3d images

3D images reveal how drugs work to stop malaria parasites

Malaria infections are caused by Plasmodium parasites that enter the bloodstream and destroy red blood cells.

Melbourne researchers from WEHI, in collaboration with Merck Sharp & Dohme (MSD), have now captured the first three-dimensional (3D) images that reveal how the compounds work to prevent parasites from spreading through the blood.

In one look

  • The first 3D images show how two antimalarial compounds interact with two key enzymes essential in malaria parasites.
  • The structures provide insight into how these compounds block the function of two enzymes, to stop the parasite from replicating in its tracks.
  • The results pave the way for the discovery of new antimalarials that effectively kill malaria parasites.

Plasmepsin IX (PMIX) and Plasmepsin X (PMX) are enzymes manufactured by the Plasmodium family of parasites, which process and activate key proteins that allow parasites to move in and out of red blood cells. Blocking these two enzymes stops the replication of the parasite in its tracks, leaving the parasite unable to multiply in the blood.

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 images that show how the activity of PMIX and PMX can be blocked by interactions with drug-like molecules.

In laboratory models, the compounds have been shown to inhibit the functions of these enzymes that block the parasite life cycle, leading to parasite death and stopping further transmission.

Posted in Structurethe results enabled WEHI and MSD researchers to make informed improvements to the design of a new generation of compounds that could be developed for use in the fight against malaria.

Pac-man effect

The two compounds used in the study, called WM4 and WM382, are the result of a six-year collaboration between WEHI and MSD.

Although the compounds are known to kill malaria parasites, little was understood about how and why they worked.

Researchers have now visualized, for the first time, the interaction between these compounds and the 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 both enzymes.

“PMIX and PMX are the equivalent of molecular scissors and can be likened to a game of pacman, where the binding site becomes the pacman’s mouth,” said lead researcher Dr. Anthony Hodder.

“The enzymes essentially bind compounds in the pacman’s mouth, which prevents these molecular scissors from cutting other proteins that would normally allow parasites to move freely between red blood cells and infect them.”

This link stops the Plasmodium parasites to be able to leave an infected red blood cell and invade uninfected red blood cells.

“With our world’s first 3D images, we were able to show exactly how and why these compounds block PMIX and PMX – or pacman,” said Dr. Hodder.

Revolutionary Imaging

Dr Janni Christensen said the findings would not have been possible without Australia’s synchrotron and WEHI’s X-ray crystallography technology.

“This technology has allowed us to capture the first 3D images of these enzymes that can be magnified up to 100 million times,” said Dr. Christensen.

“Seeing this in such exquisite molecular detail allowed us to make this significant discovery showing how these compounds can block PMIX and PMX activity and prevent parasite growth.”

Collaborative power

Professor Alan Cowman, international malaria expert and deputy director of WEHI, said his team worked alongside MSD scientist and US team leader Dr David Olsen to obtain crucial new information.

More than 600,000 people die from malaria every 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 have laid the foundation for the discovery of new drugs to more effectively block plasmepsins and prevent the invasion of these malaria parasites.

“When we know how something works, we can use that knowledge to direct the design of new and even more potent compounds,” he said.

“We now have the ability to design a new class of antimalarial 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, the Government of the State of Victoria, the National Health and Medical Research Council (NHMRC) and the Australian Cancer Research Foundation.

Reference: Hodder AN, Christensen J, Scally S, et al. Basis of drug selectivity of plasmepsin IX and X inhibition in Plasmodium falciparum and vivax. Structure. 2022. doi: 10.1016/j.str.2022.03.018

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