Small-molecules that covalently react with a human prolyl hydroxylase – towards activity modulation and substrate capture

Jacob T. Bush; Robert K. Leśniak; Tzu-Lan Yeh; Roman Belle; Holger Kramer; Anthony Tumber; Rasheduzzaman Chowdhury; Emily Flashman; Jasmin Mecinović; Christopher J. Schofield

doi:10.1039/C8CC07706A

Small-molecules that covalently react with a human prolyl hydroxylase – towards activity modulation and substrate capture†

Jacob T. Bush,

^a Robert K. Leśniak,^a Tzu-Lan Yeh,^a Roman Belle,^b Holger Kramer,^a Anthony Tumber,^a Rasheduzzaman Chowdhury,

^a Emily Flashman,^a Jasmin Mecinović

*^abc and Christopher J. Schofield

*^a

Author affiliations

* Corresponding authors

^a Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford, UK
E-mail: christopher.schofield@chem.ox.ac.uk

^b Institute for Molecules and Materials, Radboud University, Heyendaalseweg 135, 6525 AJ Nijmegen, The Netherlands

^c Department of Physics, Chemistry and Pharmacy, University of Southern Denmark, Campusvej 55, 5230 Odense, Denmark
E-mail: mecinovic@sdu.dk

Abstract

We describe covalently binding modulators of the activity of human prolyl hydroxylase domain 2 (PHD2) and studies towards a strategy for photocapture of PHD2 substrates. Reversible active site binding of electrophile bearing compounds enables susbsequent covalent reaction with a lysine residue (K408) in the flexible C-terminal region of PHD2 to give a modified protein that retains catalytic activity.

Chemical Communications

Small-molecules that covalently react with a human prolyl hydroxylase – towards activity modulation and substrate capture†

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