One feature of the metabolic pathway of T. gondii which distinguishes it form its human host is its inability to synthesize purine nucleotides de novo. Therefore, these organisms rely on the purine salvage pathways for their supply of purine nucleotides. There are unique features of purine metabolism in T. gondii which render the purine salvage pathways suitable targets for chemotherapy. T. gondii, unlike their mammalian hosts, predominantly salvage their purine precursors via adenosine kinase. On the basis of Dr. el Kouni's detailed structure-activity relationship studies on T. gondii adenosine kinase activity, he has identified a group of compounds, the 6-substituted 9-beta-D-ribofuranosylpurines, as potentially good substrates for this enzyme. One of these compounds, NBMPR, is phosphorylated by the parasite adenosine kinase and are also toxic against T. gondii. Furthermore, in collaboration with Dr. David Roos, the T. gondii adenosine kinase gene was successfully cloned to provide a potentially stable source of this enzyme for further studies. The overall goal of these studies is to exploit the differences between host and parasite adenosine kinases for the development of chemotherapeutic agents against toxoplasmosis. There are three specific aims in this proposal: (1) Overexpress a construct o the recently cloned T. gondii adenosine kinase gene to provide a stable source of this enzyme and to purify and characterize the cloned enzyme for drug screening and design; (2) determine the mechanism of selective toxicity of the 6-substituted-9-beta-D ribofuranosylpurines in T. gondii; (3) evaluate active compounds as potential antitoxoplasmosis agents in vitro and in vivo.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI042975-03
Application #
2887719
Study Section
Special Emphasis Panel (ZRG5-TMP (04))
Program Officer
Laughon, Barbara E
Project Start
1997-09-30
Project End
2002-08-31
Budget Start
1999-09-01
Budget End
2000-08-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Alabama Birmingham
Department
Pharmacology
Type
Schools of Medicine
DUNS #
004514360
City
Birmingham
State
AL
Country
United States
Zip Code
35294
El Kouni, Mahmoud H (2017) Pyrimidine metabolism in schistosomes: A comparison with other parasites and the search for potential chemotherapeutic targets. Comp Biochem Physiol B Biochem Mol Biol 213:55-80
Naguib, Fardos N M; Rais, Reem H; Al Safarjalani, Omar N et al. (2015) Kinetic mechanism of Toxoplasma gondii adenosine kinase and the highly efficient utilization of adenosine. Comp Biochem Physiol B Biochem Mol Biol 188:63-9