Molecular map inside malaria parasite could lead to new antimalarial drugs

Imperial scientists have gained unique structural insights into the production line of parasite proteins that cause malaria.

The study should ultimately help researchers to create better anti-malarial drugs, by using this new molecular map to design novel drugs or re-adapt old drugs as antimalarials.

According to statistics from the World Health Organisation increased malaria prevention and control measures, such as bed nets and anti-malarial drugs, have reduced global malaria mortality rates by 42 per cent. But with insecticide-resistant mosquitoes on the rise and the malaria-causing parasite, Plasmodium falciparum, growing ever more resistant to frontline drugs, scientists have been looking for new ways of tackling the disease. 

Ribosomes are molecular machines that are fundamental to every living cell, translating DNA messages from the nucleus into the myriad proteins that define every cell’s function. Blocking the ribosome machinery could then potentially prevent disease-causing cells from growing, making them a very attractive drug target.

Many clinically approved drugs for bacterial infections do just this, inhibiting the ribosome from functioning, as a powerful tool to fight bacterial infections. The researchers believe that such drugs could now be repurposed to inhibit the parasite’s ribosomal machinery to combat malaria disease, but until now, the parasite’s ribosome had never been mapped in any detail.

Dr Jake Baum from the Department of Life Sciences at Imperial College London, who co-led the recent study with Dr. Sjors Scheres at the MRC Laboratory for Molecular Biology, Cambridge said:  “Malaria is one of our oldest foes, and while control programmes are proving successful, it is not a long-term solution. We’ve seen in areas like the Thai-Cambodia border that there is now emerging resistance to new front line drugs. So we need new strategies, and access to drugs that will work like a sledge hammer and wipe out the parasite and the whole factory line of malaria development, and that is the ribosome. That is where our ribosome map becomes really powerful.”

The researchers used one of the most powerful and sensitive electron microscopes to create a world-first image of the malaria parasite’s ribosome in atomic detail, which is the highest resolution possible for proteins or DNA molecules. They imaged the parasite ribosome on its own and with a potent protein-inhibiting drug bound to its structure.

For the first time they were able to see in minute detail the mechanism by which a single drug can block the parasite ribosomal machinery.

They now intend to compare and contrast the map of the parasite ribosome and known maps for the human ribosome to see how drugs might be adapted to be precisely specific for the malaria parasite ribosome.

In this audio interview Gail Wilson asks Dr Baum why malaria control measures, such as bed nets, have not been enough to control the deadly disease and asks how this new research may open up a pipeline for new drug discovery.

REFERENCE: Wong et al. ‘Cryo-EM structure of the Plasmodium falciparum 80S ribosome bound to the anti-protozoan drug emetine’ eLife, June 2014.