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

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.

• Authors: Iain S Macpherson, Sivapriya Kirubakaran, Suresh Kumar Gorla, Thomas V Riera, J Alejandro D'Aquino, Minjia Zhang, Gregory D Cuny, Lizbeth Hedstrom
• Journal: Journal of the American Chemical Society (J Am Chem Soc) Vol. 132 Issue 4 Pg. 1230-1 (Feb 03 2010) ISSN: 1520-5126 [Electronic] United States
• PMID: 20052976 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antiprotozoal Agents
• Enzyme Inhibitors
• IMP Dehydrogenase

Topics

• Antiprotozoal Agents (chemical synthesis, pharmacology)
• Cryptosporidiosis (drug therapy)
• Cryptosporidium parvum (enzymology)
• Crystallography, X-Ray
• Enzyme Inhibitors (chemical synthesis, pharmacology)
• Humans
• IMP Dehydrogenase (antagonists & inhibitors, chemistry, metabolism)
• Models, Molecular