Design of Iminosugar Based Building Blocks for the Synthesis of Activity-Based Protein Profiling of Carbohydrate Processing Enzymes

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Design of Iminosugar Based Building Blocks for the Synthesis of Activity-Based Protein Profiling of Carbohydrate Processing Enzymes

Andreas Wolfsgruber 1 , Michael Schalli 1 , Patrick Weber 1 , Seyed A. Nasseri 2 , Barbara Darnhofer 3 , Ruth Birner-Grünberger 3 , Arnold E. Stütz 1 , Stephen G. Withers 2 , Tanja M. Wrodnigg 1

1 Graz University of Technology, Institute of Organic Chemistry, Graz, Austria, 2 UBC Faculty of Science, Department of Chemistry, Vancouver, Canada, 3 Medical University of Graz, Diagnostic and Research Institute of Pathology & Omics Center Graz, Graz, Austria

Carbohydrate processing enzymes (CPEs) are responsible for the metabolism of carbohydrates as well as glycoconjugates in living organisms. Malfunction of these proteins cause aberration of the structure and/or function of the corresponding carbohydrate metabolites resulting in diseases such as, for example, diabetes, bacterial as well as viral infections, immunological diseases, cancer or lysosomal storage diseases. [1]

The contribution and the role of the carbohydrate part is still unknown or even unrealised in many carbohydrate related disorders. In this respect, activity based protein profiling (ABPP) has become a powerful strategy for studying and elucidating protein activity in their native environment. Paradigmatic examples of probes for activity based protein profiling of carbohydrate processing enzymes have been developed, for example, by Withers, Overkleeft and Stubbs. [2]

We became interested in the design of probes for ABPP, taking into account our knowledge about structure activity relationship of iminosugar derivatives 1, 2, as well as 3 (Figure 1) based on parent structures such as 1-deoxynojirimycin, 1,5-dideoxy-1,5-imino-D-xylitol as well as 2,5-dideoxy-2,5-imino-D-manitol, respectively. [3]

Results and discussion of our work towards the design, synthesis as well as biological evaluation of iminosugar based building blocks for ABPP probes of CPEs will be presented.

Figure 1: Examples of iminosugar based probes for ABPP.

Stütz, A. E. and Wrodnigg, T. M.; Adv. Carbohydr. Chem. Biochem. 2016, 73, 225-302.

a) Hekmat, O.; He, S.; Warren, R. A. and Withers, S. G.; J. Proteome Res. 2008, 7, 3282-3292. b) Jiang, J.; Beenakker, T. J. M.; Kallemeijn, W. W.; van der Marel, G. A.; van den Elst, H.; Codeé, J. D. C.; Aerts, J. M. F. G. and Overkleeft, H. S.; Chem. Eur. J. 2015, 21, 10861-10869. c) Gandy, M. N.; Debowski, A. W. and Stubbs, K. A.; Chem Commun. 2011, 47, 5037-5039.

a) Zoidl, M.; Santana, A. G.; Torvisco, A.; Tysoe, C.; Siriwardena, A.; Withers, S. G. and Wrodnigg, T. M.; Carbohydr. Res. 2016, 429, 62-70. b) Pototschnig, G.; Morales De Csáky, C.; Montenegro Burke, J. R.; Schitter, G.; Stütz, A. E.; Tarling, C. A.; Withers, S. G. and Wrodnigg, T. M.; Bioorg. Med. Chem. Lett. 2010, 20, 4077-4079.

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