New drug target prevents deadly malaria transmission

Professor Vicky Avery.

A Griffith researcher has played a key role in the discovery of a new drug target for stopping the spread of malaria, after successfully blocking the world’s deadliest malaria parasite – Plasmodium falciparum – from completing the ‘transmission stage’ of its lifecycle.

Using small molecule inhibitors developed at the Walter and Eliza Hall Institute, the researchers blocked plasmepsin V, an enzyme essential for the development of gametocytes which are the only form of the malaria parasite that can be transmitted from humans to mosquitoes.

The research, published in Cell Reports, was led by Associate Professor Justin Boddey from the Walter and Eliza Hall Institute, in collaboration with Professor Vicky Avery from the Griffith Research Institute for Drug Discovery.

More than half a million people die from malaria every year and Plasmodium falciparum – the most lethal of all malaria parasites – is responsible for 90 per cent of infection cases.

Due to the parasite’s ability to constantly mutate and develop resistance to therapies, new preventions and treatments that act across different stages of the malaria parasite lifecycle – the liver stage, blood stage and transmission stage – are now required.

Associate Professor Boddey said the team had gained new ground towards malaria elimination because blocking the parasite’s transmission stage was important for developing preventative therapies that stop the spread of disease.

“It was exciting to find that plasmepsin V plays a role in malaria transmission, and that our inhibitors could target plasmepsin V and block transmission to the mosquito from occurring,” Associate Professor Boddey said.

“We showed that an optimal concentration of the inhibitors could kill gametocytes, and that even with a lower dose, the gametocytes made it all the way through their two-week development phase but still couldn’t complete the task of transmitting infection to mosquitoes. This shows plasmepsin V is a target for transmission-blocking drugs,” he said.

Using the Institute’s insectary facilities, the researchers were able to study how gametocytes transmit malaria from human blood to a mosquito. They demonstrated, using gametocyte-specific fluorescent ‘tags’, that plasmepsin V was critical for the export of gametocyte proteins – a process essential to gametocyte transmission – before proving their inhibitors could stop this process in its tracks.

The researchers are now turning their attention to the role of plasmepsin V in the remaining pillar of the malaria lifecycle: the liver stage.

Associate Professor Boddey said the aim was to assess plasmepsin V as a multi-stage drug target for treating, as well as preventing, the spread of malaria; and to understand the unique biology occurring during liver infection.

The research was supported by the Australian National Health and Medical Research Council of Australia, the CASS Foundation and the Victoria Government.