3D image of malaria ‘conductor’ Plasmepsin V paves way for new class of drugs

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A new discovery involving a malarial protein dubbed Plasmepsin V could pave way for development of a new class of antimalarial drugs, researchers have revealed.

Scientists at Melbourne’s Walter and Eliza Hall Institute have managed to capture the first three-dimensional image of a critical malaria ‘conductor’ protein Plasmepsin V, which they say acts like a bus conductor giving each protein the stamp of approval before they leave the parasite. Plasmepsin V also provides them with information on the destination they need to target.

Researchers at the institute have developed WEHI-842, a drug that blocks plasmepsin V, killing the parasite. The discovery is a new step towards developing much needed new drugs for treating and preventing malaria, they say. The research, led by Professor Alan Cowman, Dr Justin Boddey, Dr Tony Hodder, Dr Brad Sleebs and Dr Peter Czabotar was published today in the journal Nature Structural and Molecular Biology.

Professor Cowman said that the protein plasmepsin V is an important target given its critical role in the survival of malaria parasites and expression at all stages of its lifecycle.

Researchers revealed that given the nature of the protein, they were not able to solve the structure of plasmepsin V, but using their potent drug WEHI-842 they we were able to stabilise the protein sufficiently to detail its molecular structure. The new details will be critical in developing this new class of antimalarial drugs, researchers added.

Dr Boddey said targeting plasmepsin V would effectively kill the two species of malaria that caused significant death and disease.

The new drug WEHI-842, in lab tests, has proved to be a very effective agent in preventing the growth and survival of Plasmodium falciparum.

Plasmodium falciparum is the most deadly form of malaria parasite and is responsible for more than 800,000 deaths from malaria each year. Plasmodium vivax is also particularly insidious because it can hide in the body for long periods of time without symptoms, causing disease relapses much later.

Approximately half of the world’s population is at risk of contracting malaria each year, with more than 200 million people infected and though we have drugs at our disposal, they are increasingly becoming ineffective owing to the parasites’ capability to develop resistance to the drugs.

Dr Boddey said malaria parasites were shape shifters, changing how they look and how they act throughout their lifecycle to help them evade detection and elimination in the body.

“WEHI-842 is able to strongly bind to and disrupt the function of plasmepsin V, preventing the release of proteins that are critical for shaping the parasite’s environment and, effectively, killing it,” Dr Boddey said. “Plasmepsin V is expressed by the different shapeshifters across the lifecycle so we should be able to kill these different forms as well.”

Professor Cowman said the biggest challenge for the team was developing an agent that could cross the barriers that protect the malaria parasite as it hides within the cell.

“The malaria parasite hides exceptionally well in the liver and red blood cells, with four walls between the bloodstream and the protein we are targeting,” Dr Boddey said.

“We are now collaborating with a pharmaceutical company to identify drugs that act in the same way as WEHI-842, but are able to find a way through these four walls to access the parasite hidden deep inside the red blood cell.”