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Nat Chem Biol. 2015 Mar;11(3):189-91. doi: 10.1038/nchembio.1735. Epub 2015 Jan 26.

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

Author information

1
EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
2
Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
3
Department of Chemistry, Scripps Florida, The Scripps Research Institute, Jupiter, Florida, USA.
4
Cellzome GmbH, a GSK company, Heidelberg, Germany.
5
ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, USA.
6
1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Immunology Graduate Program, Division of Medical Sciences, Harvard Medical School, Boston, Massachusetts, USA.
7
1] EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK. [2] AstraZeneca, Oncology iMed, Cambridge Science Park, Cambridge, UK (R.J.S. and D.M.W.); Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA (D.J.S.); University of Massachussetts Medical School, Worcester, Massachusetts, USA (P.R.T.).
8
1] Department of Chemistry, Scripps Florida, The Scripps Research Institute, Jupiter, Florida, USA. [2] AstraZeneca, Oncology iMed, Cambridge Science Park, Cambridge, UK (R.J.S. and D.M.W.); Virginia Polytechnic Institute and State University, Blacksburg, Virginia, USA (D.J.S.); University of Massachussetts Medical School, Worcester, Massachusetts, USA (P.R.T.).
9
1] Program in Cellular and Molecular Medicine, Boston Children's Hospital, Boston, Massachusetts, USA. [2] Division of Hematology/Oncology, Boston Children's Hospital, Boston, Massachusetts, USA. [3] Department of Pediatrics, Harvard Medical School, Boston, Massachusetts, USA.

Abstract

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.

PMID:
25622091
PMCID:
PMC4397581
DOI:
10.1038/nchembio.1735
[Indexed for MEDLINE]
Free PMC Article

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