title: Synthesis and evaluation of silanediols as highly selective uncompetitive inhibitors of human neutrophil elastase.
abstract: Chronic obstructive pulmonary disease (COPD) is an increasing health problem and is estimated to be the fifth leading cause of death in 2020 according to the World Health Organization. Current treatments are only palliative, and therefore the development of new medicine for the treatment of COPD is urgent. Human Neutrophil Elastase (HNE) is a serine protease that is heavily involved in the progression of COPD through inflammatory breakdown of lung tissue. Consequently, inhibitors of HNE are of great interest as therapeutics. In this article, the development of silanediol peptide isosters as inhibitors of HNE is presented. Kinetic studies revealed that incorporation of a silanediol isoster in the inhibitor structure resulted in an uncompetitive mechanism of inhibition, which further resulted in excellent selectivity. The peculiar mechanism of inhibition and the resulting selectivity makes the presented inhibitors promising leads for the development of new HNE-inhibitor-based therapeutics for the treatment of COPD.
authors.affiliation: Center for Insoluble Protein Structures, Department of Chemistry, and Interdisciplinary Nanoscience Center, Aarhus University, Langelandsgade 140, 8000 Aarhus C, Denmark.
authors.forename: Julie L H
authors.initials: JL
authors.lastname: Madsen
authors.forename: Thomas L
authors.initials: TL
authors.lastname: Andersen
authors.forename: Salvatore
authors.initials: S
authors.lastname: Santamaria
authors.forename: Hideaki
authors.initials: H
authors.lastname: Nagase
authors.forename: Jan J
authors.initials: JJ
authors.lastname: Enghild
authors.forename: Troels
authors.initials: T
authors.lastname: Skrydstrup
mesh_terms: D004791:Enzyme Inhibitors / Q000138:chemical synthesis* / Q000494:pharmacology*; D006801:Humans; D019272:Leukocyte Elastase / Q000037:antagonists & inhibitors*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D012821:Silanes / Q000138:chemical synthesis* / Q000494:pharmacology*
chemical_list: D004791:Enzyme Inhibitors; D012821:Silanes; C475536:silanediol; D019272:Leukocyte Elastase