Structure-based design of nucleoside-derived analogues as sulfotransferase inhibitors



Kershaw, Neil M ORCID: 0000-0002-4557-1742, Byrne, Dominic P, Parsons, Hollie, Berry, Neil G ORCID: 0000-0003-1928-0738, Fernig, David G ORCID: 0000-0003-4875-4293, Eyers, Patrick A and Cosstick, Richard ORCID: 0000-0002-8687-1071
(2019) Structure-based design of nucleoside-derived analogues as sulfotransferase inhibitors. RSC ADVANCES, 9 (55). pp. 32165-32173.

[img] Text
Kershaw_RSCAdv_manuscript.pdf - Author Accepted Manuscript

Download (999kB) | Preview

Abstract

Sulfotransferases (STs) catalyse the transfer of a sulfonyl group ('sulfation') from the enzyme co-factor 3'-phosphoadenosine 5'-phosphosulfate (PAPS) to a variety of biomolecules. Tyrosine sulfation of proteins and carbohydrate sulfation play a crucial role in many protein-protein interactions and cell signalling pathways in the extracellular matrix. This is catalysed by several membrane-bound STs, including tyrosylprotein sulfotransferase 1 (TPST1) and heparan sulfate 2-<i>O</i>-sulfotransferase (HS2ST1). Recently, involvement of these enzymes and their post-translational modifications in a growing number of disease areas has been reported, including inflammation, cancer and Alzheimer's disease. Despite their growing importance, the development of small molecules to probe the biological effect of TPST and carbohydrate ST inhibition remains in its infancy. We have used a structure-based approach and molecular docking to design a library of adenosine 3',5'-diphosphate (PAP) and PAPS mimetics based upon 2'-deoxyadenosine and using 2'-deoxy-PAP as a benchmark. The use of allyl groups as masked methyl esters was exploited in the synthesis of PAP-mimetics, and click chemistry was employed for the divergent synthesis of a series of PAPS-mimetics. A suite of <i>in vitro</i> assays employing TPST1 and HS2ST, and a kinase counter screen, were used to evaluate inhibitory parameters and relative specificity for the STs.

Item Type: Article
Depositing User: Symplectic Admin
Date Deposited: 15 Oct 2019 14:17
Last Modified: 19 Jan 2023 00:22
DOI: 10.1039/c9ra07567d
Related URLs:
URI: https://livrepository.liverpool.ac.uk/id/eprint/3058268