Scientists Provide Template for Developing New Anti-malarial Drug

Washington: Scientists have identified one of the crucial molecules that instructs the malaria parasite to employ its invisibility cloak to hide from the immune system, and helps its offspring to remember how to ‘make’ the cloak.


The finding by researchers from the Walter and Eliza Hall Institute will help to better understand how the parasite causes disease and escapes from the defences mounted by the immune system.


The research team led by Professor Alan Cowman from the institute’s Infection and Immunity division has revealed details about the first molecule found to control the genetic expression of PfEMP1 (Plasmodium falciparum erythrocyte membrane protein 1), a protein that is known to be a major cause of disease during malaria infection.


“The molecule that we discovered, named PfSET10, plays an important role in the genetic control of PfEMP1; an essential parasite protein that is used during specific stages of parasite development for its survival,” Professor Cowman said.


“This is the first protein that has been found at what we call the ‘active’ site, where control of the genes that produce PfEMP1 occurs. Knowing the genes involved in the production of PfEMP1 is key to understanding how this parasite escapes the defenses deployed against it by our immune system,” he said.


A team of scientists at Washington University in St. Louis, Missouri, spent six years trying to understand the structure and function of a protein essential to the survival of Plasmodium falciparum. That's the single-celled protozoan that lives inside mosquitos and is responsible for the most lethal form of malaria. The microscopic parasite needs the protein, an enzyme called PMT, to make its cell membranes, and it cannot survive without it.


Dr. Joseph Jez, who led the research team, says cracking the code of PMT's design is like finding malaria's fatal weakness:


"If you can target the protein and basically kill the activity of the protein, you shut down the production of building blocks for membranes which will then make the organism die off, or slow down the progression," said Jez.


Jez and his colleagues used a complex and painstaking method called protein crystallization to view PMT's molecular structure in three dimensions. He says the method was critical to their study.


"If you can understand what the molecules look like in three dimensions, you can start to design or develop pharmaceuticals that target it specifically," Jez noted. "The uniqueness of it is that this is a new potential anti-parasitic target for Plasmodium and also in terms of nematodes or worms, which are parasites as well."


Jez adds that because Plasmodium PMT is NOT found in human cells, any drug that targets the protein could be safely administered to humans.


Dr. Neeraj Mistry is managing director of the Global Network for Neglected Tropical Diseases. He says the research is an important step toward powerful and safe new drugs to fight the worldwide malaria plague:


"It opens the door to developing new drugs that specifically affect the parasite - will not affect the host - that will not have severe side effects - will only affect the parasite," Mistry noted. "Which means that upon identification of that pathway, we might be able to come up with a unique drug that actually affects that malaria parasite."


The work of identifying compounds that target the Plasmodium PMT is just beginning. But the Washington University research provides new hope not only for new anti-malarial drugs, but for compounds that can destroy a variety of disease-causing parasitic worms as well as weedy plants that all depend on the same PMT protein.