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Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase

Research output: Contribution to journalArticle

  • M J Dixon
  • R I Maurer
  • C Biggi
  • J Oyarzabal
  • J W Essex
  • M Bradley

Related Edinburgh Organisations

Original languageEnglish
Pages (from-to)4513-4526
Number of pages14
JournalBioorganic and Medicinal Chemistry
Volume13
Issue number14
DOIs
Publication statusPublished - 15 Jul 2005

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. (c) 2005 Published by Elsevier Ltd.

    Research areas

  • trypanothione reductase, parallel synthesis, mechanism of action, structure-activity relationships, SOLID-PHASE SYNTHESIS, RATIONAL DRUG DESIGN, TRYPANOSOMA-CRUZI, CRITHIDIA-FASCICULATA, DIMERIZATION INHIBITORS, HIV-1 PROTEASE, SPERMIDINE DERIVATIVES, POLYAMINE DERIVATIVES, SELECTIVE INHIBITORS, DISULFIDE

ID: 1514509