Journal article
Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides
Experimental Parasitology, Vol.148, pp.40-48
2015
Abstract
Cryptosporidiosis, a gastroenteric disease characterised mainly by diarrheal illnesses in humans and mammals is caused by infection with the protozoan parasite Cryptosporidium. Treatment options for cryptosporidiosis are limited, with the current therapeutic nitazoxanide, only partly efficacious in immunocompetent individuals. The parasite lacks de novo purine synthesis, and is exclusively dependant on purine salvage from its host. Inhibition of the inosine 5' monophosphate dehydrogenase (IMPDH), a purine salvage enzyme that is essential for DNA synthesis, thereby offers a potential drug target against this parasite. In the present study, a yeast-two-hybrid system was used to identify Phylomer peptides within a library constructed from the genomes of 25 phylogenetically diverse bacteria that targeted the IMPDH of Cryptosporidium parvum (IMPcp) and Cryptosporidium hominis (IMPch). We identified 38 unique interacting Phylomers, of which, 12 were synthesised and screened against C. parvum in vitro. Two Phylomers exhibited significant growth inhibition (81.2-83.8% inhibition; P < 0.05), one of which consistently exhibited positive interactions with IMPcp and IMPch during primary and recapitulation yeast two-hybrid screening and did not interact with either of the human IMPDH proteins. The present study highlightsthe potential of Phylomer peptides as target validation tools for Cryptosporidium and other organisms and diseases because of their ability to bind with high affinity to target proteins and disrupt function.
Details
- Title
- Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides
- Authors/Creators
- R. Jefferies (Author/Creator) - The Kids Research Institute AustraliaR. Yang (Author/Creator) - Murdoch UniversityC.K. Woh (Author/Creator) - The Kids Research Institute AustraliaT. Weldt (Author/Creator) - Murdoch UniversityN. Milech (Author/Creator) - The Kids Research Institute AustraliaA. Estcourt (Author/Creator) - Murdoch UniversityT. Armstrong (Author/Creator) - Murdoch UniversityR. Hopkins (Author/Creator) - The Kids Research Institute AustraliaP. Watt (Author/Creator) - The Kids Research Institute AustraliaS. Reid (Author/Creator) - The University of QueenslandA. Armson (Author/Creator) - Murdoch UniversityU.M. Ryan (Author/Creator) - Murdoch University
- Publication Details
- Experimental Parasitology, Vol.148, pp.40-48
- Publisher
- Academic Press
- Identifiers
- 991005541187607891
- Copyright
- © 2014 Elsevier Inc.
- Murdoch Affiliation
- School of Veterinary and Life Sciences
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Domestic collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.246 Diarrheal Diseases
- 1.246.985 Cryptosporidium
- Web Of Science research areas
- Parasitology
- ESI research areas
- Microbiology