Malaria, the world's most deadly parasitic disease, afflicts 300-500 million people and causes 1-2 million deaths annually. The emergence of drug resistant parasites, primarily Plasmodium falciparum, has eroded the efficacy of all currently available chemotherapeutic agents. In addition to diminished utility, existing agents lack chemical diversity and have limited (four to six) biological targets. High-throughput screening of structurally diverse chemical libraries in screens that identify multiple targets is urgently needed. This proposal outlines the development of a high-throughput whole organism screen using the blood-stage form of P. falciparum expressing green fluorescent protein (GFP). A whole organism assay is optimal, as it will allow all relevant blood-stage targets to be screened simultaneously and will assure that screening positives have desirable pharmacokinetic properties such as cell permeability. The GFP-based assay will also enable 'screening by imaging' so that host-pathogen interactions such as red blood cell invasion and heme polymerization can be monitored. The GFP-based assay will be compared to other known or emerging assays including: radio-labeled incorporation assays, parasitic nuclei staining assays, and morphology based assays, using known anti-malarial agents as positive controls. Multi-component screens, based on the GFP-assay, will also be developed, identifying chemotypes that reverse drug resistance to previously effective agents. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Neurological Disorders and Stroke (NINDS)
Type
Small Research Grants (R03)
Project #
1R03NS050767-01
Application #
6879250
Study Section
Special Emphasis Panel (ZNS1-SRB-E (13))
Program Officer
Scheideler, Mark A
Project Start
2004-09-30
Project End
2006-08-31
Budget Start
2004-09-30
Budget End
2006-08-31
Support Year
1
Fiscal Year
2004
Total Cost
$84,750
Indirect Cost
Name
Harvard University
Department
Biochemistry
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
Baniecki, Mary Lynn; Wirth, Dyann F; Clardy, Jon (2007) High-throughput Plasmodium falciparum growth assay for malaria drug discovery. Antimicrob Agents Chemother 51:716-23