Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase.
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.
Dixon
Mark J
MJ
School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK.
Maurer
Richard I
RI
Biggi
Cristina
C
Oyarzabal
Julen
J
Essex
Jonathan W
JW
Bradley
Mark
M
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
D004791:Enzyme Inhibitors; D010455:Peptides; C006760:norspermidine; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D013095:Spermidine