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

Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase
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.
trypanothione reductase, parallel synthesis, mechanism of action, structure-activity relationshipssolid-phase synthesis, rational drug design, trypanosoma-cruzi, crithidia-fasciculata, dimerization inhibitors, hiv-1 protease, spermidine derivatives, polyamine derivatives, selective inhibitors, disulfide
0968-0896
4513-4526
Dixon, Mark J.
6ee427c9-471e-4ee2-872a-7dc27ace0cde
Maurer, Richard I.
c6411cf3-e909-4b11-b31f-999a89bb3dfa
Biggi, Cristina
5b5afaae-4cc1-4c98-80de-0ec481567f50
Oyarzabal, Julen
636fd5a2-1786-4f67-a41a-f7f79577092f
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bradley, Mark
562b9add-34c4-4620-bfa1-c7c83a0f0900
Dixon, Mark J.
6ee427c9-471e-4ee2-872a-7dc27ace0cde
Maurer, Richard I.
c6411cf3-e909-4b11-b31f-999a89bb3dfa
Biggi, Cristina
5b5afaae-4cc1-4c98-80de-0ec481567f50
Oyarzabal, Julen
636fd5a2-1786-4f67-a41a-f7f79577092f
Essex, Jonathan W.
1f409cfe-6ba4-42e2-a0ab-a931826314b5
Bradley, Mark
562b9add-34c4-4620-bfa1-c7c83a0f0900

Dixon, Mark J., Maurer, Richard I., Biggi, Cristina, Oyarzabal, Julen, Essex, Jonathan W. and Bradley, Mark (2005) Mechanism and structure-activity relationships of norspermidine-based peptidic inhibitors of trypanothione reductase. Bioorganic & Medicinal Chemistry, 13 (14), 4513-4526.

Record type: Article

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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More information

Published date: 15 July 2005
Keywords: trypanothione reductase, parallel synthesis, mechanism of action, structure-activity relationshipssolid-phase synthesis, rational drug design, trypanosoma-cruzi, crithidia-fasciculata, dimerization inhibitors, hiv-1 protease, spermidine derivatives, polyamine derivatives, selective inhibitors, disulfide

Identifiers

Local EPrints ID: 20781
URI: http://eprints.soton.ac.uk/id/eprint/20781
ISSN: 0968-0896
PURE UUID: 5f4e9ea3-ce4b-4361-a220-0bf4a42e3c16
ORCID for Jonathan W. Essex: ORCID iD orcid.org/0000-0003-2639-2746

Catalogue record

Date deposited: 28 Feb 2006
Last modified: 29 Oct 2019 02:06

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