Formation of the malarial pigment hemozoin, a microcrystalline dimer of heme, is one of the most important processes disrupted by drugs in the protozoan malaria parasite Plasmodium and is also a potential drug target in the parasitic helminth worm Schistosoma. However, the mechanism of its formation and inhibition is currently poorly understood. Since recent evidence suggests that hemozoin formation occurs within lipid (i.e. fat) droplets, the project aims to investigate the characteristics of artificial lipid droplets and the rates of beta-hematin (synthetic hemozoin) formation in these artificial lipid droplets in order to better understand the process and to develop improved methods for finding new beta-hematin inhibiting scaffolds as a first step to the discovery of antimalarial and antischistosomal drugs. To achieve this, the following specific aims are proposed:
SPECIFIC AIM 1. Investigate the interaction of heme with neutral lipids.
SPECIFIC AIM 2. Study the rate of beta-hematin formation at lipid/water interfaces and in lipid droplets dispersed in water.
SPECIFIC AIM 3. Translate our understanding of lipid droplet mediated beta-hematin formation into a high throughput screen for potential new drug scaffolds. In order to achieve these goals, the research will be conducted as a collaborative project between Timothy J. Egan at the University of Cape Town, South Africa and David W. Wright at Vanderbilt University, Nashville, TN. Studies on the behavior of neutral lipids at water surfaces and of the interaction of heme with lipids as well as on the rates of beta-hematin formation will be conducted in Cape Town. Development of the high throughput screen will be conducted at Vanderbilt University and will then be used to screen the extensive Vanderbilt University compound library at the University's high throughput screening facility. This is expected to lead to the identification of new beta-hematin inhibiting scaffolds. The collaboration between the two groups will be strongly synergistic. The considerable expertise on lipid mediated beta-hematin formation and especially studies on the rates of this process will be transferred from the University of Cape Town to Vanderbilt University. Conversely, expertise on high throughput screening methods will be transferred from Vanderbilt University to the University of Cape Town.
Malaria and schistosomiasis are the two most important human parasitic diseases affecting hundreds of millions of people around the world. Both parasites feed on blood with the consequent need for them to detoxify heme. Formation of hemozoin, a microcrystalline dimer of heme, is one of the most important processes disrupted by drugs in the malaria parasite Plasmodium and is also a potential target in the helminth parasite Schistosoma. However, the mechanism of its formation and inhibition is currently poorly understood. We propose to undertake research to better understand the process and to use this to knowledge to develop screening methods for discovering new compounds that disrupt the process as a first step to discovery of new antimalarial and antischistosomal drugs.
|Schrimpe-Rutledge, Alexandra C; Fong, Kim Y; Wright, David W (2015) Impact of 4-hydroxynonenal on matrix metalloproteinase-9 regulation in lipopolysaccharide-stimulated RAW 264.7 cells. Cell Biochem Funct 33:59-66|
|Stiebler, Renata; Majerowicz, David; Knudsen, Jens et al. (2014) Unsaturated glycerophospholipids mediate heme crystallization: biological implications for hemozoin formation in the kissing bug Rhodnius prolixus. PLoS One 9:e88976|
|Sandlin, Rebecca D; Fong, Kim Y; Wicht, Kathryn J et al. (2014) Identification of ?-hematin inhibitors in a high-throughput screening effort reveals scaffolds with in vitro antimalarial activity. Int J Parasitol Drugs Drug Resist 4:316-25|
|Combrinck, Jill M; Mabotha, Tebogo E; Ncokazi, Kanyile K et al. (2013) Insights into the role of heme in the mechanism of action of antimalarials. ACS Chem Biol 8:133-7|
|Fong, Kim Y; Wright, David W (2013) Hemozoin and antimalarial drug discovery. Future Med Chem 5:1437-50|
|Gildenhuys, Johandie; le Roex, Tanya; Egan, Timothy J et al. (2013) The single crystal X-ray structure of ýý-hematin DMSO solvate grown in the presence of chloroquine, a ýý-hematin growth-rate inhibitor. J Am Chem Soc 135:1037-47|
|Ambele, Melvin A; Sewell, B Trevor; Cummings, Franscious R et al. (2013) Synthetic Hemozoin (*-Hematin) Crystals Nucleate at the Surface of Neutral Lipid Droplets that Control Their Sizes. Cryst Growth Des 13:|
|Ambele, Melvin A; Egan, Timothy J (2012) Neutral lipids associated with haemozoin mediate efficient and rapid ýý-haematin formation at physiological pH, temperature and ionic composition. Malar J 11:337|
|Sandlin, Rebecca D; Carter, Melissa D; Lee, Patricia J et al. (2011) Use of the NP-40 detergent-mediated assay in discovery of inhibitors of beta-hematin crystallization. Antimicrob Agents Chemother 55:3363-9|
|Hoang, Anh N; Sandlin, Rebecca D; Omar, Aneesa et al. (2010) The neutral lipid composition present in the digestive vacuole of Plasmodium falciparum concentrates heme and mediates ?-hematin formation with an unusually low activation energy. Biochemistry 49:10107-16|
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