title: Inhibition of PAD4 activity is sufficient to disrupt mouse and human NET formation.
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.
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Huw D
authors.initials: HD
authors.lastname: Lewis
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: John
authors.initials: J
authors.lastname: Liddle
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Jim E
authors.initials: JE
authors.lastname: Coote
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Stephen J
authors.initials: SJ
authors.lastname: Atkinson
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Michael D
authors.initials: MD
authors.lastname: Barker
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Benjamin D
authors.initials: BD
authors.lastname: Bax
authors.affiliation: Department of Chemistry, Scripps Florida, The Scripps Research Institute, Jupiter, Florida, USA.
authors.forename: Kevin L
authors.initials: KL
authors.lastname: Bicker
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Ryan P
authors.initials: RP
authors.lastname: Bingham
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Matthew
authors.initials: M
authors.lastname: Campbell
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Yu Hua
authors.initials: YH
authors.lastname: Chen
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Chun-Wa
authors.initials: CW
authors.lastname: Chung
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Peter D
authors.initials: PD
authors.lastname: Craggs
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Rob P
authors.initials: RP
authors.lastname: Davis
authors.affiliation: Cellzome GmbH, a GSK company, Heidelberg, Germany.
authors.forename: Dirk
authors.initials: D
authors.lastname: Eberhard
authors.affiliation: Cellzome GmbH, a GSK company, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Joberty
authors.affiliation: ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, USA.
authors.forename: Kenneth E
authors.initials: KE
authors.lastname: Lind
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Kelly
authors.initials: K
authors.lastname: Locke
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Claire
authors.initials: C
authors.lastname: Maller
authors.affiliation: 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.
authors.forename: Kimberly
authors.initials: K
authors.lastname: Martinod
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Chris
authors.initials: C
authors.lastname: Patten
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Oxana
authors.initials: O
authors.lastname: Polyakova
authors.affiliation: ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, USA.
authors.forename: Cecil E
authors.initials: CE
authors.lastname: Rise
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Martin
authors.initials: M
authors.lastname: Rüdiger
authors.affiliation: 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.).
authors.forename: Robert J
authors.initials: RJ
authors.lastname: Sheppard
authors.affiliation: 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.).
authors.forename: Daniel J
authors.initials: DJ
authors.lastname: Slade
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Pamela
authors.initials: P
authors.lastname: Thomas
authors.affiliation: Molecular Discovery Research, GlaxoSmithKline, Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Jim
authors.initials: J
authors.lastname: Thorpe
authors.affiliation: ELT Boston, Platform Technology and Science, GlaxoSmithKline, Waltham, Massachusetts, USA.
authors.forename: Gang
authors.initials: G
authors.lastname: Yao
authors.affiliation: Cellzome GmbH, a GSK company, Heidelberg, Germany.
authors.forename: Gerard
authors.initials: G
authors.lastname: Drewes
authors.affiliation: 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.
authors.forename: Denisa D
authors.initials: DD
authors.lastname: Wagner
authors.affiliation: 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.).
authors.forename: Paul R
authors.initials: PR
authors.lastname: Thompson
authors.affiliation: EpiNova DPU, Immuno-Inflammation Therapy Area, GlaxoSmithKline,Medicines Research Centre, Stevenage, Hertfordshire, UK.
authors.forename: Rab K
authors.initials: RK
authors.lastname: Prinjha
authors.affiliation: 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.).
authors.forename: David M
authors.initials: DM
authors.lastname: Wilson
mesh_terms: D000818:Animals; D001562:Benzimidazoles / Q000138:chemical synthesis / Q000494:pharmacology*; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002956:Citrulline / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology*; D057809:HEK293 Cells; D006657:Histones / Q000378:metabolism; D006801:Humans; D006867:Hydrolases / Q000037:antagonists & inhibitors*; D066298:In Vitro Techniques; D051379:Mice; D008958:Models, Molecular; D009504:Neutrophils / Q000187:drug effects*; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; D054852:Small Molecule Libraries; D013379:Substrate Specificity
chemical_list: D001562:Benzimidazoles; D004791:Enzyme Inhibitors; C000607177:GSK199; D006657:Histones; D054852:Small Molecule Libraries; D002956:Citrulline; D006867:Hydrolases; C000629235:PADI4 protein, human; D000080002:Protein-Arginine Deiminase Type 4; D000076342:Protein-Arginine Deiminases; C552151:peptidylarginine deiminase 4, mouse; D002118:Calcium