Malaria infections are driven by Plasmodium parasites that enter the bloodstream and break down red blood cells.
Melbourne researchers from WEHI, in partnership with Merck Sharp & Dohme (MSD), have now obtained the first three -dimensional (3D) images that reveal how compounds work to stop the spread of blood parasite.
At a glance
- The first 3D images show how the two anti-malarial compounds interact with two important enzymes in malaria parasites.
- The structures provide a better understanding of how these compounds inhibit the function of the two enzymes, in order to stop the reproduction of parasites in their pathways.
- The findings pave the way for the discovery of new antimalarials that are effective in killing malaria parasites.
Plasmepsin IX (PMIX) and Plasmepsin X (PMX) are enzymes produced by Plasmodium parasite family, which processes and activates key proteins that enable parasites to enter and exit red blood cells. Inhibition of these two enzymes can stop parasites from replicating their pathways, leaving the parasite unable to multiply in the bloodstream.
WEHI researchers Dr Anthony Hodder, Dr Janni Christensen (now at ExpreS2ion Biotechnologies in Denmark) and Professor Alan Cowman collaborated with Dr David Olsen and his team at MSD to create the world’s first 3D visual displays how to inhibit the activity of PMIX and PMX through the interaction of drug -like molecules.
In laboratory models, compounds have been shown to inhibit the functions of these enzymes that disrupt the parasitic life cycle, resulting in parasite death and stopping further transmission.
Published on structuresthe findings allow WEHI and MSD researchers to make known improvements to the design of a new generation of compounds that can be developed to be used in the fight against malaria.
The two compounds used in the study, known as WM4 and WM382, are the result of a six -year collaboration between WEHI and MSD.
While the compounds are known to kill malaria parasites, little is understood as to how or why they work.
Now researchers are imagining, for the first time, the interaction between these compounds and PMIX and PMX enzymes at the molecular level, to show how they kill malaria parasites.
They found that the compounds bind to the active site of the same enzymes.
“PMIX and PMX are equivalent to molecular scissors and can be compared to the pacman game, where the binding site becomes the pacman’s mouth,” said lead researcher Dr Anthony Hodder.
“Enzymes primarily bind to pacman’s mouth compounds, and they stop these molecular scissors from cutting down other proteins that normally allow parasites to move freely between and infect red cells in the blood. “
This binding stopped Plasmodium The parasites are unable to get out of an infected red blood cell and invade the uninfected red blood cells.
“Using our world -first 3D images, we were able to show exactly how and why these compounds inhibit PMIX and PMX – or the pacman,” says Dr Hodder.
Dr Janni Christensen said the findings would not have been possible without the Australian Synchrotron and X-ray crystallography technology at WEHI.
“This technology allows us to capture the first 3D images of these enzymes that can be magnified up to 100 million times in size,” said Dr Christensen.
“Seeing it with such beautiful molecular detail allows us to make this important finding that shows how these compounds can inhibit the activity of PMIX and PMX and stop the growth of parasites.”
Professor Alan Cowman, an international malaria expert and deputy director of WEHI, said his team was working with MSD scientist and U.S. team leader Dr David Olsen, to gain important new insights.
More than 600,000 people die from malaria each year, highlighting the urgent need for new drugs that can be used instead of, or in combination with, existing drugs.
Professor Cowman said the 3D images lay the foundation for new drugs to be discovered to more effectively block Plasmepsins and prevent the invasion of these malaria parasites.
“If we know how something works, we can use that knowledge to lead the design of novel and even more powerful compounds,” he said.
“We now have the capability to engineer a new class of anti-malarial compounds to attack this disease, which continues to be a global health crisis.”
The research was supported by the Red Cross Blood Service (Melbourne), The Wellcome Trust, Victorian State Government, National Health and Medical Research Council (NHMRC), and Australian Cancer Research Foundation.
References: Hodder AN, Christensen J, Scally S, et al. The criterion for drug selection of plasmepsin IX and X inhibition Plasmodium falciparum and vivax. structures. 2022. doi: 10.1016 / j.str.2022.03.018
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