Parasitic nematodes infect more than two billion people, causing significant morbidity and mortality. Characterization of the genomes of parasitic nematode provides fundamental molecular information that can be used to accelerate basic research and the development of new diagnostics and therapeutics, which are a public health priority due to the limited number of currently available drugs, the limited efficacy against some species (e.g., whipworm) and increasing anti-drug resistance. To that end, we have established an extensive genomic database by sequencing and annotating genomes and transcriptomes of nematode parasites of medical importance, including representative human parasites that span the major taxonomic clades in the phylum Nematoda. Furthermore, we focused analysis on biochemical pathways conserved and/or taxonomically restricted and condition-specific, identifying proteins that may prove useful as drug targets. The three aims of this proposal build on our progress by taking advantage of the generated multi-dimensional resource to undertake a systems biology approach aimed at promoting discovery and development of new therapeutics. First, we will reconstruct metabolic networks of both intestinal and filarial parasits, and analysis will focus on pan-conserved chokepoint enzymes in taxonomically restricted and differentially expressed metabolic pathways as potential targets for anthelmintic drugs. Second, we will perform drug-sensitivity assays to test our hypothesis and validate the predicted broad control potential of the pan-phylum targets. Third, we will perform lead optimization and demonstrate increased potency and selectivity of nematode metabolic enzyme inhibitors, followed by validation of target inhibition in vitro and in vivo. Keys to our overall approach include the selection of species of parasites that span the evolutionary extremes of the Phylum (supporting the creation of a pan-phylum metabolic pathway database with the broadest scope and optimal predictive value), the development of a prioritization protocol that leverages systems biology and cheminformatics for target and drug prioritization, followed by experimental validation and, in turn, identification and optimization of leads. The expected outcome will facilitate and promote the discovery and development of novel interventions to treat and control these important parasites and reduce their associated morbidity and mortality.

Public Health Relevance

Parasitic nematodes infect more than two billion people and are a leading cause of human morbidity and maintenance of poverty. The main goals of this project are to facilitate and promote the discovery and development of novel interventions to control these important parasites, and reduce their associated morbidity and mortality. This will be achieved by studying the metabolic pathways of these pathogens, since metabolic potential is increasingly proving to be a critical determinant governing a pathogen's development/growth, infectivity, maintenance and virulence. Compounds targeting conserved pan-phylum metabolic chokepoint enzymes will be identified, tested and optimized to increase their selectivity and demonstrate their potential for a broad parasite control.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI081803-06A1
Application #
8965332
Study Section
Genomics, Computational Biology and Technology Study Section (GCAT)
Program Officer
Joy, Deirdre A
Project Start
2009-04-01
Project End
2019-06-30
Budget Start
2015-07-15
Budget End
2016-06-30
Support Year
6
Fiscal Year
2015
Total Cost
$405,180
Indirect Cost
$76,903
Name
Washington University
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
068552207
City
Saint Louis
State
MO
Country
United States
Zip Code
63130
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