Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation

• Published in: Nature chemical biology Vol. 11; no. 3; pp. 189 - 191
• Main Authors: Lewis, Huw D, Liddle, John, Coote, Jim E, Atkinson, Stephen J, Barker, Michael D, Bax, Benjamin D, Bicker, Kevin L, Bingham, Ryan P, Campbell, Matthew, Chen, Yu Hua, Chung, Chun-wa, Craggs, Peter D, Davis, Rob P, Eberhard, Dirk, Joberty, Gerard, Lind, Kenneth E, Locke, Kelly, Maller, Claire, Martinod, Kimberly, Patten, Chris, Polyakova, Oxana, Rise, Cecil E, Rüdiger, Martin, Sheppard, Robert J, Slade, Daniel J, Thomas, Pamela, Thorpe, Jim, Yao, Gang, Drewes, Gerard, Wagner, Denisa D, Thompson, Paul R, Prinjha, Rab K, Wilson, David M
• Format: Journal Article
• Language: English
• Published: New York Nature Publishing Group US 01.03.2015; Nature Publishing Group
• Subjects: 101/58; 13; 14; 631/250; 631/535; 631/92/613; 82/51; 82/80; Animals; Benzimidazoles - chemical synthesis; Benzimidazoles - pharmacology; Binding, Competitive; Biochemical Engineering; Biochemistry; Bioorganic Chemistry; brief-communication; Calcium - metabolism; Cell Biology; Chemistry; Chemistry/Food Science; Citrulline - metabolism; Enzyme Inhibitors - chemical synthesis; Enzyme Inhibitors - pharmacology; Genetics; HEK293 Cells; Histones - metabolism; Humans; Hydrolases - antagonists & inhibitors; In Vitro Techniques; Mice; Models, Molecular; Neutrophils - drug effects; Protein-Arginine Deiminases; Small Molecule Libraries; Substrate Specificity
• ISSN: 1552-4450; 1552-4469; 1552-4469
• DOI: 10.1038/nchembio.1735

Inhibitors of the PAD4 enzyme that bind the inactive enzyme link this protein deiminase and the resultant arginine-to-citrulline modification to formation of neutrophil extracellular traps, highly decondensed chromatin structures with both host-defense and pathological roles. PAD4 has been strongly implicated in the pathogenesis of autoimmune, cardiovascular and oncological diseases through clinical genetics and gene disruption in mice. New selective PAD4 inhibitors binding a calcium-deficient form of the PAD4 enzyme have validated the critical enzymatic role of human and mouse PAD4 in both histone citrullination and neutrophil extracellular trap formation for, to our knowledge, the first time. The therapeutic potential of PAD4 inhibitors can now be explored.