Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase

Krungkrai, Jerapan; Krungkrai, Sudaratana R.; Phakanont, Kritsana

doi:10.1016/0006-2952(92)90506-e

Cited by 64 publications

(48 citation statements)

References 32 publications

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“…carinii contains a DHOD which appears to be linked to the mitochondrial electron transport chain, as it is in most other eukaryotes. Consistent with this, P. carinii DHOD activity is susceptible to antimycin A, which inhibits complex III, and cyanide, which inhibits complex IV, both of which are downstream from ubiquinone (20), which is where DHOD is believed to donate electrons (5,12,22).…”

Section: Discussionsupporting

confidence: 55%

“…DHOD is a particularly important enzyme, because it is the target of several useful chemotherapeutic agents such as the antitumor agent brequinar sodium (6) and the antimalarial agents atovaquone and menoctone (13,17). Several orotate analogs have antimalarial activities (20,25). Since atovaquone is also an effective treatment for Pneumocystis carinii pneumonia (2), it is possible that the P. carinii DHOD might be an important chemotherapeutic target.…”

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confidence: 99%

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Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase

Ittarat

Asawamahasakda

Bartlett

et al. 1995

Antimicrob Agents Chemother

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Dihydroorotate dehydrogenase (DHOD) is a pyrimidine biosynthetic enzyme which is usually directly linked to the mitochondrial respiratory chain. Antimalarial naphthoquinones such as atovaquone (566c80) inhibit malarial DHOD by inhibiting electron transport. Since atovaquone also has therapeutic activity against Pneumocystis carinii, the P. carinii DHOD may also be an important drug target. Organisms were obtained from immunosuppressed rats, incubated for 24 h in a short-term in vitro culture system, and then lysed. P. carinii lysates catalyzed the generation of orotate from dihydroorotate at a rate of 852 pmol/mg of protein per min. Control preparations made from uninfected mice showed much less total enzymatic activity and enzyme specific activity. As expected, P. carinii DHOD activity was susceptible to respiratory inhibitors such as cyanide, antimycin A, and salicylhydroxamic acid (SHAM). Susceptibility to SHAM suggests the presence of an alternative oxidase. In contrast, neither pentamidine nor 5-hydroxy-6-demethylprimaquine (5H6DP), a quinone metabolite of primaquine, inhibited the enzyme. Atovaquone inhibited DHOD by 76.3% at 100 M and 36.5% at 10 M. A similar degree of inhibition was found when the organisms were preincubated with the drug. Atovaquone inhibited P. carinii growth in vitro at a somewhat lower concentration (between 0.3 and 3 M). In contrast, Plasmodium falciparum growth and enzyme activity are susceptible to nanomolar concentrations of atovaquone. Thus, while it is possible that atovaquone acts by inhibiting the P. carinii electron transport chain, the possibility of another drug target cannot be excluded.Dihydroorotate dehydrogenase (DHOD) is a key enzyme in de novo pyrimidine biosynthesis, catalyzing the conversion of dihydroorotate to orotate (5,12,22). DHOD is a particularly important enzyme, because it is the target of several useful chemotherapeutic agents such as the antitumor agent brequinar sodium (6) and the antimalarial agents atovaquone and menoctone (13,17). Several orotate analogs have antimalarial activities (20,25). Since atovaquone is also an effective treatment for Pneumocystis carinii pneumonia (2), it is possible that the P. carinii DHOD might be an important chemotherapeutic target. But little is currently known about the P. carinii DHOD.In all eukaryotic cells that have been studied except trypanosomatids (23), DHOD is bound to mitochondria. Isolated enzymes donate electrons directly to oxygen and to various artificial electron acceptors, although they usually prefer coenzyme Q (ubiquinone) (22). In intact organisms, carefully broken cells, and isolated mitochondria, most DHODs donate electrons directly to the mitochondrial respiratory chain.In a previous study we have examined the effects of various drugs on the mitochondrion-bound DHOD of Plasmodium falciparum (18). We then looked at the effects of these and other drugs on the P. carinii DHOD, which are described here. MATERIALS AND METHODSDrugs. Atovaquone (566c80) was a gift from the Burroughs Wellcome Co., Researc...

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Section: Discussionsupporting

confidence: 55%

mentioning

confidence: 99%

Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase

Ittarat

Asawamahasakda

Bartlett

et al. 1995

Antimicrob Agents Chemother

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“…In mice infected with P. berghei, 5-fluoro orotate and 5-amino orotate at a dose of 25 μg/g body weight eliminated parasitemia after a 4-day treatment, an effect comparable to that of the same dose of chloroquine. The infected mice treated with 5-fluoro orotate at a lower dose of 2.5 μg/g had a 95% reduction in parasitemia [171]. The moderate inhibition of PfDHOase by L-6-thiodihydroorotate (TDHO) in cultured parasites induced major accumulation of CP-asp and growth arrest, similar to atovaquone [172].…”

Section: Dihydroorotasementioning

confidence: 92%

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

Lunev¹,

Batista²,

Bosch³

et al. 2016

Current Topics in Malaria

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In order to counter the malarial parasite's striking ability to rapidly develop drug resistance, a constant supply of novel antimalarial drugs and potential drug targets must be available. The so-called Harlow-Knapp effect, or "searching under the lamp post," in which scientists tend to further explore only the areas that are already well illuminated, significantly limits the availability of novel drugs and drug targets. This chapter summarizes the pool of electron transport chain (ETC) and carbon metabolism antimalarial targets that have been "under the lamp post" in recent years, as well as suggest a promising new avenue for the validation of novel drug targets. The interplay between the pathways crucial for the parasite, such as pyrimidine biosynthesis, aspartate metabolism, and mitochondrial tricarboxylic acid (TCA) cycle, is described in order to create a "road map" of novel antimalarial avenues.

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“…It salvages the preformed purine bases/nucleosides from the human host and converts them to their mono-, di-and triphosphates. The parasite can only synthesize pyrimidines de novo from HCO 3 -, ATP, glutamine, aspartate, and 5-phosphoribosyl-1-pyrophosphate [43][44][45][46][47][48][49][50][51][52][53] . These unique properties on both purine and pyrimidine requirement of the parasite are key differences from the human host, in which both functional de novo and salvage pathways of the purine and pyrimidine synthesis exists [46,48,[54][55][56][57][58].…”

Section: Basic Life Cycle Genomics and Biochemistry Of Human Malariamentioning

confidence: 99%

“…By using [ 3 H]hypoxanthine incorporation for monitoring growth of P. falciparum in in vitro cell culture [45] , the 50% inhibitory concentration (IC 50 ) for AZA is 20 毺 M. Based on the morphology examination of treated parasites in in vitro culture, the effect of AZA was more pronounced in the ring/ trophozoite forms than the schizont stage of P. falciparum, as shown by clumping of nucleus and collapsing cytoplasm ( Figure 4). This is consistent with the stage-dependent activity of the enzyme in that more maturing parasites contain higher activity ( Table 1).…”

Section: In Vitro and In Vivo Antimalarial Properties Of 毩 -Carbonic mentioning

confidence: 99%

Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

Krungkrai¹,

Krungkrai²

2011

Asian Pacific Journal of Tropical Biomedicine

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Antimalarial activity of orotate analogs that inhibit dihydroorotase and dihydroorotate dehydrogenase

Cited by 64 publications

References 32 publications

Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase

Effects of atovaquone and other inhibitors on Pneumocystis carinii dihydroorotate dehydrogenase

Identification and Validation of Novel Drug Targets for the Treatment of Plasmodium falciparum Malaria: New Insights

Malaria parasite carbonic anhydrase: inhibition of aromatic/heterocyclic sulfonamides and its therapeutic potential

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