Desktop version

Home arrow Economics arrow American Trypanosomiasis Chagas Disease, Second Edition: One Hundred Years of Research

Source

Ergosterol synthesis

Squalene synthase (SQS) catalyzes the first step committed to the biosynthesis of sterols within the isoprenoid pathway, and several quinuclidine inhibitors of the enzyme were shown to have selective anti-T. cruzi activity both in vitro and in vivo.71 SQ-109, which is in clinical trials against drug-sensitive and drug- resistant tuberculosis,72 and a variety of aryloxyethyl thiocyanates73 also inhibit the enzyme. The enzyme is membrane-bound, and was expressed in truncated form in Escherichia coli and biochemically characterized.71 Its X-ray crystallographic structure in the presence of inhibitors has been reported.74 The following step in the synthesis of ergosterol is catalyzed by the squalene epoxidase, which is the target of terbinafine, a drug that is active in vitro and in vivo against T. cruzi.20 Lanosterol is then synthesized by a reaction catalyzed by the lanosterol synthase or oxidosqua- lene cyclase (Fig. 17.2). Several inhibitors of the enzyme showed activity in vitro against T. cruzi25 Interestingly, the antiarrhythmic bis-aryl-ketone amiodarone, which is used in chronic Chagas patients with heart problems, also inhibits this enzyme and has activity in vitro and in vivo against T. cruzi26 Lanosterol is converted into zymosterol by a series of reactions started by the sterol 14a-demethylase, a target of azole (imidazole and triazole) derivatives.20 This enzyme is a member of the cytochrome P450 superfamily (CYP51), and catalyzes the oxidative removal of the 14a-methyl group from postsqualene sterol precursors. The gene encoding this enzyme was cloned and expressed and its substrate preferences studied.77 The crystal structure of T. cruzi CYP51 bound to inhibitors has also been reported.78-80

Azole compounds were first detected to have activity against T. cruzi in 1981.42 Miconazole and econazole showed a potent growth inhibitory action parallel to a decrease in its 5,7-diene sterol content.42 Later studies showed that ketoconazole, and other potent antimycotic azoles were also active in protecting mice against lethal infections with T. cruzi,81,82 in inhibiting intracellular multiplication of the parasites, and in blocking their biosynthesis of fungal-type sterols. , More recent work on a number of inhibitors of this enzyme has been reviewed recently.20 Although the enzyme is present in mammalian cells, it is much less sensitive to the drugs than that present in fungi and trypanosomatids. Several of these azole compounds have undergone clinical trials against Chagas disease.21

Ergosterol differs from cholesterol, the predominant mammalian sterol, by the presence of a 24-methyl group and Д7 and Д22 double bonds. The enzymatic reactions that introduce the extra methyl group and the Д22 double bond of ergosterol have no counterpart in mammalian sterol biosynthesis, and may be regarded as targets for new antiparasitic agents. In agreement with this hypothesis it has been shown that azasterols, which are Д24(25) sterol methyl transferase inhibitors, have a potent antiproliferative effect on T. cruzi in vitro and in vivo.86

 
Source
Found a mistake? Please highlight the word and press Shift + Enter  
< Prev   CONTENTS   Next >

Related topics