The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity
Journal of the American Chemical Society2010Vol. 132(4), pp. 1230–1231
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Iain Macpherson, Sivapriya Kirubakaran, Suresh Kumar Gorla, Thomas V. Riera, J. Alejandro D’Aquino, Minjia Zhang, Gregory D. Cuny, Lizbeth Hedstrom
Abstract
Cryptosporidium parvum is a potential biowarfare agent, an important AIDS pathogen, and a major cause of diarrhea and malnutrition. No vaccines or effective drug treatment exist to combat Cryptosporidium infection. This parasite relies on inosine 5'-monophosphate dehydrogenase (IMPDH) to obtain guanine nucleotides, and inhibition of this enzyme blocks parasite proliferation. Here, we report the first crystal structures of CpIMPDH. These structures reveal the structural basis of inhibitor selectivity and suggest a strategy for further optimization. Using this information, we have synthesized low-nanomolar inhibitors that display 10(3) selectivity for the parasite enzyme over human IMPDH2.
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