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Targeting GNE myopathy: A dual prodrug approach for the delivery of N-acetylmannosamine 6-phosphate

Morozzi, Chiara, Sedláková, Jana, Serpi, Michaela ORCID:, Avigliano, Marialuce, Carbajo, Rosangela, Sandoval, Lucia, Valles-Ayoub, Yadira, Crutcher, Patrick, Thomas, Stephen and Pertusati, Fabrizio ORCID: 2019. Targeting GNE myopathy: A dual prodrug approach for the delivery of N-acetylmannosamine 6-phosphate. Journal of Medicinal Chemistry 62 (17) , pp. 8178-8193. 10.1021/acs.jmedchem.9b00833

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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-O-acetylated N-acetylmannosamine (Ac3ManNAc) 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 GNE that limit the production of ManNAc-6-P. Synthetic methods were developed to provide a library of Ac3ManNAc-6-phosphoramidates that were evaluated in a series of studies for their potential as a treatment for GNE myopathy. Prodrug 12b 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.

Item Type: Article
Date Type: Publication
Status: Published
Schools: Pharmacy
Publisher: American Chemical Society
ISSN: 0022-2623
Date of First Compliant Deposit: 4 September 2019
Date of Acceptance: 6 August 2019
Last Modified: 09 Nov 2023 17:09

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