Evaluation of Purine Salvage as a Chemotherapeutic Target in the Plasmodium yoelli Rodent Model
Annual rept. 1 Feb 2006-31 Jan 2007
ALBERT EINSTEIN SCHOOL OF MEDICINE BRONX NY
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Because resistance to current antimalarials is widespread, new targets for malaria chemotherapy are needed to protect military personnel stationed in developing countries. Malaria parasites cannot make purines needed for RNA and DNA and must salvage purines from their host. Our preliminary studies reveal purine salvage is unique in malaria parasites. We would like to determine whether the unique activities of the malaria enzymes can be exploited to develop specific treatments for malaria that will be effective but not toxic. While study of drug targets in vivo is critical for all infectious diseases, evaluation in an animal model is especially critical for evaluation of purine salvage as a drug target. Malaria parasites are routinely maintained in the laboratory with high concentrations of purines, but levels of purines in mammalian blood are tightly regulated and 100-fold less than typical culture conditions. Therefore the efficacy of purine salvage inhibition and importance of purine salvage enzymes must be examined under physiological conditions that cannot be replicated during in vitro culture conditions. We plan to perform our studies in Plasmodium yoelli, a rodent malaria whose genome has been sequenced and for which there are techniques for genetic manipulation. Using this system we will genetically disrupt purine salvage genes and test their importance to the parasite. We will test the effects of malaria-specific purine salvage inhibitors on malaria infection in mice. These novel drugs will be tested in combination with other antimalarials and will also be evaluated for efficacy against exoerythrocytic malaria forms. We hope these experiments will lead to the development of new effective and nontoxic agents that can protect our military personnel from the lethal effects of malaria infection.
- Medicine and Medical Research