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

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

doi:10.1038/nchembio.1735

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

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

Authors

Huw D Lewis¹, John Liddle¹, Jim E Coote², Stephen J Atkinson¹, Michael D Barker¹, Benjamin D Bax², Kevin L Bicker³, Ryan P Bingham², Matthew Campbell¹, Yu Hua Chen², Chun-Wa Chung², Peter D Craggs², Rob P Davis¹, Dirk Eberhard⁴, Gerard Joberty⁴, Kenneth E Lind⁵, Kelly Locke², Claire Maller¹, Kimberly Martinod⁶, Chris Patten¹, Oxana Polyakova², Cecil E Rise⁵, Martin Rüdiger², Robert J Sheppard⁷, Daniel J Slade⁸, Pamela Thomas², Jim Thorpe², Gang Yao⁵, Gerard Drewes⁴, Denisa D Wagner⁹, Paul R Thompson⁸, Rab K Prinjha¹, David M Wilson⁷

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural

MeSH terms

Animals
Benzimidazoles / chemical synthesis
Benzimidazoles / pharmacology*
Binding, Competitive
Calcium / metabolism
Citrulline / metabolism
Enzyme Inhibitors / chemical synthesis
Enzyme Inhibitors / pharmacology*
HEK293 Cells
Histones / metabolism
Humans
Hydrolases / antagonists & inhibitors*
In Vitro Techniques
Mice
Models, Molecular
Neutrophils / drug effects*
Protein-Arginine Deiminase Type 4
Protein-Arginine Deiminases
Small Molecule Libraries
Substrate Specificity

Substances

Benzimidazoles
Enzyme Inhibitors
GSK199
Histones
Small Molecule Libraries
Citrulline
Hydrolases
PADI4 protein, human
Protein-Arginine Deiminase Type 4
Protein-Arginine Deiminases
peptidylarginine deiminase 4, mouse
Calcium

Associated data

PubChem-Substance/223652462
PubChem-Substance/223652463
PubChem-Substance/223652464
PubChem-Substance/223652465
PubChem-Substance/223652466
PubChem-Substance/223652467
PubChem-Substance/223652468
PubChem-Substance/223652469
PubChem-Substance/223652470
PubChem-Substance/223652471
PubChem-Substance/223652472
PubChem-Substance/223652473
PubChem-Substance/223652474
PubChem-Substance/223652475
PubChem-Substance/223652476
PubChem-Substance/223652477
PubChem-Substance/223652478
PubChem-Substance/223652479
PubChem-Substance/223652480
PubChem-Substance/223652481
PubChem-Substance/223652482
PubChem-Substance/223652483
PubChem-Substance/223652484
PubChem-Substance/223652485
PubChem-Substance/223652486
PubChem-Substance/223652487
PubChem-Substance/223652488
PubChem-Substance/223652489
PubChem-Substance/223652490
PubChem-Substance/223652491
PubChem-Substance/223652492
PubChem-Substance/223652493
PubChem-Substance/223652494
PubChem-Substance/223652495
PubChem-Substance/223652496
PubChem-Substance/223652497
PubChem-Substance/223652498
PubChem-Substance/223652499
PubChem-Substance/223652500
PubChem-Substance/223652501
PubChem-Substance/223652502

Abstract

Publication types

MeSH terms

Substances

Associated data

Grants and funding