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Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

de Souza W, Rodrigues JC - Interdiscip Perspect Infect Dis (2009)

Bottom Line: In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT).Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells.Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísicia Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, 21941-902, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.

No MeSH data available.


Related in: MedlinePlus

(a)-(b) Growth curves of promastigotes and (c)-(d) intracellular amastigotes of Leishmania amazonensis treated with two potent squalene synthase inhibitors, E5700 and ER-119884. The graphics are reproduced with permission from [37] American Society for Microbiology.
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fig4: (a)-(b) Growth curves of promastigotes and (c)-(d) intracellular amastigotes of Leishmania amazonensis treated with two potent squalene synthase inhibitors, E5700 and ER-119884. The graphics are reproduced with permission from [37] American Society for Microbiology.

Mentions: In trypanosomatids and fungi, there are several works describing the potent and selective activity of zaragozic acids and quinuclidines [35–37, 63–68]. For example, ER-119884 and E5700, two novel quinuclidine derivatives produced by Eisai Co. (Tokyo, Japan), have been shown to be potent anti-Trypanosoma and Leishmania agents in vitro, leading to a dramatic depletion of the parasite's endogenous sterols, that is, associated with an intense antiproliferative activity [36, 37]. Figures 4(a)–4(d) shows the antiproliferative effect of E5700 (Figures 4(a) and 4(c)) and ER-119884 (Figures 4(b) and 4(d)) in promastigotes and intracellular amastigotes of Leishmania amazonensis. These compounds are very potent against both forms of the life cycle, presenting MIC values of 30 and 10 nM for promastigote, and 2.0 and 0.5 nM for intracellular amastigotes [37]. When compared with the minimal concentration that affects macrophages, these values are, respectively, 100 000 and 25 000 fold greater than the corresponding IC50, indicating that they are selective against the parasite without any effect in the host cells.


Sterol Biosynthesis Pathway as Target for Anti-trypanosomatid Drugs.

de Souza W, Rodrigues JC - Interdiscip Perspect Infect Dis (2009)

(a)-(b) Growth curves of promastigotes and (c)-(d) intracellular amastigotes of Leishmania amazonensis treated with two potent squalene synthase inhibitors, E5700 and ER-119884. The graphics are reproduced with permission from [37] American Society for Microbiology.
© Copyright Policy - open-access
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2721973&req=5

fig4: (a)-(b) Growth curves of promastigotes and (c)-(d) intracellular amastigotes of Leishmania amazonensis treated with two potent squalene synthase inhibitors, E5700 and ER-119884. The graphics are reproduced with permission from [37] American Society for Microbiology.
Mentions: In trypanosomatids and fungi, there are several works describing the potent and selective activity of zaragozic acids and quinuclidines [35–37, 63–68]. For example, ER-119884 and E5700, two novel quinuclidine derivatives produced by Eisai Co. (Tokyo, Japan), have been shown to be potent anti-Trypanosoma and Leishmania agents in vitro, leading to a dramatic depletion of the parasite's endogenous sterols, that is, associated with an intense antiproliferative activity [36, 37]. Figures 4(a)–4(d) shows the antiproliferative effect of E5700 (Figures 4(a) and 4(c)) and ER-119884 (Figures 4(b) and 4(d)) in promastigotes and intracellular amastigotes of Leishmania amazonensis. These compounds are very potent against both forms of the life cycle, presenting MIC values of 30 and 10 nM for promastigote, and 2.0 and 0.5 nM for intracellular amastigotes [37]. When compared with the minimal concentration that affects macrophages, these values are, respectively, 100 000 and 25 000 fold greater than the corresponding IC50, indicating that they are selective against the parasite without any effect in the host cells.

Bottom Line: In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT).Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells.Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle.

View Article: PubMed Central - PubMed

Affiliation: Laboratório de Ultraestrutura Celular Hertha Meyer, Instituto de Biofísicia Carlos Chagas Filho, Universidade Federal do Rio de Janeiro, CCS-Bloco G, 21941-902, Rio de Janeiro, RJ, Brazil.

ABSTRACT
Sterols are constituents of the cellular membranes that are essential for their normal structure and function. In mammalian cells, cholesterol is the main sterol found in the various membranes. However, other sterols predominate in eukaryotic microorganisms such as fungi and protozoa. It is now well established that an important metabolic pathway in fungi and in members of the Trypanosomatidae family is one that produces a special class of sterols, including ergosterol, and other 24-methyl sterols, which are required for parasitic growth and viability, but are absent from mammalian host cells. Currently, there are several drugs that interfere with sterol biosynthesis (SB) that are in use to treat diseases such as high cholesterol in humans and fungal infections. In this review, we analyze the effects of drugs such as (a) statins, which act on the mevalonate pathway by inhibiting HMG-CoA reductase, (b) bisphosphonates, which interfere with the isoprenoid pathway in the step catalyzed by farnesyl diphosphate synthase, (c) zaragozic acids and quinuclidines, inhibitors of squalene synthase (SQS), which catalyzes the first committed step in sterol biosynthesis, (d) allylamines, inhibitors of squalene epoxidase, (e) azoles, which inhibit C14alpha-demethylase, and (f) azasterols, which inhibit Delta(24(25))-sterol methyltransferase (SMT). Inhibition of this last step appears to have high selectivity for fungi and trypanosomatids, since this enzyme is not found in mammalian cells. We review here the IC50 values of these various inhibitors, their effects on the growth of trypanosomatids (both in axenic cultures and in cell cultures), and their effects on protozoan structural organization (as evaluted by light and electron microscopy) and lipid composition. The results show that the mitochondrial membrane as well as the membrane lining the protozoan cell body and flagellum are the main targets. Probably as a consequence of these primary effects, other important changes take place in the organization of the kinetoplast DNA network and on the protozoan cell cycle. In addition, apoptosis-like and autophagic processes induced by several of the inhibitors tested led to parasite death.

No MeSH data available.


Related in: MedlinePlus