Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0024530 (malaria)
 44,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Trypanothione reductases (TR; EC 1.6.4.8) and thioredoxin reductases (TrxR; EC 1.6.4.5.) are enzymes central to cellular thiol metabolism. Trypanosoma cruzi TR (TcTR) is therefore considered as a potential candidate for drug design against trypanosomiasis. Inhibition of human TrxR (hTrxR) is likely to be beneficial in psoriasis, cancer, and autoimmune diseases, while inhibition of a putative TrxR from Plasmodium falciparum (PfTrxR) might prove effective against malaria. The natural substrates of the first two enzymes are very expensive and difficult to obtain; in the case of PfTrxR, the physiological substrate has not yet been identified. We have therefore synthesized and tested three different 5,5'-dithiobis(2-nitrobenzamides) as alternative substrates of the above enzymes. As with 5, 5'-dithiobis(2-nitrobenzoate) (DTNB), which can be reduced by TRs and TrxRs, the new compounds are converted to their corresponding chromophoric thiolates; however, they have much lower Km values and are therefore less likely to interfere with inhibitor testing. Using the new substrates, a novel enzyme assay has been developed which is identical for all three enzymes, can be performed in a microtiter plate, and is amenable to automation. Thus, the assay provides a versatile and inexpensive tool for kinetic studies and high-throughput inhibitor screening.
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PMID:Synthesis of 5,5'-dithiobis(2-nitrobenzamides) as alternative substrates for trypanothione reductase and thioredoxin reductase: a microtiter colorimetric assay for inhibitor screening. 1003 54

Trypanothione reductase (TR) is an essential enzyme of trypanosomatids and therefore a promising target for the development of new drugs against African sleeping sickness and Chagas' disease. Diaryl sulfides with a central anilino moiety, decorated with a flexible N-alkyl side chain bearing a terminal ammonium ion, are a known class of inhibitors. Using computer modelling, we revised the binding model for this class of TR inhibitors predicting simultaneous interactions of the ammonium ion-terminated N-alkyl chain with Glu18 as well as Glu465'/Glu466' of the second subunit of the homodimer, whereas the hydrophobic substituent of the aniline ring occupies the "mepacrine binding site" near Trp21 and Met113. Systematic alteration of the carboxylate-binding fragments and the diaryl sulfide core of the inhibitor scaffold provided evidence for the proposed binding mode. In vitro studies showed IC(50) values in the low micromolar to submicromolar range against Trypanosoma brucei rhodesiense as well as the malaria parasite Plasmodium falciparum.
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PMID:Diaryl sulfide-based inhibitors of trypanothione reductase: inhibition potency, revised binding mode and antiprotozoal activities. 1893

Trypanothione reductase (TR) is a flavoenzyme unique to trypanosomatid parasites and a target for lead discovery programs. Various inhibitor scaffolds have emerged in the past, exhibiting moderate affinity for the parasite enzyme. Herein we show that the combination of two structural motifs of known TR inhibitors - diaryl sulfides and mepacrine - enables the simultaneous addressing of two hydrophobic patches in the active site. The binding efficacy of these conjugates is enhanced over that of the respective parent inhibitors. They show K(ic) values for the parasite enzyme down to 0.9+/-0.1 microm and exhibit high selectivity for TR over human glutathione reductase (GR). Despite their considerable molecular mass and in some cases permanent positive charges, in vitro studies revealed IC(50) values in the low micromolar to sub-micromolar range against Trypanosoma brucei rhodesiense and Trypanosoma cruzi, as well as the malaria parasite Plasmodium falciparum, which lack trypanothione metabolism. The inhibitors exhibit strong fluorescence due to their aminoacridine moiety. This feature allows visualization of the drugs in the parasite where high accumulation was observed by fluorescence microscopy even after short exposure times.
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PMID:Synthesis, inhibition potency, binding mode, and antiprotozoal activities of fluorescent inhibitors of trypanothione reductase based on mepacrine-conjugated diaryl sulfide scaffolds. 1984 46