Rationally Designed Inhibitors of Sterol Biosynthesis

Ultrastructural and Biochemical Alterations Induced by 22,26-Azasterol, a Δ 24(25) -Sterol Methyltransferase Inhibitor, on Promastigote and Amastigote Forms of Leishmania amazonensis

“…When these cells were incubated in the presence of 50 nM ketoconazole, a known inhibitor of the sterol C14-demethylase of fungi and trypanosomatid parasites (37,54), the normal parasite sterols were replaced by lanosterol, 4,14-dimethylfecosterol, and 14-methyl-fecosterol (Table 1); a simultaneous incubation of the cells with 100 nM 22,26-azasterol and 50 nM ketoconazole led instead to the accumulation of lanosterol, 4,14-dimethyl-zymosterol, and 14-methyl-zymosterol (Table 1). Taken together, these results support the notion that the primary mechanism of action of 22,26-azasterol against trypanosomatids is inhibition of 24-SMT, as is found in fungi, yeasts, and plants (2,11,28,31,36). They also indicate that 24-SMT in L. amazonensis can use zymosterol or its 14-methyl or 4,14-dimethyl derivatives as substrates, as reported before for L. braziliensis and L. mexicana (40); similar results were obtained with T. cruzi (23,52,53).…”

“…These enzymes, which catalyze the S-adenosylmethionine-mediated incorporation of methenyl groups at position 24 in sterols, are essential for the biosynthesis of fungal and protozoal sterol molecules. Indeed, inhibitors of these enzymes have been shown to be antiproliferative agents against yeasts, fungi, and plants in vitro (2,11,28,31,36). One important feature is the absence of this enzyme in the sterol of the parasite's vertebrate host, which exclusively produces the 24-desalkyl sterol cholesterol (54).…”

Antiproliferative Effects of △²⁴⁽²⁵⁾ Sterol Methyl Transferase Inhibitors on <i>Trypanosoma (Schizotrypanum) cruzi</i>: In vitro and in vivo Studies

“…1.43], an enzyme found in fungi, yeast, protozoa and plants which catalyzes an essential step in the biosynthesis of sterols in these organisms but not in vertebrates [15][16][17][18][19], and thus repre sents an ideal target for chemotherapeutic in tervention in diseases caused by pathogens belonging to these biological groups. Sterol analogs with positive charges at specific loca tions of its side chains have been found to be very effective inhibitors of 24(25)-SMT and growth inhibitors of yeasts, fungi, plants and protozoa in vitro [15,16,[20][21][22][23] but to the best of our knowledge there have been no reports on their successful therapeutic appli cation in vivo. In the present study we found that two of these inhibitors, a cholestanol ana log with a 6-membcred aza ring as a side chain (22,AZA, fig.…”

Human Mycoses: Drugs and Targets for Emerging Pathogens

“…However, even targets with counterparts in the cholesterol pathway may be clinically useful, because contrary to fungi, which have no uptake system for sterols, mammalian cells can take up dietary cholesterol via the low density lipoprotein (LDL) pathway (14). Targets in the early steps of ergosterol synthesis include hyhdroxymethyl glutaryl coenzyme A -(CoA) and mevalonic acid synthesis (13), although so far inhibitors of these steps do not have antifungal activity-probably because they cannot penetrate the membrane.…”

“…2). Other targets in the ergosterol pathway are oxido-51 squalene cyclase and A24 methyltransferase (13), the latter being unique to ergosterol synthesis and thus a particularly attractive tar--, get. However, even targets with counterparts in the cholesterol pathway may be clinically useful, because contrary to fungi, which have no uptake system for sterols, mammalian cells can take up dietary cholesterol via the low density lipoprotein (LDL) pathway (14).…”