The structural basis of Cryptosporidium -specific IMP dehydrogenase inhibitor selectivity.

Publication Type:

Journal Article

Authors:

Macpherson, Iain S; Kirubakaran, Sivapriya; Gorla, Suresh Kumar; Riera, Thomas V; D'Aquino, J Alejandro; Zhang, Minjia; Cuny, Gregory D; Hedstrom, Lizbeth

Source:

J Am Chem Soc, Volume 132, Issue 4, p.1230-1 (2010)

Keywords:

Antiprotozoal Agents, Cryptosporidiosis, Cryptosporidium parvum, Crystallography, X-Ray, Enzyme Inhibitors, Humans, IMP Dehydrogenase, Models, Molecular

Abstract:

<p>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.</p>