Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides

Jefferies, R., Yang, R., Woh, C. K., Weldt, T., Milech, N., Estcourt, A., Armstrong, T., Hopkins, R., Watt, P., Reid, S., Armson, A. and Ryan, U. M. (2015) Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides. Experimental Parasitology, 148 40-48. doi:10.1016/j.exppara.2014.11.003


Author Jefferies, R.
Yang, R.
Woh, C. K.
Weldt, T.
Milech, N.
Estcourt, A.
Armstrong, T.
Hopkins, R.
Watt, P.
Reid, S.
Armson, A.
Ryan, U. M.
Title Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides
Formatted title
Target validation of the inosine monophosphate dehydrogenase (IMPDH) gene in Cryptosporidium using Phylomer® peptides
Journal name Experimental Parasitology   Check publisher's open access policy
ISSN 1090-2449
0014-4894
Publication date 2015-01
Year available 2014
Sub-type Article (original research)
DOI 10.1016/j.exppara.2014.11.003
Open Access Status
Volume 148
Start page 40
End page 48
Total pages 9
Place of publication Maryland Heights, MO United States
Publisher Academic Press
Collection year 2015
Language eng
Formatted 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.
Keyword Cryptosporidium
Drug target validation
Peptide
Phylomer®
Inosine 5'-monophosphate dehydrogenase
IMPDH
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Published online ahead of print 20 Nov 2014

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2015 Collection
School of Public Health Publications
 
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