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 10(3) selectivity for the parasite enzyme over human IMPDH2.
Macpherson
Iain S
IS
Departments of Biology, Brandeis University, MS009, 415 South Street, Waltham, Massachusetts 02454, USA.
Kirubakaran
Sivapriya
S
Gorla
Suresh Kumar
SK
Riera
Thomas V
TV
D'Aquino
J Alejandro
JA
Zhang
Minjia
M
Cuny
Gregory D
GD
Hedstrom
Lizbeth
L
D000981:Antiprotozoal Agents / Q000138:chemical synthesis / Q000494:pharmacology*; D003457:Cryptosporidiosis / Q000188:drug therapy*; D016785:Cryptosporidium parvum / Q000201:enzymology*; D018360:Crystallography, X-Ray; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000494:pharmacology; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry* / Q000378:metabolism; D008958:Models, Molecular
D000981:Antiprotozoal Agents; D004791:Enzyme Inhibitors; D007168:IMP Dehydrogenase