Inhibition of triosephosphate isomerase from Trypanosoma brucei with cyclic hexapeptides.
Two series of oligopeptides have been synthesized. Their effects on the activity of purified triosephosphate isomerase from Trypanosoma brucei and various other organisms have been studied. Using detailed three-dimensional structure information, the first series consisted of both cyclic and linear hydrophilic peptides that were designed to mimic the beta turns of the subunit interface loops of the trypanosome triosephosphate isomerase dimer. None of these exerted any inhibitory effect. The second series consisted of more hydrophobic cyclic peptides, originally designed to inhibit a hepatic transport system. Several of these were very effective in inhibiting the trypanosome triosephosphate isomerase, but not the homologous enzymes from rabbit, dog, yeast or Escherichia coli. The most active peptide, cyclo[-Trp-Phe-D-Pro-Phe-Phe-Lys(Z)-], exerted 50% inhibitory activity at a concentration of 3 microM. The nature of the inhibitory action of one of these compounds cyclo[-Trp-Tyr(OSO3Na)-D-Pro-Phe-Thr(OSO3Na)-Lys(Z)-] was studied in more detail. Its inhibition was noncompetitive and reversible and more than one peptide was able to bind/active site.
Kuntz
D A
DA
Research Unit for Tropical Diseases, International Institute of Molecular Pathology, Brussels, Belgium.
Osowski
R
R
Schudok
M
M
Wierenga
R K
RK
Müller
K
K
Kessler
H
H
Opperdoes
F R
FR
D000595:Amino Acid Sequence; D000818:Animals; D007700:Kinetics; D008958:Models, Molecular; D008969:Molecular Sequence Data; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology*; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology; D012995:Solubility; D013329:Structure-Activity Relationship; D013997:Time Factors; D014305:Triose-Phosphate Isomerase / Q000037:antagonists & inhibitors* / Q000648:ultrastructure; D014346:Trypanosoma brucei brucei / Q000201:enzymology*
D009842:Oligopeptides; D010456:Peptides, Cyclic; D014305:Triose-Phosphate Isomerase