Aryloxy Triester Phosphoramidates as Phosphoserine Biocleavable Masking Motifs

13 November 2019, Version 1
This content is a preprint and has not undergone peer review at the time of posting.

Abstract

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.

Keywords

phosphoserine
protein-protein interactions
inhibitor
Biocleavable
prodrug
drug

Supplementary materials

Title
Description
Actions
Title
Ageo pSer ChemRxiv SI
Description
Actions

Comments

Comments are not moderated before they are posted, but they can be removed by the site moderators if they are found to be in contravention of our Commenting Policy [opens in a new tab] - please read this policy before you post. Comments should be used for scholarly discussion of the content in question. You can find more information about how to use the commenting feature here [opens in a new tab] .
This site is protected by reCAPTCHA and the Google Privacy Policy [opens in a new tab] and Terms of Service [opens in a new tab] apply.