title: Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase.
abstract: A library of polyamine-peptide conjugates based around some previously identified inhibitors of trypanothione reductase was synthesised by parallel solid-phase chemistry and screened. Kinetic analysis of library members established that subtle structural changes altered their mechanism of action, switching between competitive and non-competitive inhibition. The mode of action of the non-competitive inhibitors was investigated in detail by a variety of techniques including enzyme kinetic analysis (looking at both NADPH and trypanothione disulfide substrates), gel filtration chromatography and analytical ultracentrifugation, leading to the identification of an allosteric mode of inhibition.
authors.affiliation: School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
authors.forename: Mark J
authors.initials: MJ
authors.lastname: Dixon
authors.forename: Richard I
authors.initials: RI
authors.lastname: Maurer
authors.forename: Cristina
authors.initials: C
authors.lastname: Biggi
authors.forename: Julen
authors.initials: J
authors.lastname: Oyarzabal
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Essex
authors.forename: Mark
authors.initials: M
authors.lastname: Bradley
mesh_terms: D002850:Chromatography, Gel; D002851:Chromatography, High Pressure Liquid; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D009682:Magnetic Resonance Spectroscopy; D013058:Mass Spectrometry; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology*; D013095:Spermidine / Q000031:analogs & derivatives* / Q000737:chemistry; D013329:Structure-Activity Relationship; D014461:Ultracentrifugation
chemical_list: D004791:Enzyme Inhibitors; D010455:Peptides; C006760:norspermidine; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D013095:Spermidine