Elusive Protein Protects Malaria Parasite From Heme

Worldwide, the annual death toll of malaria exceeds 1 million, and children under the age of five are its major victims. The Plasmodium parasite that causes malaria in humans is transmitted through the bites of infected mosquitoes. Once inside the human body, the parasite initially develops in the liver and subsequently, upon release, infects red blood cells. After infecting host red blood cells, a rapid growth ensues, supported by the parasite's consumption of hemoglobin, the oxygen-transporting protein that constitutes a massive 90% of the total protein present inside each red blood cell.

Destruction on this scale releases large quantities of heme, the prosthetic group responsible for oxygen transport in hemoglobin. Free heme is extremely damaging and to protect itself from this toxic onslaught, the parasite utilizes a novel mechanism where it rapidly converts heme into a crystalline material known as hemozoin.

Dr. Dharmendar Rathore, Assistant Professor at VBI, remarked: "We discovered HDP as part of a functional genomics initiative that is focused on the identification of malaria proteins involved in disease pathology. A combination of cellular and biochemical approaches allowed us to rigorously characterize HDP. It appears that HDP has a number of striking features that make it a promising candidate as a drug target. HDP is not only capable of rapidly converting heme into its non-toxic counterpart hemozoin, but it is highly conserved in all the species of the parasite and also appears to be critical for its survival." He added: "The beauty of this discovery is that, while HDP has robust interactions with heme, it lacks homology to any of the known heme-binding proteins and has therefore eluded detection during previous attempts by several groups to identify parasite factors responsible for hemozoin formation."

The conversion of heme into hemozoin is regarded as one of the weakest links in the lifecycle of the Plasmodium parasite. For example, chloroquine, the most widely used malaria drug, works by interacting with heme and preventing its detoxification into hemozoin. However drugs are not yet available that target any of the parasite-specific molecules involved in this process.

Dr. Rana Nagarkatti, research scientist at VBI, commented: "The identification of new drug targets is an essential step in the development of next-generation drugs for treating malaria. Drugs that specifically interact with HDP and inhibit its detoxification activities could potentially have drastic effects on the viability of the malaria parasite." Dr. Dewal Jani, a member of the VBI research team, remarked: "The identification of HDP fills an important gap in our understanding of the mechanism of hemozoin production in the malaria parasite. We have also established the route by which the HDP is transported out of Plasmodium and into the red blood cell before it subsequently returns to the parasite food vacuole where hemozoin is synthesized. This gives us an interesting insight into the inner workings of the parasite."

Dr. Rathore concluded: "New drugs are urgently needed to address the huge public health burden posed by malaria across the globe. We have recently undertaken a high-throughput screening of chemical libraries to identify compounds that can inhibit the activity of HDP. Several lead compounds were identified and have been characterized in our laboratory at VBI and subsequently validated at the Swiss Tropical Institute in Basel, Switzerland. We see considerable potential in developing these lead compounds into new drugs that can act by blocking the function of HDP in the parasite."

Otto Folkerts, Associate Director of Technology Development at VBI, added: "Virginia Tech Intellectual Properties Inc. has filed patents that cover the intellectual property behind this discovery. We are actively seeking partners who are interested in licensing this intellectual property or jointly pursuing the development of potential malaria drug candidates that may arise from this work."

Journal reference: Jani D, Nagarkatti R, Beatty W, Angel R, Slebodnick C, Andersen J, Kumar S, Rathore D (2008) HDP-A Novel Heme Detoxification Protein from the Malaria Parasite. PLoS Pathogens 4(4): e1000053. doi:10.1371/journal.ppat.1000053

The work was supported by Virginia Tech-Johns Hopkins University infectious diseases research and ASPIRES (A Support Program for Innovative Research Strategies) program grants.