cycloSaligenyl-mannose-1-monophosphates as a New Strategy in CDG-Ia Therapy: Hydrolysis, Mechanistic Insights and Biological Activity
cycloSaligenyl-mannose-1-monophosphates as a New Strategy in CDG-Ia Therapy: Hydrolysis, Mechanistic Insights and Biological Activity
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环水杨酰甘露糖-1-单磷酸作为 CDG-Ia 治疗的新策略：水解、机理见解和生物活性
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发表时间：
2004
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影响因子：
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通讯作者：
C. Meier
中科院分区：
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作者：
U. Muus;C. Kranz;T. Marquardt;C. Meier
磷酸腺苷转氨酶2 （PMM-2）缺乏导致细胞内甘露糖-1-磷酸形成效率低下(1)，从而导致具有多系统异常的遗传性代谢性疾病（先天性糖基化障碍Ia型，CDG-Ia）。为了避免这种代谢缺陷，cycloSal方法被应用于甘露糖-1-单磷酸的细胞内递送(1)。从适当保护的d -吡喃糖开始，通过磷酸化/氧化过程获得cyclosaligenyl -pyranose-1-单磷酸6−11。报道了环saligenyl-甘露糖-1-单磷酸酯6−9及其表聚物葡萄糖10,11的化学水解数据和涉及的水解机制。此外，我们在pmm -2缺陷成纤维细胞中体外测试了环盐甘露糖-1-磷酸6−9的生物活性。3-甲基-环盐-2,3,4,6-四- o -乙酰-α- d -甘露糖-1-单磷酸(8)显示了表型的完全纠正，从而证明甘露糖-1-磷酸的传递。这可能为CDG-Ia的治疗提供了一种合适的可能性。（©Wiley-VCH Verlag GmbH & Co. KGaA，德国Weinheim 69451, 2004）
Phosphomannomutase 2 (PMM-2) deficiency leads to an inefficient intracellular formation of mannose-1-phosphate (1), which causes an inherited metabolic disease with multisystemic abnormalities (Congenital Disorder of Glycosylation type Ia, CDG-Ia). In order to circumvent this metabolic deficiency, the cycloSal approach was applied for the intracellular delivery of mannose-1-monophosphate (1). cycloSaligenyl-pyranose-1-monophosphates 6−11 were obtained by a phosphitylation/oxidation procedure starting from appropriately protected D-pyranoses. The chemical hydrolysis data and the involved hydrolysis mechanisms of cyclosaligenyl-mannose-1-monophosphates 6−9 and their epimeric glucose analogues 10, 11 are reported. Furthermore, the biological activity of cycloSal-mannose-1-phosphates 6−9 was tested in vitro in PMM-2-deficient fibroblasts. 3-Methyl-cycloSal-2,3,4,6-tetra-O-acetyl-α-D-mannopyranose-1-monophosphate (8) showed a total correction of the phenotype, thus proving the delivery of mannose-1-phosphate. This may offer a suitable possibility for a therapy of CDG-Ia. (© Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004)