Targeting prolyl endopeptidase with valproic acid as a potential modulator of neutrophilic inflammation.
A novel neutrophil chemoattractant derived from collagen, proline-glycine-proline (PGP), has been recently characterized in chronic obstructive pulmonary disease (COPD). This peptide is derived via the proteolytic activity of matrix metalloproteases (MMP's)-8/9 and PE, enzymes produced by neutrophils and present in COPD serum and sputum. Valproic acid (VPA) is an inhibitor of PE and could possibly have an effect on the severity of chronic inflammation. Here the interaction site of VPA to PE and the resulting effect on the secondary structure of PE is investigated. Also, the potential inhibition of PGP-generation by VPA was examined in vitro and in vivo to improve our understanding of the biological role of VPA. UV-visible, fluorescence spectroscopy, CD and NMR were used to determine kinetic information and structural interactions between VPA and PE. In vitro, PGP generation was significantly inhibited by VPA. In vivo, VPA significantly reduced cigarette-smoke induced neutrophil influx. Investigating the molecular interaction between VPA and PE showed that VPA modified the secondary structure of PE, making substrate binding at the catalytic side of PE impossible. Revealing the molecular interaction VPA to PE may lead to a better understanding of the involvement of PE and PGP in inflammatory conditions. In addition, the model of VPA interaction with PE suggests that PE inhibitors have a great potential to serve as therapeutics in inflammatory disorders.
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Mojtaba
M
Abdul Roda
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands; Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Mariam
M
Sadik
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Amit
A
Gaggar
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Matthew T
MT
Hardison
Department of Chemistry, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Michael J
MJ
Jablonsky
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands.
Saskia
S
Braber
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
James Edwin
JE
Blalock
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Frank A
FA
Redegeld
Division of Pharmacology, Utrecht Institute for Pharmaceutical Sciences, Faculty of Sciences, Utrecht University, Utrecht, The Netherlands.
Gert
G
Folkerts
Department of Medicine, Division of Pulmonary, Allergy and Critical Care Medicine and UAB Lung Health Center, University of Alabama at Birmingham, Birmingham, Alabama, United States of America.
Patricia L
PL
Jackson
D000818:Animals; D003094:Collagen / Q000378:metabolism; D005260:Female; D006801:Humans; D007249:Inflammation / Q000201:enzymology; D051379:Mice; D009504:Neutrophils / Q000187:drug effects* / Q000276:immunology; D000085822:Prolyl Oligopeptidases; D017433:Protein Structure, Secondary / Q000187:drug effects; D029424:Pulmonary Disease, Chronic Obstructive / Q000201:enzymology / Q000276:immunology; D012697:Serine Endopeptidases / Q000737:chemistry / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000737:chemistry / Q000494:pharmacology*; D012906:Smoke; D014026:Nicotiana; D014635:Valproic Acid / Q000737:chemistry / Q000494:pharmacology*
D015842:Serine Proteinase Inhibitors; D012906:Smoke; D014635:Valproic Acid; D003094:Collagen; D012697:Serine Endopeptidases; C000705287:PREPL protein, human; D000085822:Prolyl Oligopeptidases