Targeting a prokaryotic protein in a eukaryotic pathogen: identification of lead compounds against cryptosporidiosis.
Cryptosporidium parvum is an important human pathogen and potential bioterrorism agent. No vaccines exist against C. parvum, the drugs currently approved to treat cryptosporidiosis are ineffective, and drug discovery is challenging because the parasite cannot be maintained continuously in cell culture. Mining the sequence of the C. parvum genome has revealed that the only route to guanine nucleotides is via inosine-5'-monophosphate dehydrogenase (IMPDH). Moreover, phylogenetic analysis suggests that the IMPDH gene was obtained from bacteria by lateral gene transfer. Here we exploit the unexpected evolutionary divergence of parasite and host enzymes by designing a high-throughput screen to target the most diverged portion of the IMPDH active site. We have identified four parasite-selective IMPDH inhibitors that display antiparasitic activity with greater potency than paromomycin, the current gold standard for anticryptosporidial activity.
Umejiego
Nwakaso N
NN
Department of Biochemistry, Brandeis University, 415 South Street, Waltham, MA 02454, USA.
Gollapalli
Deviprasad
D
Sharling
Lisa
L
Volftsun
Anna
A
Lu
Jennifer
J
Benjamin
Nicole N
NN
Stroupe
Adam H
AH
Riera
Thomas V
TV
Striepen
Boris
B
Hedstrom
Lizbeth
L
D000818:Animals; D000977:Antiparasitic Agents / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use*; D001665:Binding Sites; D003457:Cryptosporidiosis / Q000188:drug therapy* / Q000201:enzymology; D016785:Cryptosporidium parvum / Q000187:drug effects* / Q000201:enzymology / Q000472:pathogenicity; D005057:Eukaryotic Cells / Q000201:enzymology*; D020730:Guanine Nucleotide Dissociation Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D006150:Guanine Nucleotides / Q000378:metabolism; D006801:Humans; D007168:IMP Dehydrogenase / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D007700:Kinetics; D010303:Paromomycin / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011387:Prokaryotic Cells / Q000201:enzymology*
D000977:Antiparasitic Agents; D020730:Guanine Nucleotide Dissociation Inhibitors; D006150:Guanine Nucleotides; D010303:Paromomycin; D007168:IMP Dehydrogenase