Thiamet G

Thiamet G, a potent inhibitor of O-GlcNAcase (Ki =21 nM) was used to increase O-GlcNAcylation levels ^[1]. Thiamet G is a stable compound whose fused thiazoline ring system geometrically mimics a transition state of the substrate-assisted enzymatic hydrolysis of protein-O-GlcNAc units and, in this way, effectively inhibits O-GlcNAcase function ^[2]. Thiamet-G is orally bioavailable, and thiamet-G can cross the blood brain barrier ^[1].

Thiamet G (5 μM, 24h) could markedly elevate the O-GlcNAcylation of human lung epithelial carcinoma A549, non-small cell lung carcinoma H1299 and colon tumor HT29 cells ^[3]. Thiamet G (25 μM, 24 h) treated PC-12 cells showed a gradual time-dependent increase in cellular O-GlcNAc levels that reached a maximum after approximately 12 h of exposure ^[1].

Thiamet G (2.5 μl of 35 μg/μl) dissolved in 0.9% NaCl was injected bilaterally into the lateral ventricles of the brains at a dose of 175 μg/mouse, RL2 positive bands showed a 5-fold increase in global O-GlcNAcylation 4.5 h after thiamet G injection and a 10-fold increase 24 h after injection ^[4]. Thiamet G (500 mg/kg/day p.o.) treatment was able to decrease the number of neurons showing tau pathology, decrease behavioral defects and reduce mice mortality in the Tau.P301L mouse model ^[5]. Thiamet-G treated Tau.P301L mice for 3 days in the drinking water (2.5 mg/ml) in the home-cage, improved their breathing deficit in normocapnia and in hypercapnia ^[6].

References:
[1]. 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[J]. Nature chemical biology, 2008, 4(8): 483-490.
[2]. Fischer P M. Turning down tau phosphorylation[J]. Nature chemical biology, 2008, 4(8): 448-449.
[3]. Mi W, Gu Y, Han C, et al. O-GlcNAcylation is a novel regulator of lung and colon cancer malignancy[J]. Biochimica et Biophysica Acta (BBA)-Molecular Basis of Disease, 2011, 1812(4): 514-519.
[4]. Yu Y, Zhang L, Li X, et al. Differential effects of an O-GlcNAcase inhibitor on tau phosphorylation[J]. PloS one, 2012, 7(4): e35277.
[5]. Graham DL, Gray AJ, Joyce JA, Yu D, O'Moore J, Carlson GA, Shearman MS, Dellovade TL, Hering H. Increased O-GlcNAcylation reduces pathological tau without affecting its normal phosphorylation in a mouse model of tauopathy[J]. Neuropharmacology, 2014,1;79:307-13.
[6]. Borghgraef P, Menuet C, Theunis C, Louis JV, Devijver H, Maurin H, Smet-Nocca C, Lippens G, Hilaire G, Gijsen H, Moechars D. Increasing brain protein O-GlcNAc-ylation mitigates breathing defects and mortality of Tau. P301L mice[J]. PloS one, 2013, Dec 23;8(12):e84442.

Thiamet G 是一种有效的 O-GlcNAcase 抑制剂 (Ki =21 nM)，用于提高 O-GlcNAcylation 水平^[1]。 Thiamet G 是一种稳定的化合物，其稠合噻唑啉环系统在几何上模拟了蛋白质-O-GlcNAc 单元底物辅助酶水解的过渡态，从而有效抑制 O-GlcNAcase 功能^{[2]。 Thiamet-G 具有口服生物利用度，thiamet-G 可以穿过血脑屏障[1]。}

Thiamet G (5 μM, 24h) 可显着提高人肺上皮癌 A549、非小细胞肺癌 H1299 和结肠肿瘤 HT29 细胞的 O-GlcNAcylation^[3]。 Thiamet G（25 μM，24 小时）处理的 PC-12 细胞显示细胞 O-GlcNAc 水平随时间逐渐增加，在暴露约 12 小时后达到最大值^[1]。

将溶解在 0.9% NaCl 中的 Thiamet G（2.5 μl，35 μg/μl）以 175 μg/小鼠的剂量双侧注射到大脑的侧脑室，RL2 阳性条带显示整体 O2 增加了 5 倍-Thiamet G 注射后 4.5 小时的 GlcNAcylation，注射后 24 小时增加 10 倍^[4]。在 Tau.P301L 小鼠模型中，Thiamet G（500 mg/kg/天口服）处理能够减少显示 tau 病理的神经元数量，减少行为缺陷并降低小鼠死亡率^[5]。 Thiamet-G 在饲养笼中用饮用水 (2.5 mg/ml) 处理 Tau.P301L 小鼠 3 天，改善了正常碳酸血症和高碳酸血症时的呼吸缺陷^[6]。