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

2015; Nature Portfolio; Volume: 11; Issue: 3 Linguagem: Inglês

10.1038/nchembio.1735

1552-4469

Huw D. Lewis, John Liddle, Jim Coote, Stephen J. Atkinson, Michael D. Barker, B.D. Bax, Kevin L. Bicker, Ryan P. Bingham, Matthew Campbell, Yu Hua Chen, Chun‐wa Chung, Peter D. Craggs, Rob P. Davis, Dirk Eberhard, Gérard Joberty, Kenneth Lind, Kelly Locke, Claire Maller, Kimberly Martinod, Chris Patten, Oxana Polyakova, Cecil Rise, Martin Rüdiger, Robert J. Sheppard, Daniel J. Slade, Pamela J. Thomas, Jim Thorpe, Gang Yao, Gerard Drewes, Denisa D. Wagner, Paul R. Thompson, Rab K. Prinjha, David M. Wilson,

Cell Adhesion Molecules Research

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.