Braga Marina V, Urbina Julio A, de Souza Wanderley
Instituto de Biofísica Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, Ilha de Fundão, 21949-900 Rio de Janeiro, RJ, Brazil.
Int J Antimicrob Agents. 2004 Jul;24(1):72-8. doi: 10.1016/j.ijantimicag.2003.12.009.
Squalene synthase (SQS) catalyses the first committed step of sterol biosynthesis; a blockade of this enzyme does not affect the production of other essential isoprenoids. In the present study, 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH) and ER27856, two specific inhibitors of SQS, were tested against epimastigote forms of Trypanosoma cruzi. Both compounds inhibited parasite multiplication with IC(50) values of 24.3 and 4.5 microM, respectively and induced marked morphological changes. These changes included: (a) detachment of the plasma membrane from the cell body, forming blebs; (b) detachment of the membrane lining the cell body and the flagellum from the sub-pellicular and axonemal microtubules; (c) enlargement of the flagellar pocket; (d) enlargement of a vacuole localised close to the flagellar pocket, which may correspond to a contractile vacuole; (e) mitochondrial swelling, with the appearance of concentric structures formed by invaginations of the inner mitochondrial membrane; (f) alterations in the nucleus of some cells, where the chromatin appears in clumps, as described for apoptotic cells; and (g) blockage of cytokinesis. These alterations are interpreted as a consequence of the depletion of essential parasite sterols induced by the experimental compounds and the concomitant alteration of the physical properties of the parasite membranes.
角鲨烯合酶（SQS）催化甾醇生物合成的首个关键步骤；对该酶的阻断不会影响其他必需类异戊二烯的产生。在本研究中，测试了两种SQS特异性抑制剂3 - （联苯 - 4 - 基） - 3 - 羟基奎宁环（BPQ - OH）和ER27856对克氏锥虫前鞭毛体形式的作用。两种化合物均抑制寄生虫增殖，IC（50）值分别为24.3和4.5 microM，并诱导明显的形态变化。这些变化包括：（a）质膜从细胞体脱离，形成泡状凸起；（b）衬于细胞体和鞭毛的膜从表膜下微管和轴丝微管脱离；（c）鞭毛袋扩大；（d）位于鞭毛袋附近的一个液泡扩大，可能对应于一个收缩泡；（e）线粒体肿胀，出现由线粒体内膜内陷形成的同心结构；（f）一些细胞的细胞核发生改变，其中染色质呈团块状，如同凋亡细胞中所描述的那样；以及（g）胞质分裂受阻。这些改变被解释为由实验化合物诱导的必需寄生虫甾醇耗竭以及随之而来的寄生虫膜物理性质改变的结果。
