Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate

Journal of Medicinal Chemistry
2019.0

Abstract

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-<i>O</i>-acetylated <i>N</i>-acetylmannosamine (Ac<sub>3</sub>ManNAc) 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 <i>GNE</i> that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac<sub>3</sub>ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug <b>12b</b> 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.

Knowledge Graph

Similar Paper

Targeting GNE Myopathy: A Dual Prodrug Approach for the Delivery of N-Acetylmannosamine 6-Phosphate
Journal of Medicinal Chemistry 2019.0
The ProTide Prodrug Technology: From the Concept to the Clinic
Journal of Medicinal Chemistry 2018.0
Phosphate Prodrugs Derived from N-Acetylglucosamine Have Enhanced Chondroprotective Activity in Explant Cultures and Represent a New Lead in Antiosteoarthritis Drug Discovery
Journal of Medicinal Chemistry 2008.0
Application of the phosphoramidate ProTide approach to the antiviral drug ribavirin
Bioorganic &amp; Medicinal Chemistry 2010.0
Phosphoramidate ProTides of the Anticancer Agent FUDR Successfully Deliver the Preformed Bioactive Monophosphate in Cells and Confer Advantage over the Parent Nucleoside
Journal of Medicinal Chemistry 2011.0
Synthesis and biological evaluation of 6-substituted-5-fluorouridine ProTides
Bioorganic &amp; Medicinal Chemistry 2018.0
Anchimerically Activated ProTides as Inhibitors of Cap-Dependent Translation and Inducers of Chemosensitization in Mantle Cell Lymphoma
Journal of Medicinal Chemistry 2017.0
Application of ProTide Technology to Gemcitabine: A Successful Approach to Overcome the Key Cancer Resistance Mechanisms Leads to a New Agent (NUC-1031) in Clinical Development
Journal of Medicinal Chemistry 2014.0
The Application of Phosphoramidate Protide Technology to Acyclovir Confers Anti-HIV Inhibition
Journal of Medicinal Chemistry 2009.0
l-Aspartic and l-glutamic acid ester-based ProTides of anticancer nucleosides: Synthesis and antitumoral evaluation
Bioorganic &amp; Medicinal Chemistry Letters 2016.0