Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:1.5.1.3 (dihydrofolate reductase)
 5,819 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Diseases caused by pathogenic trypanosomatids cause great suffering throughout the developing world. New drugs for these diseases are urgently needed. Recent technological advances have permitted the identification and validation of numerous drug targets in these organisms. However, efforts to develop inhibitors of these targets, that may then be taken forward for development into new drugs, have been comparatively scarce. In this review we discuss the design, synthesis and evaluation of inhibitors of two drug targets in trypanosomatids, 6-phosphogluconate dehydrogenase, the third enzyme of the pentose phosphate pathway, and dihydrofolate reductase, a key enzyme involved in DNA synthesis. Enzyme inhibitors can only be useful as drugs if they can enter cells and bind to their targets. Therefore we also discuss approaches to designing molecules that can specifically cross the plasma membrane of African trypanosomes via unusual nutrient transporters.
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PMID:Perspectives for new drugs against trypanosomiasis and leishmaniasis. 1196 68

Chagas disease, a parasitic infection typically spread by triatomine bugs, affects millions of people throughout Latin America. Current chemotherapy based on the nitroaromatic compounds, benzonidazole and nifurtimox provides unsatisfactory results and suffers from considerable side effects. Therefore, there is still an urgent need for new drugs to treat this neglected disease. During the last decade, the advances and understanding in the biology and biochemistry of Trypanosoma cruzi have allowed the identification of multiple new targets for Chagas' disease chemotherapy. Among the most promising targets for antiparasitic drugs are: cruzipain, the main cysteine protease of T. cruzi, essential for parasite survival and proliferation in mammalian host; ergosterol biosynthesis pathway; trypanothione synthesis and thiol-dependant redox metabolism. Specific enzymes of the glycolytic, pentose phosphate, polyisoprenoid (farnesylpyrophosphate synthase) and other particular biosynthetic pathways as well as enzymes from purine salvage (hypoxanthine-guanine phosphoribosyl-transferase, dihydrofolate reductase) have also been intensively studied in T. cruzi. In particular, trypanocidal agents that target the validated biochemical pathways of the parasite including cysteine proteinase inhibitors and inhibitors capable to block ergosterol biosynthesis are currently in the pipeline. Among the latter, posaconazole and ravuconazole, are planned to enter in clinical trials for trypanocidal chemotherapy in the near future. This review will summarize advances on antichagasic agents directed to specific parasite targets such as metabolic pathways or specific enzymes. Related patents filed and issued from 2000 to 2010 claiming inhibitors for specific parasite targets will be also discussed. Among them, the most represented were those related with cysteine proteinase inhibitors.
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PMID:A decade of targets and patented drugs for chemotherapy of Chagas disease. 2182 73

NADPH donates high energy electrons for antioxidant defense and reductive biosynthesis. Cytosolic NADP is recycled to NADPH by the oxidative pentose phosphate pathway (oxPPP), malic enzyme 1 (ME1) and isocitrate dehydrogenase 1 (IDH1). Here we show that any one of these routes can support cell growth, but the oxPPP is uniquely required to maintain a normal NADPH/NADP ratio, mammalian dihydrofolate reductase (DHFR) activity and folate metabolism. These findings are based on CRISPR deletions of glucose-6-phosphate dehydrogenase (G6PD, the committed oxPPP enzyme), ME1, IDH1, and combinations thereof in HCT116 colon cancer cells. Loss of G6PD results in high NADP, which induces compensatory increases in ME1 and IDH1 flux. But the high NADP inhibits dihydrofolate reductase (DHFR), resulting in impaired folate-mediated biosynthesis, which is reversed by recombinant expression of E. coli DHFR. Across different cancer cell lines, G6PD deletion produced consistent changes in folate-related metabolites, suggesting a general requirement for the oxPPP to support folate metabolism.
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PMID:NADPH production by the oxidative pentose-phosphate pathway supports folate metabolism. 3105 57