A novel class of powerful and selective hexosaminidase and protein O-GlcNAcase inhibitors: N-modified cyclopentanoid sugar analogs

Session: 
S7.1 Synthetic glycomimetic glycosidase inhibitors
Code: 
OL7.1.2
Location (hall): 
Glucose
Start/end time: 
Wednesday, July 3, 2019 - 12:00 to 12:15
Patrick
Weber

Patrick Weber1, Arnold E. Stütz1

1Glycogroup, Institute of Organic Chemistry, Graz University Of Technology, Graz, Austria

Half of the nearly sixty lysosomal storage diseases described to date are caused by the lack or catalytic incompetence of carbohydrate processing enzymes such as glycosidases, phosphorylases as well as other hydrolases which manipulate sugar moieties. Hexosaminidases as well as O-GlcNAcase are involved in the chemical manipulation or catalytic removal of N-acetyl-D-glucosaminyl or N-acetyl-D-galactosaminyl residues from degradation-bound polysaccharides and glycoconjugates.

Regulation of O-GlcNAcase, which belongs to the family of hexosaminidases, prevents the tau protein from hyperphosphorylation which is a pathological hallmark for diseases such as Alzheimer’s. [1] It has been shown that inhibition of O-GlcNAcase enhances the autophagy in the brain and thus shows a benefit in neurodegenerative diseases such as Parkinson’s. [2] Selective inhibition of O-GlcNAcase can be achieved by elongation of the C-2 substituent to exploit a deep pocket at the active site of the enzyme. [3] In this presentation the synthesis as well as the biological activities of novel and selective cyclopentanoid O-GlcNAcase inhibitors (1) as well as hexosaminidase inhibitors (2) will be presented.

Figure 1: Synthesized O-GlcNAcase and hexosaminidase inhibitors.

References: 
  1. Lim, S.; Haque, M.; Nam, G.; Ryoo, N.; Rhim, H.; and Kim, Y. K.; Int. J. Mol. Sci. 2015, 16(9), 20212-20224.
  2. Zhu, Y.; Shan, X.; Safarpur, F.; Go, E. N.; Li, N.; Shan, A.; Huang, M. C.; Deen, M.; Holicek, V.; Shmus, R.; Madden, Z.; Gorski, S.; Silverman, M. A. and Vocadlo D. J.; ACS Chem. Neurosci. 2018, 9, 1366-1379.
  3. Alonso, J.; Schimpl, M. and van Aalten, D. M. F.; J. Biol. Chem. 2014, 289(50), 34433-34439.

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