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

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

doi:10.1016/j.bmc.2005.04.039

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

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

Research output: Contribution to journal › Article › peer-review

Abstract / Description of output

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.

Original language	English
Pages (from-to)	4513-4526
Number of pages	14
Journal	Bioorganic and Medicinal Chemistry
Volume	13
Issue number	14
DOIs	https://doi.org/10.1016/j.bmc.2005.04.039
Publication status	Published - 15 Jul 2005

Keywords / Materials (for Non-textual outputs)

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

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10.1016/j.bmc.2005.04.039

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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. (c) 2005 Published by Elsevier Ltd.",

keywords = "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",

author = "Dixon, {M J} and Maurer, {R I} and C Biggi and J Oyarzabal and Essex, {J W} and M Bradley",

year = "2005",

month = jul,

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doi = "10.1016/j.bmc.2005.04.039",

language = "English",

volume = "13",

pages = "4513--4526",

journal = "Bioorganic and Medicinal Chemistry",

issn = "0968-0896",

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TY - JOUR

T1 - Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase

AU - Dixon, M J

AU - Maurer, R I

AU - Biggi, C

AU - Oyarzabal, J

AU - Essex, J W

AU - Bradley, M

PY - 2005/7/15

Y1 - 2005/7/15

N2 - 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.

AB - 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.

KW - trypanothione reductase

KW - parallel synthesis

KW - mechanism of action

KW - structure-activity relationships

KW - SOLID-PHASE SYNTHESIS

KW - RATIONAL DRUG DESIGN

KW - TRYPANOSOMA-CRUZI

KW - CRITHIDIA-FASCICULATA

KW - DIMERIZATION INHIBITORS

KW - HIV-1 PROTEASE

KW - SPERMIDINE DERIVATIVES

KW - POLYAMINE DERIVATIVES

KW - SELECTIVE INHIBITORS

KW - DISULFIDE

U2 - 10.1016/j.bmc.2005.04.039

DO - 10.1016/j.bmc.2005.04.039

M3 - Article

SN - 0968-0896

VL - 13

SP - 4513

EP - 4526

JO - Bioorganic and Medicinal Chemistry

JF - Bioorganic and Medicinal Chemistry

IS - 14

ER -

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

Abstract / Description of output

Keywords / Materials (for Non-textual outputs)

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