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Abstract
Grant Number: 1R03MH076449-01 Project Title: HTS Inhibitors:Schistosoma Mansoni Peroxiredoxins(RMI)
PI Information: Name Title WILLIAMS, DAVID LEE. david_l_williams@rush.edu ASSOCIATE PROFESSOR Abstract: DESCRIPTION (provided by applicant): Schistosomiasis is an important, debilitating disease affecting ~250 million people in more than 70 countries. The annual mortality of this disease is estimated to be ~280,000 in sub-Saharan Africa, while 20 million individuals suffer from extreme disability. In the coming years the Bill and Melinda Gates Foundation and endemic country programs will treat tens of millions of people with the single anti-schistosomiasis drug in widespread use, praziquantel. There is already clinical and laboratory evidence for the existence of praziquantel resistance parasites and widespread use is expected to generate strong selective pressure for drug resistance. Clearly, there is an urgent need for new anti-schistosome drugs. Studies on schistosome redox balance mechanisms indicate a distinct and compressed pathway in the parasite compared to its human host. Schistosoma mansoni peroxiredoxins (Prx) are important parasite antioxidant proteins that play a crucial role in redox balance mechanisms. Our data strongly suggest the possible use of Prx as novel drug targets. First, the proteins are essential for the parasite survival. Second, the proteins exhibits sufficient biochemical and structural differences from host Prx proteins. Third, the protein(s) is amenable for study at the molecular level and can be produced in bacteria in large quantities, in soluble and active form. Moreover, Prx activity can be screened in high throughput, inexpensive, and sensitive assays. Since no parasite-specific inhibitors of Prx are currently available, our overall goal is the identification of inhibitors of Schistosoma mansoni Prx by conducting a high throughput screen of the Small Molecule Repository of the Molecular Libraries Screening Centers Network (MLSCN). This will be the first step in the development of novel antischistosome chemotherapies, which are essential for continued public health measures.
Public Health Relevance:
This Public Health Relevance is not available.Thesaurus Terms:
Schistosoma mansoni, anthelmintic, drug discovery /isolation, drug screening /evaluation, high throughput technology, inhibitor /antagonist, redoxin, schistosomiasis
chemical registry /resource, oxidation reduction reaction, small molecule
Institution: ILLINOIS STATE UNIVERSITY HOVEY HALL 310 NORMAL, IL 61790 Fiscal Year: 2005 Department: BIOLOGICAL SCIENCES Project Start: 15-SEP-2005 Project End: 30-SEP-2007 ICD: NATIONAL INSTITUTE OF MENTAL HEALTH IRG: ZMH1