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Aryloxy Triester Phosphoramidates as Phosphoserine Biocleavable Masking Motifs

preprint
submitted on 06.11.2019 and posted on 13.11.2019 by Ageo Miccoli, Binar A. Dhiani, Peter J. Thornton, Olivia A. Lambourne, Edward James, Hachemi Kadri, Youcef Mehellou
Many cellular protein-protein interactions (PPIs) are mediated by phosphoserine. The specific targeting of these PPIs by phosphoserine-containing small molecules has been scarce due to the dephosphorylation of phosphoserine and its charged nature at physiological pH, which hinders its uptake into cells. To address these issues, we herein report the masking of the phosphate group of phosphoserine with biocleavable aryloxy triester phosphoramidate groups. A combination of in vitro enzymatic assays and in silico studies, using carboxypeptidase Y and Hint-1 respectively, showed that the phosphate masking groups are metabolized to release phosphoserine. To probe the applicability of this phosphoserine masking approach, it was applied to a phosphoserine-containing inhibitor of 14-3-3 dimerization, and this generated molecules with improved pharmacological activity in cells compared to their unmasked phosphoserine-containing parent compound. Collectively, the data showcases the masking of phosphoserine with biocleavable aryloxy triester phosphoramidate masking groups as an efficient intracellular delivery system for phosphoserine-containing molecules.

History

Email Address of Submitting Author

MehellouY1@cardiff.ac.uk

Institution

Cardiff University

Country

United Kingdom

ORCID For Submitting Author

0000-0001-5720-8513

Declaration of Conflict of Interest

There are no conflicts to declare.

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