Antiproliferative synergism of azasterols and antifolates against Toxoplasma gondii

Dantas-Leite, Lucas; Urbina, Julio A.; Souza, Wanderley de; Vommaro, Rossiane C.

doi:10.1016/j.ijantimicag.2004.08.016

Cited by 19 publications

(14 citation statements)

References 25 publications

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“…To control toxoplasmosis, a combination of antifolates, such as pyrimethamine and sulfadiazine, has been used with success and it is the first choice in most clinical settings [6,7]. On the other hand, a large percentage of undesirable side effects such as haematological toxicity (caused by pyrimethamine), cutaneous rash, leukopenia and thrombocytopenia (caused by sulphonamides) are often reported [7][8][9].…”

Section: Introductionmentioning

confidence: 99%

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Anti-Toxoplasma gondii RH strain activity of herbal extracts used in traditional medicine

Choi¹,

Gang

Yun

2008

International Journal of Antimicrobial Agents

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Section: Introductionmentioning

confidence: 99%

“…On the other hand, a large percentage of undesirable side effects such as haematological toxicity (caused by pyrimethamine), cutaneous rash, leukopenia and thrombocytopenia (caused by sulphonamides) are often reported [7][8][9]. * Corresponding author.…”

Section: Introductionmentioning

confidence: 99%

Anti-Toxoplasma gondii RH strain activity of herbal extracts used in traditional medicine

Choi¹,

Gang

Yun

2008

International Journal of Antimicrobial Agents

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“…These include the statins (or HMG-CoA reductase inhibitors), a class of drug used to lower plasma cholesterol level, that inhibit the enzyme HMG-CoA reductase. Multiple statins have been reported to have a selective inhibitory effect on T. gondii, including simvastatin [7] and the azasterols, which are known inhibitors of 24(25)-sterol methyltransferase in protozoa and fungi [8,9]. Squalene synthase inhibitors and quinuclidine derivatives also produce anti-proliferative effects [17].…”

mentioning

confidence: 99%

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Nishikawa

Ibrahim

Kameyama

et al. 2011

The Journal of Veterinary Medical Science

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ABSTRACT. The intracellular protozoan Toxoplasma gondii lacks the ability to synthesize sterol and scavenges cholesterol from the lowdensity lipoprotein receptor (LDLR) pathway of its host to facilitate replication. Sterol biosynthesis inhibitors, however, have a demonstrated anti-Toxoplasma effect. In this study, we examined the host mevalonate pathway as a novel source of cholesterol for T. gondii and its effects on parasite growth in macrophages. Parasite growth did not significantly change in the absence of LDLR or when LDL was exogenously supplemented. Lovastatin and compactin, both inhibitors of hydroxymethylglutaryl-CoA (HMG-CoA) reductase in the mevalonate pathway, significantly inhibited T. gondii growth in both wild-type and LDLR-knockout macrophages. Parasite growth was also suppressed by squalestatin, an inhibitor of squalene synthase, despite mevalonate producing isoprenoid intermediates in host cells. The present study demonstrates that lovastatin, compactin and squalestatin have anti-Toxoplasma activities and that the host cholesterol synthesis may contribute to parasite growth in macrophages.

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“…24-Alkyl sterols have not yet been identified in T. gondii; however, it would be possible that the selective accumulation of these compounds in parasite membranes such as the mitochondria could alter their function. In addition, a synergistic effect is observed when a combination of pyrimethamine-sulphadiazine therapy with azasterols is used [276]. A significant improvement of their antiproliferative activity is observed.…”

Section: Toxoplasmosismentioning

confidence: 99%

Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases

Liñares

Ravaschino²,

Rodríguez

2006

CMC

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The progresses made in the field of drug design to combat tropical protozoan parasitic diseases, such as Chagas' disease, leishmaniasis, and sleeping sickness are discussed. This article is focused on different approaches based on unique aspects of parasites biochemistry and physiology, selecting the more promising molecular targets for drug design. In spite of the enormous amount of work on the above features, the chemotherapy for all of these diseases remains unsolved. It is based on old and fairly not specific drugs associated, in several cases, with long-term treatments and severe side effects. Drug resistance and different strains susceptibility are further drawbacks of the existing chemotherapy. In this review article, a thorough analysis of selected molecular targets, mainly those that are significantly different compared with the mammalian host or, even, are not present in mammals would be described in terms of their potencial usefulness for drug design. Therefore, this article covers rational approaches to the chemotherapeutic control of these parasitic infections, such as the progresses in the search for novel metabolic pathways in parasites that may be essential for parasites survival but with no counterpart in the host. Ergosterol biosynthesis is a very interesting example. There are many enzymes involved in this biosynthetic pathway such us squalene synthase, farnesylpyrophosphate synthase, and other enzymes that are able to deplete endogenous sterols will be treated in this article. The enzymes involved in trypanothione biosynthesis, glutathionyl spermidine synthetase and trypanothione synthetase do not have an equivalent in mammals, and therefore it can be predicted low toxicity for compounds that are able to produce highly selective inhibition. Trypanothione reductase (TR), glyceraldehyde-3-phosphate dehydrogenase, dihydrofolate reductase, prenyltransferases, ornithine decarboxylase, etc, will be thoroughly analyzed. The design of specific inhibitors of such metabolic activities as possible means of controlling the parasites without damaging the hosts will be presented. The recent advances in the biochemistry of pathogenic parasites including the discovery of novel organelles will be discussed.

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Antiproliferative synergism of azasterols and antifolates against Toxoplasma gondii

Cited by 19 publications

References 25 publications

Anti-Toxoplasma gondii RH strain activity of herbal extracts used in traditional medicine

Anti-Toxoplasma gondii RH strain activity of herbal extracts used in traditional medicine

Host Cholesterol Synthesis Contributes to Growth of Intracellular Toxoplasma gondii in Macrophages

Progresses in the Field of Drug Design to Combat Tropical Protozoan Parasitic Diseases

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