Rational design of peptide-based inhibitors of trypanothione reductase as potential antitrypanosomal drugs

J. Garforth; J. H. McKie; R. Jaouhari; T. J. Benson; A. H. Fairlamb; K. T. Douglas

doi:10.1007/BF00813749

Rational design of peptide-based inhibitors of trypanothione reductase as potential antitrypanosomal drugs

J. Garforth, J. H. McKie, R. Jaouhari, T. J. Benson, A. H. Fairlamb, K. T. Douglas

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26 Citations (Scopus)

Abstract

The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that for T. cruzi TR benzoyl-Leu-Arg-Arg-ß-naphthylamide was an inhibitor (K_i 13.8 μM) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase.

Original language	English
Pages (from-to)	295-299
Number of pages	5
Journal	Amino Acids
Volume	6
Issue number	3
DOIs	https://doi.org/10.1007/BF00813749
Publication status	Published - Oct 1994

Keywords

Amino acids
Drug design
Glutathione reductase
Homology model
Leishmaniasis
Trypanosomiasis
Trypanothione reductase

ASJC Scopus subject areas

Biochemistry
Organic Chemistry
Clinical Biochemistry

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10.1007/BF00813749

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title = "Rational design of peptide-based inhibitors of trypanothione reductase as potential antitrypanosomal drugs",

abstract = "The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that for T. cruzi TR benzoyl-Leu-Arg-Arg-{\ss}-naphthylamide was an inhibitor (Ki 13.8 μM) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase.",

keywords = "Amino acids, Drug design, Glutathione reductase, Homology model, Leishmaniasis, Trypanosomiasis, Trypanothione reductase",

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AU - Garforth, J.

AU - McKie, J. H.

AU - Jaouhari, R.

AU - Benson, T. J.

AU - Fairlamb, A. H.

AU - Douglas, K. T.

PY - 1994/10

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AB - The rational design of ligands for the substrate-binding site of a homology-modelled trypanothione reductase (TR) was performed. Peptides were designed to be selective for TR over human glutathione reductase (GR). The design process capitalized on the proposed differences between the activesites of TR and human GR, subsequently confirmed by the TR crystal structure. Enzyme kinetics confirmed that for T. cruzi TR benzoyl-Leu-Arg-Arg-ß-naphthylamide was an inhibitor (Ki 13.8 μM) linearly competitive with the native substrate, trypanothione disulphide, and did not inhibit glutathione reductase.

KW - Amino acids

KW - Drug design

KW - Glutathione reductase

KW - Homology model

KW - Leishmaniasis

KW - Trypanosomiasis

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Rational design of peptide-based inhibitors of trypanothione reductase as potential antitrypanosomal drugs

Abstract

Keywords

ASJC Scopus subject areas

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