Effects of inhibitors of Delta24(25)-sterol methyl transferase on the ultrastructure of epimastigotes of Trypanosoma cruzi.
Trypanosoma cruzi is the ethiological agent of Chagas disease. New compounds are being developed based on the biosynthesis and function of sterols, because T. cruzi has a requirement for specific endogenous sterols for growth and survival. Sterol biosynthesis inhibitors (SBIs) are drugs commonly used against fungal diseases. These drugs act by depleting essential and specific membrane components and/or inducing the accumulation of toxic intermediary or lateral products of the biosynthetic pathway. In this work we present the effects of WSP488, WSP501, and WSP561, specific inhibitors of Delta24(25)-sterol methyl transferase, on the ultrastructure of T. cruzi epimastigotes. All three drugs inhibited parasite multiplication at low concentrations, with IC50 values of 0.48, 0.44, and 0.48 muM, respectively, and induced marked morphological changes including (a) blockage of cell division; (b) swelling of the mitochondrion, with several projections and depressions; (c) swelling of the perinuclear space; (d) presence of autophagosomes and myelin-like figures; (e) enlargement of the flagellar pocket and of a cytoplasmic vacuole located in close association with the flagellar pocket; (f) detachment of the membrane of the cell body; and (g) formation of a vesicle at the surface of the parasite between the flagellar pocket and the cytostome. Our results show that these drugs are potent in vitro inhibitors of growth of T. cruzi.
Braga
Marina V
MV
Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, Ilha do Fundão, 21949-900, Rio de Janeiro-RJ, Brasil.
Magaraci
Filippo
F
Lorente
Silvia Orenes
SO
Gilbert
Ian
I
de Souza
Wanderley
W
D000818:Animals; D001343:Autophagy; D002462:Cell Membrane / Q000187:drug effects / Q000648:ultrastructure; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D008780:Methyltransferases / Q000037:antagonists & inhibitors*; D014344:Trypanocidal Agents / Q000494:pharmacology; D014349:Trypanosoma cruzi / Q000187:drug effects / Q000254:growth & development* / Q000648:ultrastructure; D014617:Vacuoles / Q000187:drug effects / Q000648:ultrastructure
D004791:Enzyme Inhibitors; D014344:Trypanocidal Agents; D008780:Methyltransferases; C022670:delta 24-sterol methyltransferase