Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase |
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Authors: | Dixon Mark J Maurer Richard I Biggi Cristina Oyarzabal Julen Essex Jonathan W Bradley Mark |
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Institution: | School of Chemistry, University of Southampton, Southampton SO17 1BJ, UK. |
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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. |
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