Malaria is a devastating disease that causes significant mortality in many countries of the developing world. The most deadly form of the disease is caused by the opportunistic pathogen, Plasmodium falciparum. Significant efforts have been made to understand the process by which the parasite invades a host cell to establish infection, yet relatively little is known about the process by which the parasite mediates its release after replication has occurred. This process is essential for propagation of the pathogen and agents that block rupture are likely to be valuable for development as novel anti-malarial agents. This proposal outlines plans to use small molecules to study the functional roles of proteases that regulate the process of host cell rupture. Specifically, it describes the use of phenotypic screens using libraries of protease inhibitors to identify compounds that block the release of parasites from host red blood cells. Screening hits will be used to identify protease targets and to dissect the details of their regulation of host cell rupture. Finally, lead compounds will be applied to mouse models of malaria to validate multiple proteases as drug targets for novel anti-malarial therapies.

Public Health Relevance

This project outlines plans to use small molecules to identify proteases used by the parasite pathogen, Plasmodium falciparum, to mediate rupture of host red blood cells during the blood stage infection of a human host. This work will lead to the identification of potentially valuable targets for development of new therapeutic treatment strategies for malaria.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI078947-03
Application #
8015240
Study Section
Synthetic and Biological Chemistry B Study Section (SBCB)
Program Officer
Rogers, Martin J
Project Start
2009-02-01
Project End
2014-01-31
Budget Start
2011-02-01
Budget End
2012-01-31
Support Year
3
Fiscal Year
2011
Total Cost
$393,824
Indirect Cost
Name
Stanford University
Department
Pathology
Type
Schools of Medicine
DUNS #
009214214
City
Stanford
State
CA
Country
United States
Zip Code
94305
Li, Hao; Bogyo, Matthew; da Fonseca, Paula C A (2016) The cryo-EM structure of the Plasmodium falciparum 20S proteasome and its use in the fight against malaria. FEBS J 283:4238-4243
Li, Hao; O'Donoghue, Anthony J; van der Linden, Wouter A et al. (2016) Structure- and function-based design of Plasmodium-selective proteasome inhibitors. Nature 530:233-6
Li, Hao; van der Linden, Wouter A; Verdoes, Martijn et al. (2014) Assessing subunit dependency of the Plasmodium proteasome using small molecule inhibitors and active site probes. ACS Chem Biol 9:1869-76
Li, Hao; Tsu, Christopher; Blackburn, Christopher et al. (2014) Identification of potent and selective non-covalent inhibitors of the Plasmodium falciparum proteasome. J Am Chem Soc 136:13562-5
Puri, Aaron W; Bogyo, Matthew (2013) Applications of small molecule probes in dissecting mechanisms of bacterial virulence and host responses. Biochemistry 52:5985-96
Buchholz, Kerry R; Bowyer, Paul W; Boothroyd, John C (2013) Bradyzoite pseudokinase 1 is crucial for efficient oral infectivity of the Toxoplasma gondii tissue cyst. Eukaryot Cell 12:399-410
Deu, Edgar; Chen, Ingrid T; Lauterwasser, Erica M W et al. (2013) Ferrous iron-dependent drug delivery enables controlled and selective release of therapeutic agents in vivo. Proc Natl Acad Sci U S A 110:18244-9
Verdoes, Martijn; Oresic Bender, Kristina; Segal, Ehud et al. (2013) Improved quenched fluorescent probe for imaging of cysteine cathepsin activity. J Am Chem Soc 135:14726-30
Child, Matthew A; Hall, Carolyn I; Beck, Josh R et al. (2013) Small-molecule inhibition of a depalmitoylase enhances Toxoplasma host-cell invasion. Nat Chem Biol 9:651-6
Child, Matthew A (2013) Chemical biology approaches for the study of apicomplexan parasites. Mol Biochem Parasitol 192:1-9

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