Antiproliferative and ultrastructural effects of BPQ-OH, a specific inhibitor of squalene synthase, on Leishmania amazonensis

Federal University of Rio de Janeiro, Rio de Janeiro, Rio de Janeiro, Brazil
Experimental Parasitology (Impact Factor: 1.64). 01/2006; 111(4):230-8. DOI: 10.1016/j.exppara.2005.08.006
Source: PubMed


Parasites of the Leishmania genus require for the growth and viability the de novo synthesis of specific sterols as such as episterol and 5-dehydroepisterol because cholesterol, which is abundant in their mammalian hosts, does not fulfill the parasite sterol requirements. Squalene synthase catalyzes the first committed step in the sterol biosynthesis and has been studied as a possible target for the treatment of high cholesterol levels in humans. In this work we investigated the antiproliferative and ultrastructural effects induced by 3-(biphenyl-4-yl)-3-hydroxyquinuclidine (BPQ-OH), a specific inhibitor of squalene synthase, on promastigote and amastigote forms of Leishmania amazonensis. BPQ-OH had a potent dose-dependent growth inhibitory effect against promastigotes and amastigotes, with IC(50) values 0.85 and 0.11 microM, respectively. Ultrastructural analysis of the treated parasites revealed several changes in the morphology of promastigote forms. The main ultrastructural change was found in the plasma membrane, which showed signs of disorganization, with the concomitant formation of elaborated structures. We also observed alterations in the mitochondrion-kinetoplast complex such as mitochondrial swelling, rupture of its internal membrane and an abnormal compaction of the kinetoplast. Other alterations included the appearance of multivesicular bodies, myelin-like figures, alterations of the flagellar membrane and presence of parasites with two or more nuclei and kinetoplasts. We conclude that the BPQ-OH was a potent growth inhibitor of L. amazonensis, which led to profound changes of the parasite's ultrastructure and might be a valuable lead compound for the development of novel anti-Leishmania agents.

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    • "These drugs have high toxicity and adverse side effects [5]. Amphotericin B and pentamidine are second-line therapies but are associated with long-term treatment, limited effectiveness, significant side effects, and toxicity [6] [7] [8]. Consequently, an urgent need exists to discover new drugs that are effective against leishmaniasis. "
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    • "BPQ-OH was one of the first arylquinuclidines (originally developed as a potential cholesterol-lowering agent) reported to have potent activity against the Leishmania major SQS [27], blocking sterol biosynthesis and the growth of Leishmania spp. and T. cruzi in the low-nanomolar to subnanomolar range [9-12,28]. However, BPQ-OH is not active against Candida spp. "
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    ABSTRACT: Sterol biosynthesis is an essential pathway for fungal survival, and is the biochemical target of many antifungal agents. The antifungal drugs most widely used to treated fungal infections are compounds that inhibit cytochrome P450-dependent C14α-demethylase (CYP51), but other enzymes of this pathway, such as squalene synthase (SQS) which catalyses the first committed step in sterol biosynthesis, could be viable targets. The aim of this study was to evaluate the antifungal activity of SQS inhibitors on Candida albicans, Candida tropicalis and Candida parapsilopsis strains. Ten arylquinuclidines that act as SQS inhibitors were tested as antiproliferative agents against three ATCC strains and 54 clinical isolates of Candida albicans, Candida tropicalis and Candida parapsilopsis. Also, the morphological alterations induced in the yeasts by the experimental compounds were evaluated by fluorescence and transmission electron microscopy. The most potent arylquinuclidine derivative (3-[1'-{4'-(benzyloxy)-phenyl}]-quinuclidine-2-ene) (WSP1267) had a MIC50 of 2 μg/ml for all species tested and MIC90 varying from 4 μg/ml to 8 μg/ml. Ultrathin sections of C. albicans treated with 1 μg/ml of WSP1267 showed several ultrastructural alterations, including (a) loss of cell wall integrity, (b) detachment of the plasma membrane from the fungal cell wall, (c) accumulation of small vesicles in the periplasmic region, (d) presence of large electron-dense vacuoles and (e) significantly increased cell size and cell wall thickness. In addition, fluorescence microscopy of cells labelled with Nile Red showed an accumulation of lipid droplets in the cytoplasm of treated yeasts. Nuclear staining with DAPI revealed the appearance of uncommon yeast buds without a nucleus or with two nuclei. Taken together, our data demonstrate that arylquinuclidine derivatives could be useful as lead compounds for the rational synthesis of new antifungal drugs.
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