The overall program project will test the hypothesis that a combination of thymidine and select antifolates directed at the thymidylate synthase domain of PIasmodium falciparum dihydrofolate reductase-thymidylate synthase (DHFR-TS) can be potent and safe antimalarial agents, worthy of future clinical trials in humans. Blood-stage forms of malaria parasites are completely dependent on de novo pyrimidine biosynthesis and fail to salvage preformed pyrimidines, unlike human cells. Of all the enzymes available in de novo pyrimidine biosynthesis, DHFR-TS is of particular interest. Inhibitors of the DHFR domain are proven drug targets in malaria. The PI's laboratory has previously demonstrated that one TS antifolate (1843U89) inhibits Plasmodium TS with a Ki of 1 nM and inhibits parasite proliferation with an EC50 of 70 riM. With 10 uM thymidine, mammalian cells show no toxicity to this compound, even at 10,000 times higher concentrations. Starting with this very strong lead, we will develop additional compounds that are even more potent.
The aim of this core will be to provide specialty chemicals. The ability to synthesize published antifolate molecules and key intermediates is demonstrated in this application. Hundreds of new derivatives will be synthesized as needed for the Program Project. The PI's current appointment in a large chemistry department allows Core A access to the experiences and advice of 40 tenured or tenure-track chemistry faculty, additional research scientists, about 200 chemistry graduate students, and state of the science synthesis and analytical facilities including five high-field NMRs and three MS instruments. Even though the PI has personnel interested in the biology of malaria chemotherapy, since moving to the UW Chemistry Department in 2001, he has recruited three excellent organic chemists in his lab. They will synthesize about 50 to 100 variants of TS inhibitors per year. These will be used by all three Projects to arrive at compounds and formulations that are potent antimalarials and safe for mammalian cells.
|Begley, Darren W; Zheng, Suxin; Varani, Gabriele (2010) Fragment-based discovery of novel thymidylate synthase leads by NMR screening and group epitope mapping. Chem Biol Drug Des 76:218-33|
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|Gujjar, Ramesh; Marwaha, Alka; El Mazouni, Farah et al. (2009) Identification of a metabolically stable triazolopyrimidine-based dihydroorotate dehydrogenase inhibitor with antimalarial activity in mice. J Med Chem 52:1864-72|
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|Ganesan, Karthikeyan; Ponmee, Napawan; Jiang, Lei et al. (2008) A genetically hard-wired metabolic transcriptome in Plasmodium falciparum fails to mount protective responses to lethal antifolates. PLoS Pathog 4:e1000214|
|Gonzales, Joseph M; Patel, Jigar J; Ponmee, Napawan et al. (2008) Regulatory hotspots in the malaria parasite genome dictate transcriptional variation. PLoS Biol 6:e238|
|Eastman, Richard T; White, John; Hucke, Oliver et al. (2007) Resistance mutations at the lipid substrate binding site of Plasmodium falciparum protein farnesyltransferase. Mol Biochem Parasitol 152:66-71|
|Mudeppa, Devaraja G; Pang, Cullen K T; Tsuboi, Takafumi et al. (2007) Cell-free production of functional Plasmodium falciparum dihydrofolate reductase-thymidylate synthase. Mol Biochem Parasitol 151:216-9|
|Hunt, Sonia Y; Detering, Carsten; Varani, Gabriele et al. (2005) Identification of the optimal third generation antifolate against P. falciparum and P. vivax. Mol Biochem Parasitol 144:198-205|
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