Plasmodium falciparum dihydrofolate reductase

Toyoda T, Brobey RKB, Sano G, Horii T, Tomioka N, Itai Akiko. Lead discovery of inhibitors of the dihydrofolate reductase domain of Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Biochem Biophys Res Commun 1997 235 515-19. 

Rastelli G, Pacchioni S, Sirawaraporn W, Sirawaraporn R, Parenti MD, Ferrari AM. Docking and database screening reveal new classes of Plasmodium falciparum dihydrofolate reductase inhibitors. J Med Chem 2003 46 2834-45. 

JF Cortese, CV Plowe. Antifolate resistance due to new and known Plasmodium falciparum dihydrofolate reductase mutations expressed in yeast. Mol Biochem Parasitol 94 205-214, 1998. 

Res. Commun., 235, 515 (1997). Lead Discovery of Inhibitors of the Dihydrofolate Reductase Domain of Plasmodium falciparum Dihydrofolate Reductase-Thymidylate... 

Santos-Filho. O.A., Mishra, R.K and Hopfinger, A.J. (2001) Free energy force field (FEFF) 3D-QSAR analysis of a set of Plasmodium falciparum dihydrofolate reductase inhibitors. J. Comput. Aid. Mol Des., 15. 787-810. 

Bzik, D. J., Li, W. B., Horii, T., and Inselburg, J. (1987). Molecular cloning and sequence analysis of the Plasmodium falciparum dihydrofolate reductase-thymidylate synthase gene. Proc. Natl. Acad. Sci. USA 84, 8360-8364. 

Mudeppa, D. G., Pang, C. K., Tsuboi, T., Endo, Y., Buckner, F. S., Varani, G., and Rathod, P. K. (2007). Cell-free production of functional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Mol. Biochem. Parasitol. 151,216-219. 

Yuthavong, Y., Yuvaniyama, J., Chitnumsub, P., Vanichtanankul, J., Chusacultanachai, S., Tarnchompoo, B., Vilaivan, T., and Kamchonwongpaisan, S. (2005). Malarial (Plasmodium falciparum) dihydrofolate reductase-thymidylate synthase Structural basis for antifolate resistance and development of effective inhibitors. Parasitology 130,249-259. 

VI.a.2.2. Biguanides. Proguanil is a dihydrofolate reductase inhibitor. It is a slow acting blood schizonticide and not effective on its own. It has also a marked effect on the primary tissue stages of Plasmodium falciparum. It is used in combination with chloroquine for the prophylaxis of chloroquine-resistant Plasmodium falciparum. 

VI.a.2.4. Diaminopyrimidines. Pyrimethamine is a dihydrofolate reductase inhibitor, like the biguanides, and is structurally related to trimethoprim. It is seldom used alone. Pyrimethamine in fixed combinations with dapsone or sulfadoxine is used for treatment and prophylaxis of chloroquine-resistant falciparum malaria. The synergistic activities of pyrimethamine and sulfonamides are similar to those of trimethoprim/sulfonamide combinations. Resistant strains of Plasmodium falciparum have appeared world wide. Prophylaxis against falciparum... 

A novel approach to the production of antimalarial drugs has been described taking advantage of the in vivo transformation of pteridines by resident enzymes <2005AAC3652>. It was shown that simple precursors such as 2,4-diamino-6-hydroxymethylpterin can be converted into aminopterin or methotrexate, depending upon the precursor chosen, and that the dihydrofolate reductase inhibitors so formed were active against Plasmodium falciparum. 

Intracellular protozoa of the phylum Apicomplexa such as plasmodium, toxoplasma, and eimeria have long been known to respond to sulfonamides and sulfones. This has led to the assumption that Apicomplexa must synthesize their own folate in order to survive. The reaction of 2-amino-4-hydroxy-6-hydroxymethyl-dihydropteridine diphosphate with />aminobenzoate to form 7,8-dihydropteroate has been demonstrated in cell-free extracts of the human malaria parasite Plasmodium falciparum. 2-Amino-4-hydroxy-6-hydroxymethyl-dihydropteridine pyrophosphokinase and 7,8-dihydropteroate synthase have also been identified. Sulfathiazole, sulfaguanidine, and sulfanilamide act as competitive inhibitors of p-aminobenzoate. It has not been possible to demonstrate dihydrofolate synthase activity in the parasites, which raises the possibility that 7,8-dihydropteroate may have substituted for dihydrofolate in malaria parasites. Similar lack of recognition of folate as substrate was also observed in the dihydrofolate reductase of Eimeria tenella, a parasite of chickens. 

The sulfones and sulfonamides synergize with the inhibitors of dihydrofolate reductase, and the combinations have been effective in controlling malaria, toxoplasmosis, and coccidiosis. Fansidar, a combination of sulfadoxine and pyrimethamine, has been successful in controlling some strains of chloroquine-resistant Plasmodium falciparum malaria (see Chapter 53 Antiprotozoal Drugs). However, reports of Fansidar resistance have increased in recent years. New inhibitors effective against the sulfonamide-resistant 7,8-dihydropteroate synthase are needed. 

Dihydrofolate reductase (DHFR), a classic target in antimicrobial and anticancer chemotherapy, has been shown to be a useful therapeutic target in plasmodium, toxoplasma, and eimeria species. Pyrimethamine is the prototypical DHFR inhibitor, exerting inhibitory effects in all three groups. However, pyrimethamine resistance in P falciparum has become widespread in recent years. This is largely attributable to specific point mutations in P falciparum DHFR that have rendered the enzyme less susceptible to the inhibitor. 

JM Wooden, LH Hartwell, B Vasquez, CH Sibley. Analysis in yeast of antimalaria drugs that target the dihydrofolate reductase of Plasmodium falciparum. Mol Biochem Parasitol 85 25 10, 1997. 

Enzymes that are addressed by major drugs have been studied in particular detail. Thus, well above one hundred stmctures have been reported for dihydrofolate reductases from a variety of organisms, including major pathogens such as Mycobacterium tuberculosis, which is the causative agent of tuberculosis, and of Plasmodium falciparum, which is the most important of the Plasmodium spp. that causes malaria. The interaction of mammalian dihydrofolate reductases with inhibitors that are used as cytostatic agents and/or immunosuppressants is also documented extensively by X-ray stmctures. 

Hall, S. J., Sims, P. F., and Hyde, J. E. (1991). Functional expression of the dihydrofolate reductase and thymidylate synthetase activities of the human malaria parasite Plasmodium falciparum in Escherichia coli. Mol. Biochem. Parasitol. 45,317-330. 

Walter, R. D. (1986). Altered dihydrofolate reductase in pyrimethamine-resistant Plasmodium falciparum. Mol. Biochem. Parasitol. 19, 61-66. 

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