Ergosterol biosynthesis inhibition by the thiocarbamate antifungal agents tolnaftate and tolciclate

Ryder, Neil S.; Frank, Ingeborg; Dupont, Marie-Claude

doi:10.1128/aac.29.5.858

Cited by 120 publications

(52 citation statements)

References 13 publications

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“…They have a higher inhibitory activity than the starting compound and are reversible, non-competitive inhibitors of C. albicans squalene monooxygenase with respect to squalene, FAD, NADH and NADPH (Ryder and Dupont , 1985 ;Abe et al , 1994 ). IC 50 values for mammalian SE are several orders of magnitude higher than for the fungal enzyme (e.g., IC 50 for terbinafi ne for C. albicans = 30 n m , for rat > 100000 n m ) (Ryder et al , 1986 ). It suggests that during antimycotic therapy they do not disturb the cholesterol biosynthesis pathway of the host.…”

Section: Antimycotic Compoundsmentioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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Squalene monooxygenase catalyzes the epoxidation of C-C double bond of squalene to yield 2,3-oxidosqualene, the key step of sterol biosynthesis pathways in eukaryotes. Sterols are essential compounds of these organisms and squalene epoxidation is an important regulatory point in their synthesis. Squalene monooxygenase downregulation in vertebrates and fungi decreases synthesis of cholesterol and ergosterol, respectively, which makes squalene monooxygenase a potent and attractive target of hypercholesterolemia and antifungal therapies. Currently some fungal squalene monooxygenase inhibitors (terbinafi ne, naftifi ne, butenafi ne) are in clinical use, whereas mammalian enzymes ' inhibitors are still under investigation. Research on new squalene monooxygenase inhibitors is important due to the prevalence of hypercholesterolemia and the lack of both suffi cient and safe remedies. In this paper we (i) review data on activity and the structure of squalene monooxygenase, (ii) present its inhibitors, (iii) compare current strategies of lowering cholesterol level in blood with some of the most promising strategies, (iv) underline advantages of squalene monooxygenase as a target for hypercholesterolemia therapy, and (v) discuss safety concerns about hypercholesterolemia therapy based on inhibition of cellular cholesterol biosynthesis and potential usage of squalene monooxygenase inhibitors in clinical practice. After many years of use of statins there is some clinical evidence for their adverse effects and only partial effectiveness. Currently they are drugs of choice but are used with many restrictions, especially in case of children, elderly patients and women of childbearing potential. Certainly, for the next few years, statins will continue to be a suitable tool for cost-effective cardiovascular prevention; however research on new hypolipidemic drugs is highly desirable. We suggest that squalene monooxygenase inhibitors could become the hypocholesterolemic agents of the future.

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Section: Antimycotic Compoundsmentioning

confidence: 99%

Squalene monooxygenase – a target for hypercholesterolemic therapy

Belter¹,

Skupińska²,

Giel-Pietraszuk

et al. 2011

BCHM

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“…The latter enzyme is of considerable practical interest as the target of a new class of antimycotic agents, the allylamines [4,5]. Surprisingly, the thiocarbamate antifungals have also been found to inhibit squalene epoxidase [6]. In this report we show that I and II inhibit both squalene epoxidase and the cyclase in microsomes from the pathogenic yeast Candida albicans, and from rat liver.…”

Section: Methodsmentioning

confidence: 64%

“…Although 240 this latter inhibition was quantitatively reproducible, Lineweaver-Burk plots were variable between experiments and failed to show a pattern typical of either competitive or non-competitive inhibition. 6 Results are mean of 2 separate experiments each with triplicate incubations. Mean incorporation of radioactivity into total non-saponifiable lipids was 158 800 dpm Table 3 Inhibitory effects of I and II on sterol biosynthesis enzymes in C. albicuns and rat liver The lack of specificity and the effects on mammalian enzymes appear to rule out these derivatives as potential antifungal agents, but they may be of interest in the development of hypocholesterolemic agents.…”

Section: Methodsmentioning

confidence: 99%

Inhibition of fungal and mammalian sterol biosynthesis by 2‐aza‐2,3‐dihydrosqualene

1986

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2-Aza-2,3_dihydrosqualene (I) and a quaternary ammonium derivative (II) inhibited ergosterol biosynthesis in cells and cell-free extracts of the pathogenic yeast Candida albicans as measured by incorporation of radiolabelled precursors. The compounds inhibited squalene epoxidase and 2,3-oxidosqualene cyclase to varying degrees in microsomes from C. albicans and from rat liver. The rat liver epoxidase was 50% inhibited by I at 2.4 PM. In C. afbicans cells, but not in cell-free extracts, I also inhibited lanosterol demethylation and led to accumulation of an unidentified polar product.(Candida albicans)

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“…In vivo Ryder et al, 1986 Examined the incorporation of U-14 C-acetate and L-methyl-14 C-methionine into ergosterol.…”

Section: Sterol Biosynthesismentioning

confidence: 99%

Secondary Assays for Testing the Mode of Action of Natural Products with Bioactivity Against Fungi

Smith

Cruz

Golshani

et al. 2008

Pharmaceutical Biology

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Identification of novel antifungals is needed, and plantderived compounds offer important leads in this respect. This article initiates a compendium of secondary assays for testing hypotheses on mode of action of plant-derived compounds. Three assays were developed to evaluate compounds that are hypothesized to effect cell wall function, transcription, and oxidative stress. A hypothesized perturbation on cell wall integrity by chimaphilin and Echinacea root extracts was supported using sonication and heat shock assays. Heat shock treatments reduced the number of viable cells recovered when yeast was grown in the presence of subinhibitory concentrations of chimaphilin. A reduction in cell numbers was also observed with both sonicationbased and heat shock-based assays when yeast was grown in the presence of Echinacea purpurea (L.) Moench (Asteraceae) extracts. The hypothesis that chimaphilin impedes mRNA transcription processes was also supported by a β-galactosidase reporter gene assay. The antioxidant activity of nordihydroguaiaretic acid (NDGA) and ascorbic acid were assessed using a yeast strain that does not grow under hyperoxic conditions. At the concentrations assayed, NDGA did not remediate this sensitivity to hyperoxia, whereas ascorbic acid did. These and additional assays are further reviewed with an aim to collate and standardize secondary assays and streamline antifungal mode of action determinations.

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Ergosterol biosynthesis inhibition by the thiocarbamate antifungal agents tolnaftate and tolciclate

Cited by 120 publications

References 13 publications

Squalene monooxygenase – a target for hypercholesterolemic therapy

Squalene monooxygenase – a target for hypercholesterolemic therapy

Inhibition of fungal and mammalian sterol biosynthesis by 2‐aza‐2,3‐dihydrosqualene

Secondary Assays for Testing the Mode of Action of Natural Products with Bioactivity Against Fungi

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