The research program proposed in this application is to understand three levels of regulation of P. falciparum (Pf) ribonucleotide reductase--the allosteric control of substrate catalysis, subunit interaction and the iron/tyrosine redox center and to use this fundamental information in the design and testing of specific antimalarial agents. Malaria remains one of the leading causes of death worldwide, being responsible for more than 2 million deaths per year. The increasing incidence of drug resistant malaria makes the development of new approaches to antimalarials a high priority. RR is a two subunit, cell cycle regulated, iron and oxygen dependent allosteric enzyme that is the first committed step in DNA replication catalyzing a radical mediated 2' reduction of ribonucleoside diphosphates to deoxyribonucleoside diphosphates. Agents that inhibit RR are known to inhibit growth patterns of P. falciparum. RR is therefore a prime target for the development of specific antimalarial agents. In this research, we plan to l) Utilize recombinant Pf RR to characterize the unique biochemical properties of the enzyme. 2) Design and synthesize peptides, peptide-mimetics and constrained peptides that disrupt the subunit interaction and test these RR inhibitors in Pf infected red cell cultures 3) Analyze the structure-function-activity properties of classes of compounds that destroy the iron/tyrosine redox center of the enzyme and test these agents in Pf infected red cell cultures.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI039165-02
Application #
2442688
Study Section
Tropical Medicine and Parasitology Study Section (TMP)
Project Start
1996-07-01
Project End
1999-06-30
Budget Start
1997-07-01
Budget End
1998-06-30
Support Year
2
Fiscal Year
1997
Total Cost
Indirect Cost
Name
University of Pennsylvania
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19104