Toxoplasma gondii, the causative agent of toxoplasmosis, results in severe disease in neonates and the immunocompromised, including AIDS patients. Currently there are few effective chemotherapeutic options, and those that are available are frequently associated with adverse side effects. Ribonucleotide reductase is an enzyme which catalyzes the conversion of ribonucleotides to deoxyribonucleotides and therefore is essential for DNA synthesis. Ribonucleotide reductase (RNR) has proven to be a promising target for chemotherapy of herpes virus infections. The primary goal of this project is to characterize ribonucleotide reductase of Toxoplasma gondii and evaluate the enzyme as a potential target for chemotherapy of toxoplasmosis. As part of this effort we plan to clone the RNR genes and express biologically active enzyme. This recombinant enzyme will be fully biochemically characterized. In vitro RNR assays, in conjunction with parasite tissue culture will be used to screen candidate inhibitors. Effective agents and currently available anti-Toxoplasma agents will be tested for synergistic action against parasites. Any agents which appear to have promise as specific anti- Toxoplasma agents will also be tested in in vivo models of toxoplasmosis. In addition, peptides corresponding to the C-terminal sequences of the small subunit of RNR will be tested for their ability to inhibit RNR. Mutant parasites resistant to candidate drugs will be generated and analyzed in order to more fully understand the basis of drug-enzyme interaction. Our hope is that these studies will form the basis for design of new novel agents for treatment of toxoplasmosis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Clinical Investigator Award (CIA) (K08)
Project #
5K08AI001113-04
Application #
2057167
Study Section
Microbiology and Infectious Diseases B Subcommittee (MID)
Project Start
1993-07-01
Project End
1996-06-30
Budget Start
1995-07-01
Budget End
1996-06-30
Support Year
4
Fiscal Year
1995
Total Cost
Indirect Cost
Name
Albert Einstein College of Medicine
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
009095365
City
Bronx
State
NY
Country
United States
Zip Code
10461