Identification of multiple structurally distinct, nonpeptidic small molecule inhibitors of protein arginine deiminase 3 using a substrate-based fragment method

Journal of the American Chemical Society
Haya JamaliJonathan A Ellman

Abstract

The protein arginine deiminases (PADs) are a family of enzymes that catalyze the post-translational hydrolytic deimination of arginine residues. Four different enzymologically active PAD subtypes have been characterized and exhibit tissue-specific expression and association with a number of different diseases. In this Article we describe the development of an approach for the reliable discovery of low molecular weight, nonpeptidic fragment substrates of the PADs that then can be optimized and converted to mechanism-based irreversible PAD inhibitors. The approach is demonstrated by the development of potent and selective inhibitors of PAD3, a PAD subtype implicated in the neurodegenerative response to spinal cord injury. Multiple structurally distinct inhibitors were identified with the most potent inhibitors having >10,000 min(-1) M(-1) k(inact)/K(I) values and ≥10-fold selectivity for PAD3 over PADs 1, 2, and 4.

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Citations

Dec 22, 2015·ACS Chemical Biology·Jakob Fuhrmann, Paul R Thompson
Sep 24, 2016·ACS Medicinal Chemistry Letters·Haya JamaliJonathan A Ellman
Oct 16, 2016·Journal of Medicinal Chemistry·Christopher N JohnsonDavid C Rees
Mar 23, 2017·Journal of Medicinal Chemistry·Aaron MuthPaul R Thompson
Feb 5, 2016·ChemMedChem·Rafaela GladyszPieter Van der Veken
Feb 28, 2020·Chemical Communications : Chem Comm·Aline Umuhire JuruAmanda E Hargrove
Oct 23, 2019·Biological Chemistry·Shiyu ChenMatthew Bogyo
Aug 7, 2019·Chemistry, an Asian Journal·Sambasivarao KothaVikas R Aswar
Mar 7, 2021·Current Opinion in Chemical Biology·Santanu Mondal, Paul R Thompson
Apr 27, 2021·Expert Opinion on Therapeutic Targets·Ylke BruggemanMaria J L Kracht
May 11, 2021·Archives of Biochemistry and Biophysics·Kazumasa FunabashiMasaki Unno
Jun 24, 2017·Chemical Reviews·Laure KonnertEvelina Colacino
Oct 19, 2017·Journal of Medicinal Chemistry·Elizabeth J Curiel TejedaLakshmi P Kotra
Oct 23, 2018·ACS Medicinal Chemistry Letters·Caroline Chandra TjinJonathan A Ellman

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