicinal chemistry. Nat. Rev. Drug Discov. 6, 881–890 (2007).

    Article  CAS  PubMed  Google Scholar 

  14. Cantarel, B.L. et al. The Carbohydrate-Active EnZymes database (CAZy): an expert resource for glycogenomics. Nucleic Acids Res. 37, D233–D238 (2009).

    Article  CAS  PubMed  Google Scholar 

  15. Vocadlo, D.J. & Davies, G.J. Mechanistic insights into glycosidase chemistry. Curr. Opin. Chem. Biol. 12, 539–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  16. Mader, M.M. & Bartlett, P.A. Binding energy and catalysis: the implications for transition-state analogs and catalytic antibodies. Chem. Rev. 97, 1281–1302 (1997).

    Article  CAS  PubMed  Google Scholar 

  17. Gloster, T.M. & Davies, G.J. Glycosidase inhibition: assessing mimicry of the transition state. Org. Biomol. Chem. 8, 305–320 (2010).

    Article  CAS  PubMed  Google Scholar 

  18. Gloster, T.M. et al. Glycosidase inhibition: an assessment of the binding of eighteen putative transition-state mimics. J. Am. Chem. Soc. 129, 2345–2354 (2007).

    Article  CAS  PubMed  Google Scholar 

  19. Tropak, M.B., Blanchard, J.E., Withers, S.G., Brown, E.D. & Mahuran, D. High-throughput screening for human lysosomal b-N-acetyl hexosaminidase inhibitors acting as pharmacological chaperones. Chem. Biol. 14, 153–164 (2007).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  20. Cole, D.C. et al. Identification and characterization of acidic mammalian chitinase inhibitors. J. Med. Chem. 53, 6122–6128 (2010).

    Article  CAS  PubMed  Google Scholar 

  21. Zheng, W. et al. Three classes of glucocerebrosidase inhibitors identified by quantitative high-throughput screening are chaperone leads for Gaucher disease. Proc. Natl. Acad. Sci. USA 104, 13192–13197 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Nahoum, V. et al. Crystal structures of human pancreatic a-amylase in complex with carbohydrate and proteinaceous inhibitors. Biochem. J. 346, 201–208 (2000).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  23. Qin, X. et al. Structures of human pancreatic a-amylase in complex with acarviostatins: implications for drug design against type II diabetes. J. Struct. Biol. 174, 196–202 (2011).

    Article  CAS  PubMed  Google Scholar 

  24. Tarling, C.A. et al. The search for novel human pancreatic a-amylase inhibitors: high-throughput screening of terrestrial and marine natural product extracts. ChemBioChem 9, 433–438 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Kageyama, S., Nakamichi, N., Sekino, H. & Nakano, S. Comparison of the effects of acarbose and voglibose in healthy subjects. Clin. Ther. 19, 720–729 (1997).

    Article  CAS  PubMed  Google Scholar 

  26. Madar, Z. The effect of acarbose and miglitol (BAY-M-1099) on postprandial glucose levels following ingestion of various sources of starch by nondiabetic and streptozotocin-induced diabetic rats. J. Nutr. 119, 2023–2029 (1989).

    Article  CAS  PubMed  Google Scholar 

  27. Sim, L. et al. Structural basis for substrate selectivity in human maltase-glucoamylase and sucrase-isomaltase N-terminal domains. J. Biol. Chem. 285, 17763–17770 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Benalla, W., Bellahcen, S. & Bnouham, M. Antidiabetic medicinal plants as a source of alpha glucosidase inhibitors. Curr. Diabetes Rev. 6, 247–254 (2010).

    Article  CAS  PubMed  Google Scholar 

  29. Parenti, G. Treating lysosomal storage diseases with pharmacological chaperones: from concept to clinics. EMBO Mol. Med. 1, 268–279 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  30. Sawkar, A.R. et al. Chemical chaperones increase the cellular activity of N370S b-glucosidase: a therapeutic strategy for Gaucher disease. Proc. Natl. Acad. Sci. USA 99, 15428–15433 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Steet, R.A. et al. The iminosugar isofagomine increases the activity of N370S mutant acid beta-glucosidase in Gaucher fibroblasts by several mechanisms. Proc. Natl. Acad. Sci. USA 103, 13813–13818 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Khanna, R. et al. The pharmacological chaperone isofagomine increases the activity of the Gaucher disease L444P mutant form of b-glucosidase. FEBS J. 277, 1618–1638 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  33. Khanna, R. et al. The pharmacological chaperone 1-deoxygalactonojirimycin reduces tissue globotriaosylceramide levels in a mouse model of Fabry disease. Mol. Ther. 18, 23–33 (2010).

    Article  CAS  PubMed  Google Scholar 

  34. Clarke, J.T. et al. An open-label Phase I/II clinical trial of pyrimethamine for the treatment of patients affected with chronic GM2 gangliosidosis (Tay-Sachs or Sandhoff variants). Mol. Genet. Metab. 102, 6–12 (2011).

    Article  CAS  PubMed  Google Scholar 

  35. Shen, J.S., Edwards, N.J., Hong, Y.B. & Murray, G.J. Isofagomine increases lysosomal delivery of exogenous glucocerebrosidase. Biochem. Biophys. Res. Commun. 369, 1071–1075 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  36. Hart, G.W., Housley, M.P. & Slawson, C. Cycling of O-linked b-N-acetylglucosamine on nucleocytoplasmic proteins. Nature 446, 1017–1022 (2007).

    Article  CAS  PubMed  Google Scholar 

  37. Laczy, B., Marsh, S.A., Brocks, C.A., Wittmann, I. & Chatham, J.C. Inhibition of O-GlcNAcase in perfused rat hearts by NAG-thiazolines at the time of reperfusion is cardioprotective in an O-GlcNAc-dependent manner. Am. J. Physiol. Heart Circ. Physiol. 299, H1715–H1727 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  38. Caldwell, S.A. et al. Nutrient sensor O-GlcNAc transferase regulates breast cancer tumorigenesis through targeting of the oncogenic transcription factor FoxM1. Oncogene 29, 2831–2842 (2010).

    Article  CAS  PubMed  Google Scholar 

  39. Shi, Y. et al. Aberrant O-GlcNAcylation characterizes chronic lymphocytic leukemia. Leukemia 24, 1588–1598 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  40. Liu, F., Iqbal, K., Grundke-Iqbal, I., Hart, G.W. & Gong, C.X. O-GlcNAcylation regulates phosphorylation of tau: a mechanism involved in Alzheimer's disease. Proc. Natl. Acad. Sci. USA 101, 10804–10809 (2004).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Yuzwa, S.A. et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat. Chem. Biol. 4, 483–490 (2008).

    Article  CAS  PubMed  Google Scholar 

  42. Lefebvre, T. et al. Evidence of a balance between phosphorylation and O-GlcNAc glycosylation of Tau proteins–a role in nuclear localization. Biochim. Biophys. Acta 1619, 167–176 (2003).

    Article  CAS  PubMed  Google Scholar 

  43. Macauley, M.S., Whitworth, G.E., Debowski, A.W., Chin, D. & Vocadlo, D.J. O-GlcNAcase uses substrate-assisted catalysis. J. Biol. Chem. 280, 25313–25322 (2005).

    Article  CAS  PubMed  Google Scholar 

  44. Whitworth, G.E. et al. Analysis of PUGNAc and NAG-thiazoline as transition state analogues for human O-GlcNAcase: mechanistic and structural insights into inhibitor selectivity and transition state poise. J. Am. Chem. Soc. 129, 635–644 (2007).

    Article  CAS  PubMed  Google Scholar 

  45. Macauley, M.S., Shan, X., Yuzwa, S.A., Gloster, T.M. & Vocadlo, D.J. Elevation of Global O-GlcNAc in rodents using a selective O-GlcNAcase inhibitor does not cause insulin resistance or perturb glucohomeostasis. Chem. Biol. 17, 949–958 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  46. Dennis, R.J. et al. Structure and mechanism of a bacterial b-glucosaminidase having O-GlcNAcase activity. Nat. Struct. Mol. Biol. 13, 365–371 (2006).

    Article  CAS  PubMed  Google Scholar 

  47. Dorfmueller, H.C., Borodkin, V.S., Schimpl, M. & van Aalten, D.M. GlcNAcstatins are nanomolar inhibitors of human O-GlcNAcase inducing cellular hyper-O-GlcNAcylation. Biochem. J. 420, 221–227 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Dorfmueller, H.C. et al. GlcNAcstatin: a picomolar, selective O-GlcNAcase inhibitor that modulates intracellular O-glcNAcylation levels. J. Am. Chem. Soc. 128, 16484–16485 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Dorfmueller, H.C. et al. Cell-penetrant, nanomolar O-GlcNAcase inhibitors selective against lysosomal hexosaminidases. Chem. Biol. 17, 1250–1255 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  50. Dorfmueller, H.C. & van Aalten, D.M. Screening-based discovery of drug-like O-GlcNAcase inhibitor scaffolds. FEBS Lett. 584, 694–700 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Yuzwa, S.A. et al. Increasing O-GlcNAc slows neurodegeneration and stabilizes tau against aggregation. Nat. Chem. Biol. 8, 393–399 (2012).

    Article  CAS  PubMed  Google Scholar 

  52. Zhu, Z. et al. Acidic mammalian chitinase in asthmatic Th2 inflammation and IL-13 pathway activation. Science 304, 1678–1682 (2004).

    Article  CAS  PubMed  Google Scholar 

  53. Sutherland, T.E., Maizels, R.M. & Allen, J.E. Chitinases and chitinase-like proteins: potential therapeutic targets for the treatment of T-helper type 2 allergies. Clin. Exp. Allergy 39, 943–955 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Olland, A.M. et al. Triad of polar residues implicated in pH specificity of acidic mammalian chitinase. Protein Sci. 18, 569–578 (2009).

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Andersen, O.A., Nathubhai, A., Dixon, M.J., Eggleston, I.M. & van Aalten, D.M. Structure-based dissection of the natural product cyclopentapeptide chitinase inhibitor argifin. Chem. Biol. 15, 295–301 (2008).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  56. Fitz, L.J. et al. Acidic mammalian chitinase is not a critical target for allergic airway disease. Am. J. Respir. Cell Mol. Biol. 46, 71–79 (2012).

    Article  CAS  PubMed  Google Scholar 

  57. Lairson, L.L., Henrissat, B., Davies, G.J. & Withers, S.G. Glycosyltransferases: structures, functions, and mechanisms. Annu. Rev. Biochem. 77, 521–555 (2008).

    Article  CAS  PubMed  Google Scholar 

  58. Soya, N., Fang, Y., Palcic, M.M. & Klassen, J.S. Trapping and characterization of covalent intermediates of mutant retaining glycosyltransferases. Glycobiology 21, 547–552 (2011).

    Article  CAS  PubMed  Google Scholar 

  59. Lee, S.S. et al. Mechanistic evidence for a front-side, SNi-type reaction in a retaining glycosyltransferase. Nat. Chem. Biol. 7, 631–638 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Müller, B., Schaub, C. & Schmidt, R. Efficient sialyltransferase inhibitors based on transition-state analogues of the sialyl donor. Angew. Chem. Int. Ed. Engl. 37, 2893–2897 (1998).

    Article  PubMed  Google Scholar 

  61. Lee, L.V. et al. A potent and highly selective inhibitor of human a-1,3-fucosyltransferase via click chemistry. J. Am. Chem. Soc. 125, 9588–9589 (2003).

    Article  CAS  PubMed  Google Scholar 

  62. Hosoguchi, K. et al. An efficient approach to the discovery of potent inhibitors against glycosyltransferases. J. Med. Chem. 53, 5607–5619 (2010).

    Article  CAS  PubMed  Google Scholar 

  63. Rillahan, C.D., Brown, S.J., Register, A.C., Rosen, H. & Paulson, J.C. High-throughput screening for inhibitors of sialyl- and fucosyltransferases. Angew. Chem. Int. Edn. Engl. 50, 12534–12537 (2011).

    Article  CAS  Google Scholar 

  64. Fuster, M.M. & Esko, J.D. The sweet and sour of cancer: glycans as novel therapeutic targets. Nat. Rev. Cancer 5, 526–542 (2005).

    Article  CAS  PubMed  Google Scholar 

  65. Lowe, J.B. & Marth, J.D. A genetic approach to mammalian glycan function. Annu. Rev. Biochem. 72, 643–691 (2003).

    Article  CAS  PubMed  Google Scholar 

  66. Pesnot, T., Jorgensen, R., Palcic, M.M. & Wagner, G.K. Structural and mechanistic basis for a new mode of glycosyltransferase inhibition. Nat. Chem. Biol. 6, 321–323 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  67. Wang, R. et al. A search for pyrophosphate mimics for the development of substrates and inhibitors of glycosyltransferases. Bioorg. Med. Chem. 5, 661–672 (1997).

    Article  CAS  PubMed  Google Scholar 

  68. Niewiadomski, S. et al. Rationally designed squaryldiamides—a novel class of sugar-nucleotide mimics? Org. Biomol. Chem. 8, 3488–3499 (2010).

    Article  CAS  PubMed  Google Scholar 

  69. Mahoney, W.C. & Duksin, D. Biological activities of the two major components of tunicamycin. J. Biol. Chem. 254, 6572–6576 (1979).

    Article  CAS  PubMed  Google Scholar 

  70. Platt, F.M., Neises, G.R., Dwek, R.A. & Butters, T.D. N-butyldeoxynojirimycin is a novel inhibitor of glycolipid biosynthesis. J. Biol. Chem. 269, 8362–8365 (1994).

    Article  CAS  PubMed  Google Scholar 

  71. Vunnam, R.R. & Radin, N.S. Analogs of ceramide that inhibit glucocerebroside synthetase in mouse brain. Chem. Phys. Lipids 26, 265–278 (1980).

    Article  CAS  PubMed  Google Scholar 

  72. Lukina, E. et al. A phase 2 study of eliglustat tartrate (Genz-112638), an oral substrate reduction therapy for Gaucher disease type 1. Blood 116, 893–899 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  73. Masciullo, M. et al. Substrate reduction therapy with miglustat in chronic GM2 gangliosidosis type Sandhoff: results of a 3-year follow-up. J. Inherit. Metab. Dis. published online, doi:10.1007/s10545-010-9186-3 (7 September 2010).

  74. Patterson, M.C. et al. Long-term miglustat therapy in children with Niemann-Pick disease type C. J. Child Neurol. 25, 300–305 (2010).

    Article  PubMed  Google Scholar 

  75. Zhao, H. et al. Inhibiting glycosphingolipid synthesis improves glycemic control and insulin sensitivity in animal models of type 2 diabetes. Diabetes 56, 1210–1218 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Natoli, T.A. et al. Inhibition of glucosylceramide accumulation results in effective blockade of polycystic kidney disease in mouse models. Nat. Med. 16, 788–792 (2010).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  77. Kuan, S.F., Byrd, J.C., Basbaum, C. & Kim, Y.S. Inhibition of mucin glycosylation by aryl-N-acetyl-a-galactosaminides in human colon cancer cells. J. Biol. Chem. 264, 19271–19277 (1989).

    Article  CAS  PubMed  Google Scholar 

  78. Brown, J.R. et al. A disaccharide-based inhibitor of glycosylation attenuates metastatic tumor cell dissemination. Clin. Cancer Res. 12, 2894–2901 (2006).

    Article  CAS  PubMed  Google Scholar 

  79. Laferté, S., Chan, N.W., Sujino, K., Lowary, T.L. & Palcic, M.M. Intracellular inhibition of blood group A glycosyltransferase. Eur. J. Biochem. 267, 4840–4849 (2000).

    Article  PubMed  Google Scholar 

  80. Brown, J.R. et al. Deoxygenated disaccharide analogs as specific inhibitors of b1-4-galactosyltransferase 1 and selectin-mediated tumor metastasis. J. Biol. Chem. 284, 4952–4959 (2009).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  81. Ralton, J.E., Milne, K.G., Guther, M.L., Field, R.A. & Ferguson, M.A. The mechanism of inhibition of glycosylphosphatidylinositol anchor biosynthesis in Trypanosoma brucei by mannosamine. J. Biol. Chem. 268, 24183–24189 (1993).

    Article  CAS  PubMed  Google Scholar 

  82. Dimitroff, C.J., Kupper, T.S. & Sackstein, R. Prevention of leukocyte migration to inflamed skin with a novel fluorosugar modifier of cutaneous lymphocyte-associated antigen. J. Clin. Invest. 112, 1008–1018 (2003).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  83. Barthel, S.R. et al. Peracetylated 4-fluoro-glucosamine reduces the content and repertoire of N- and O-glycans without direct incorporation. J. Biol. Chem. 286, 21717–21731 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  84. Gloster, T.M. et al. Hijacking a biosynthetic pathway yields a glycosyltransferase inhibitor within cells. Nat. Chem. Biol. 7, 174–181 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  85. Rillahan, C.D. et al. Global metabolic inhibitors of sialyl- and fucosyltransferases remodel the glycome. Nat. Chem. Biol. 8, 661–668 (2012).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  86. Gross, B.J., Swoboda, J.G. & Walker, S. A strategy to discover inhibitors of O-linked glycosylation. J. Am. Chem. Soc. 130, 440–441 (2008).

    Article  CAS  PubMed  Google Scholar 

  87. Dehennaut, V. et al. O-linked N-acetylglucosaminyltransferase inhibition prevents G2/M transition in Xenopus laevis oocytes. J. Biol. Chem. 282, 12527–12536 (2007).

    Article  CAS  PubMed  Google Scholar 

  88. Lazarus, M.B., Nam, Y., Jiang, J., Sliz, P. & Walker, S. Structure of human O-GlcNAc transferase and its complex with a peptide substrate. Nature 469, 564–567 (2011).

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  89. Lee, K.Y. et al. The hexapeptide inhibitor of Galβ1,3GalNAc-specific a2,3-sialyltransferase as a generic inhibitor of sialyltransferases. J. Biol. Chem. 277, 49341–49351 (2002).

    Article  CAS  PubMed  Google Scholar 

  90. Chiang, C.H. et al. A novel sialyltransferase inhibitor AL10 suppresses invasion and metastasis of lung cancer cells by inhibiting integrin-mediated signaling. J. Cell. Physiol. 223, 492–499 (2010).

    CAS  PubMed  Google Scholar 

  91. Chen, J.Y. et al. A novel sialyltransferase inhibitor suppresses FAK/paxillin signaling and cancer angiogenesis and metastasis pathways. Cancer Res. 71, 473–483 (2011).

    Article  CAS  PubMed  Google Scholar 

  92. Yamashita, T. et al. A vital role for glycosphingolipid synthesis during development and differentiation. Proc. Natl. Acad. Sci. USA 96, 9142–9147 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Platt, F.M. et al. Prevention of lysosomal storage in Tay-Sachs mice treated with N-butyldeoxynojirimycin. Science 276, 428–431 (1997).

    Article  CAS  PubMed  Google Scholar 

  94. Cox, T. et al. Novel oral treatment of Gaucher's disease with N-butyldeoxynojirimycin (OGT 918) to decrease substrate biosynthesis. Lancet 355, 1481–1485 (2000).

    Article  CAS  PubMed  Google Scholar 

  95. Rishton, G.M. Nonleadlikeness and leadlikeness in biochemical screening. Drug Discov. Today 8, 86–96 (2003).

    Article  CAS  PubMed  Google Scholar 

  96. Shah, N., Kuntz, D.A. & Rose, D.R. Golgi a-mannosidase II cleaves two sugars sequentially in the same catalytic site. Proc. Natl. Acad. Sci. USA 105, 9570–9575 (2008).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Lillelund, V.H., Jensen, H.H., Liang, X. & Bols, M. Recent developments of transition-state analogue glycosidase inhibitors of non-natural product origin. Chem. Rev. 102, 515–553 (2002).

    Article  CAS  PubMed  Google Scholar 

  98. von Itzstein, M. The war against influenza: discovery and development of sialidase inhibitors. Nat. Rev. Drug Discov. 6, 967–974 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Ho, C.W. et al. Development of GlcNAc-inspired iminocyclitiols as potent and selective N-acetyl-b-hexosaminidase inhibitors. ACS Chem. Biol. 5, 489–497 (2010).

    Article  CAS  PubMed  Google Scholar 

  100. Hrmova, M. et al. Structural rationale for low-nanomolar binding of transition state mimics to a family GH3 b-D-glucan glucohydrolase from barley. Biochemistry 44, 16529–16539 (2005).

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

T.M.G. is a Wellcome Trust Research Career Development Fellow. D.J.V. is a scholar of the Michael Smith Foundation for Health Research, holds a Canada Research Chair in Chemical Glycobiology and is an E.W.R. Steacie memorial fellow. We thank the Natural Sciences and Engineering Research Council of Canada, the Canadian Institutes of Health Research and Simon Fraser University for funding support.

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  1. Tracey M Gloster

    Present address: Present address: Biomedical Sciences Research Complex, University of St. Andrews, St. Andrews, UK.,

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  1. Department of Chemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    Tracey M Gloster & David J Vocadlo

  2. Department of Molecular Biology and Biochemistry, Simon Fraser University, Burnaby, British Columbia, Canada

    David J Vocadlo

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D.J.V. is eligible to receive royalties from Simon Fraser University. D.J.V. is a founder, shareholder, consultant and member of the scientific advisory board of Alectos Therapeutics.

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Gloster, T., Vocadlo, D. Developing inhibitors of glycan processing enzymes as tools for enabling glycobiology. Nat Chem Biol 8, 683–694 (2012). https://doi.org/10.1038/nchembio.1029

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