The Structural Basis of Cryptosporidium-Specific IMP Dehydrogenase Inhibitor Selectivity


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 103 selectivity for the parasite enzyme over human IMPDH2.




Copyright 2010 Journal of the American Chemical Society . This is a post-print version of a published paper that is available at: Recommended citation: MacPherson, Iain S., Sivapriya Kirubakaran, Suresh Kumar Gorla, Thomas V. Riera, J. Alejandro D’Aquino, Minjia Zhang, Gregory D. Cuny, and Lizbeth Hedstrom. "The structural basis of Cryptosporidium-specific IMP dehydrogenase inhibitor selectivity." Journal of the American Chemical Society 132, no. 4 (2010): 1230-1231. doi:10.1021/ja909947a. This item has been deposited in accordance with publisher copyright and licensing terms and with the author's permission.