School of Pharmacy and Pharmaceutical Sciences , Cardiff University , Cardiff, King Edward VII Avenue , Cardiff CF10 3NB , U.K.
FirmaLab Bio-Diagnostics , 21053 Devonshire Street, Suite 106 , Chatsworth , California 91311 , United States.
J Med Chem. 2019 Sep 12;62(17):8178-8193. doi: 10.1021/acs.jmedchem.9b00833. Epub 2019 Aug 20.
ProTides comprise an important class of prodrugs currently marketed and developed as antiviral and anticancer therapies. The ProTide technology employs phosphate masking groups capable of providing more favorable druglike properties and an intracellular activation mechanism for enzyme-mediated release of a nucleoside monophosphate. Herein, we describe the application of phosphoramidate chemistry to 1,3,4--acetylated -acetylmannosamine (AcManNAc) to deliver ManNAc-6-phosphate (ManNAc-6-P), a critical intermediate in sialic acid biosynthesis. Sialic acid deficiency is a hallmark of GNE myopathy, a rare congenital disorder of glycosylation (CDG) caused by mutations in that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of AcManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug showed rapid activation in a carboxylesterase (CPY) enzymatic assay and favorable ADME properties, while also being more effective than ManNAc at increasing sialic acid levels in GNE-deficient cell lines. These results provide a potential platform to address substrate deficiencies in GNE myopathy and other CDGs.
ProTides 是一类重要的前药，目前已作为抗病毒和抗癌疗法上市和开发。ProTide 技术采用磷酸酯掩蔽基团，能够提供更有利的类药性和一种细胞内激活机制，用于酶介导释放核苷一磷酸。本文描述了磷酰胺化学在 1,3,4-乙酰化乙酰甘露糖胺（AcManNAc）中的应用，以递送甘露糖-6-磷酸（ManNAc-6-P），这是唾液酸生物合成中的关键中间产物。唾液酸缺乏是 GNE 肌病的标志，GNE 肌病是一种罕见的糖基化先天性疾病（CDG），由 基因突变引起，限制了 ManNAc-6-P 的产生。开发了合成方法来提供一系列 AcManNAc-6-磷酰胺前药，对它们作为 GNE 肌病治疗药物的潜力进行了一系列研究评估。前药 在羧酯酶（CPY）酶促测定中迅速激活，具有良好的 ADME 特性，并且在增加 GNE 缺陷细胞系中的唾液酸水平方面比 ManNAc 更有效。这些结果为解决 GNE 肌病和其他 CDG 中的底物缺乏提供了一个潜在的平台。
