Structure-Based Design of Nucleoside-Derived Analogues as Sulfotransferase Inhibitors

Kershaw, Neil ORCID: 0000-0002-4557-1742, Byrne, Dominic, Parsons, Hollie, Berry, Neil, Fernig, David ORCID: 0000-0003-4875-4293, Eyers, Patrick ORCID: 0000-0002-9220-2966 and Cosstick, Richard (2019) Structure-Based Design of Nucleoside-Derived Analogues as Sulfotransferase Inhibitors. RSC Advances: an international journal to further the chemical sciences.

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Official URL: http://dx.doi.org/10.26434/chemrxiv.9944243.v1

Abstract

Sulfotransferases (STs) catalyse the transfer of a sulfonyl group (‘sulfation’) from the enzyme co-factor 3ʹ-phosphoadenosine 5ʹ-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-O-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 in vitro 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
Uncontrolled Keywords:	Cancer
Depositing User:	Symplectic Admin
Date Deposited:	27 Jan 2020 16:06
Last Modified:	14 Mar 2024 17:49
DOI:	10.1039/C9RA07567D
Related URLs:	Publisher
URI:	https://livrepository.liverpool.ac.uk/id/eprint/3072142