Specific peptide inhibitors of trypanothione reductase with backbone structures unrelated to that of substrate: potential rational drug design lead frameworks

J H McKie; J Garforth; R Jaouhari; C Chan; H Yin; T Besheya; A H Fairlamb; K T Douglas

doi:10.1007/s007260170055

Specific peptide inhibitors of trypanothione reductase with backbone structures unrelated to that of substrate: potential rational drug design lead frameworks

Amino Acids. 2001;20(2):145-53. doi: 10.1007/s007260170055.

Authors

J H McKie¹, J Garforth, R Jaouhari, C Chan, H Yin, T Besheya, A H Fairlamb, K T Douglas

Affiliation

¹ School of Pharmacy & Pharmaceutical Sciences, University of Manchester, United Kingdom.

PMID: 11332449
DOI: 10.1007/s007260170055

Abstract

By introducing cationic charge sites novel peptide lead inhibitor structures for trypanothione reductase have been designed using molecular modelling methods. The inhibitors showed reversible, linear competitive inhibition and the strongest peptide inhibitor to date was found to be N-benzyloxycarbonyl-Ala-Arg-Arg-4-methoxy-beta-naphthylamide with a Ki value of 2.4 microM and a selectivity for parasitic enzyme (trypanothione reductase) over the host enzyme (human glutathione reductase) of over 3 orders of magnitude.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Drug Design
Enzyme Inhibitors / chemistry*
Enzyme Inhibitors / pharmacology*
Glutathione / analogs & derivatives
Glutathione / chemistry
Glutathione Reductase / drug effects
Glutathione Reductase / metabolism
Inhibitory Concentration 50
Models, Molecular
NADH, NADPH Oxidoreductases / antagonists & inhibitors*
Oligopeptides
Peptides / chemistry*
Peptides / pharmacology
Spermidine / analogs & derivatives
Spermidine / chemistry
Structure-Activity Relationship

Substances

Enzyme Inhibitors
Oligopeptides
Peptides
N-benzyloxycarbonyl-alanyl-arginyl-arginine 4-methoxy-2-naphthylamide
trypanothione
NADH, NADPH Oxidoreductases
trypanothione reductase
Glutathione Reductase
Glutathione
Spermidine