Food-borne trematodiases affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of food-borne tremotodiases, effective drugs are the only practical means of morbidity control. Importantly, new drugs for these diseases are urgently needed as praziquantel and triclabendazole are the only drugs available and the development of resistance cannot be ignored, particularly in view of the large- scale use of praziquantel in many endemic countries. At the root of this project is our discovery that several synthetic peroxides also possess strong trematocidal activity. We propose to further explore the potential of synthetic peroxides as novel trematocidal drugs. The identification of a new, broad-spectrum, orally-active synthetic peroxide trematocidal drug development candidate will minimize drug-resistance and lead to superior treatment and control options for food-borne trematodiases. Essential characteristics of a new drug development candidate include an economically-feasible and scalable synthesis, excellent oral activity, low potential for toxicity and resistance development, broad spectrum of trematocidal activity, and high efficacy against all parasite stages in the vertebrate host. More specifically, our objective is to identify a drug development candidate with 100% worm burden reductions against juvenile and adult F. hepatica and C. sinensis at doses of <100 mg/kg and with an excellent ADME profile (predicted ER <0.30, CYP450 IC50s >25 5M, oral BA >30%). To address this overarching objective, we propose the following three specific aims:
Specific Aim 1 : To synthesize and characterize a focused and structurally diverse library of synthetic peroxides.
Specific Aim 2 : To assess trematocidal activity and selectivity of target synthetic peroxides against two major human food-borne trematode species, Fasciola hepatica and Clonorchis sinensis.
Specific Aim 3 : To determine metabolism and pharmacokinetic parameters and initiate mechanism of action studies for selected synthetic peroxides.

Public Health Relevance

Food-borne trematodiases, caused by infection with liver flukes, affect hundreds of millions of people, particularly the rural poor in the developing world. Since vaccines are currently unavailable, and are unlikely to become available anytime soon for the prevention of these diseases, new drugs are urgently needed. Praziquantel and triclabendazole are the only drugs now available and the development of resistance cannot be ignored, particularly in view of the large-scale use of praziquantel in many endemic countries. In this proposal, we propose to identify a new broad-spectrum orally-active trematocidal drug development candidate.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI076783-02
Application #
7648067
Study Section
Drug Discovery and Mechanisms of Antimicrobial Resistance Study Section (DDR)
Program Officer
Rogers, Martin J
Project Start
2008-07-15
Project End
2010-12-30
Budget Start
2009-07-01
Budget End
2010-12-30
Support Year
2
Fiscal Year
2009
Total Cost
$158,051
Indirect Cost
Name
University of Nebraska Medical Center
Department
Other Basic Sciences
Type
Schools of Pharmacy
DUNS #
168559177
City
Omaha
State
NE
Country
United States
Zip Code
68198
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Wang, Xiaofang; Zhao, Qingjie; Vargas, Mireille et al. (2011) The activity of dispiro peroxides against Fasciola hepatica. Bioorg Med Chem Lett 21:5320-3
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Zhao, Qingjie; Vargas, Mireille; Dong, Yuxiang et al. (2010) Structure-activity relationship of an ozonide carboxylic acid (OZ78) against Fasciola hepatica. J Med Chem 53:4223-33
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