Identification and development of novel inhibitors of Toxoplasma gondii enoyl reductase
- Tipparaju, Suresh K
- Muench, Stephen P
- Mui, Ernest J
- Ruzheinikov, Sergey N
- Lu, Jeffrey Z.
- Hutson, Samuel L
- Kirisits, Michael J.
- Prigge, Sean T.
- Roberts, Craig
- Henriquez, Fiona L
- Kozikowski, Alan P
- Rice, David W
- McLeod, Rima L
DOIAbstract
Toxoplasmosis causes significant morbidity and mortality, and yet available medicines are limited by toxicities and hypersensitivity. Because improved medicines are needed urgently, rational approaches were used to identify novel lead compounds effective against Toxoplasma gondii enoyl reductase (TgENR), a type II fatty acid synthase enzyme essential in parasites but not present in animals. Fifty-three compounds, including three classes that inhibit ENRs, were tested. Six compounds have antiparasite MIC(90)s <or = 6 microM without toxicity to host cells, three compounds have IC(90)s <45 nM against recombinant TgENR, and two protect mice. To further understand the mode of inhibition, the cocrystal structure of one of the most promising candi...
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