Hyperphosphorylation of the tau protein leads to its aggregation and formation of neurofibrillary tangles, a hallmark of Alzheimer’s disease and other tauopathic, neurodegenerative disorders. Tau is also dynamically modified by the addition and cleavage of O-linked β-N-acetylglucosamine (O-GlcNAc) moieties, which is mediated in part by O-GlcNAcase. Levels of O-GlcNAcylated proteins from Alzheimer’s disease brain extracts are decreased as compared to that in controls, suggesting that impaired brain glucose metabolism may contribute to pathogenesis.1 Thiamet G is a potent and selective inhibitor of O-GlcNAcase that demonstrates a Ki value of 21 nM.2 It increases cellular O-GlcNAc-modified protein levels (EC50 = 30 nM) and blocks phosphorylation of tau protein both in cultured PC-12 cells and in rats (200 mg/kg/day).2 Thiamet G is the first highly potent O-GlcNAcase inhibitor known to be orally bioavailable and effectively cross the blood brain barrier.2
1
Liu, F., Iqbal, K., Grundke-Iqbal, I., et al. O-GlnNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA101(29)10804-10809(2004).
2
Yuzwa, S.A., Macauley, M.S., Heinonen, J.E., et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol4(8)483-490(2008).
Liu, F., Iqbal, K., Grundke-Iqbal, I., et al. O-GlnNAcylation regulates phosphorylation of tau: A mechanism involved in Alzheimer’s disease. Proc Natl Acad Sci USA101(29)10804-10809(2004).
Yuzwa, S.A., Macauley, M.S., Heinonen, J.E., et al. A potent mechanism-inspired O-GlcNAcase inhibitor that blocks phosphorylation of tau in vivo. Nat Chem Biol4(8)483-490(2008).
Thiamet G is available in the following screening
library: