Specific peptide inhibitors of trypanothione reductase with backbone structures unrelated to that of substrate: potential rational drug design lead frameworks.
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.
McKie
J H
JH
School of Pharmacy & Pharmaceutical Sciences, University of Manchester, United Kingdom.
Garforth
J
J
Jaouhari
R
R
Chan
C
C
Yin
H
H
Besheya
T
T
Fairlamb
A H
AH
Douglas
K T
KT
D015195:Drug Design; D004791:Enzyme Inhibitors / Q000737:chemistry* / Q000494:pharmacology*; D005978:Glutathione / Q000031:analogs & derivatives / Q000737:chemistry; D005980:Glutathione Reductase / Q000187:drug effects / Q000378:metabolism; D020128:Inhibitory Concentration 50; D008958:Models, Molecular; D009247:NADH, NADPH Oxidoreductases / Q000037:antagonists & inhibitors*; D009842:Oligopeptides; D010455:Peptides / Q000737:chemistry* / Q000494:pharmacology; D013095:Spermidine / Q000031:analogs & derivatives / Q000737:chemistry; D013329:Structure-Activity Relationship
D004791:Enzyme Inhibitors; D009842:Oligopeptides; D010455:Peptides; C070514:N-benzyloxycarbonyl-alanyl-arginyl-arginine 4-methoxy-2-naphthylamide; C044809:trypanothione; D009247:NADH, NADPH Oxidoreductases; C049608:trypanothione reductase; D005980:Glutathione Reductase; D005978:Glutathione; D013095:Spermidine