A trypanosome oligopeptidase as a target for the trypanocidal agents pentamidine, diminazene and suramin.
African trypanosomes contain a cytosolic serine oligopeptidase, called OP-Tb, that is reversibly inhibited by the active principles of three of the five most commonly used trypanocidal drugs: pentamidine, diminazene and suramin. OP-Tb was inhibited by pentamidine in a competitive manner, and by suramin in a partial, non-competitive manner. The inhibition of OP-Tb by a variety of suramin analogues correlated with the trypanocidal efficacy of these analogues (P=0.03; by paired Student's t-test). Since intracellular (therapeutic) concentrations of pentamidine and suramin are reported to reach approximately 206Ki and 15Ki respectively, we suggest that these drugs may exert part of their trypanocidal activity through the inhibition of OP-Tb.
Morty
R E
RE
Department of Biochemistry, University of Natal, Scottsville, South Africa.
Troeberg
L
L
Pike
R N
RN
Jones
R
R
Nickel
P
P
Lonsdale-Eccles
J D
JD
Coetzer
T H
TH
D000818:Animals; D004133:Diminazene / Q000494:pharmacology*; D010419:Pentamidine / Q000494:pharmacology*; D012697:Serine Endopeptidases / Q000378:metabolism*; D015842:Serine Proteinase Inhibitors / Q000494:pharmacology*; D013329:Structure-Activity Relationship; D013498:Suramin / Q000031:analogs & derivatives* / Q000494:pharmacology*; D014344:Trypanocidal Agents / Q000494:pharmacology*; D014345:Trypanosoma / Q000187:drug effects / Q000201:enzymology*
D015842:Serine Proteinase Inhibitors; D014344:Trypanocidal Agents; D013498:Suramin; D010419:Pentamidine; D012697:Serine Endopeptidases; C100685:oligopeptidase Tb; D004133:Diminazene