For centuries, one of the biggest challenges for medical research has been controlling malaria.

More than half of the world's population is at risk of contracting the disease, which is caused by Plasmodium parasites.

Humans are infected by the bite of a disease-carrying mosquito. The parasites first migrate to the human liver, where they multiply undetected by their host's immune system.

The parasites mature and are released into the blood, causing the classic symptoms of malaria – fever, headache and chills. Once in the blood, a mosquito then picks up the parasite from the infected individual, and transmits it to the next victim.

Most current antimalarial drugs are active against the malaria parasite during this blood stage of infection, but many parasites have now developed resistance to commonly used drugs. In some areas, parasites are resistant to all three frontline malaria treatments, so novel drugs are urgently needed.

Now, researchers from the Walter and Eliza Hall Institute and global pharmaceutical company MSD have developed a novel class of antimalarial compounds that has been shown to effectively kill the malaria parasites at multiple stages of its life cycle.

Hitting the targets

The new compound, named WM382, packs a one-two punch – targeting two essential molecules that interrupt several critical stages of the parasite's life cycle, says Professor Alan Cowman, deputy director at the Walter and Eliza Hall Institute of Medical Research, who led the Australian research team.

"WM382 not only killed malaria parasites in the blood in preclinical testing, it also killed parasites in the liver and prevented parasites in the blood being transmitted to mosquitoes," says Professor Cowman.

"This new class of drug candidates has the potential to not only cure people with malaria, but also prevent transfer of the parasite to the mosquito and halt further transmission of the disease.

"It is an exciting prospect, as current antimalarial drugs kill the malaria parasite in the blood but don't fully prevent transmission back to the mosquito. These new compounds have the potential to fill a critical and widening gap in our efforts to control and eliminate malaria."

Preclinical testing in laboratory models showed WM382 was also effective against different species of malaria parasites, including the deadly Plasmodium falciparum, which is responsible for almost all malaria cases and deaths in Africa.

The team hope that drugs based on these compounds will soon progress to human phase I clinical trials.

A global problem

More than 600,000 people – predominantly pregnant women and children under the age of five – die from malaria every year. According to the World Health Organization, one child in Africa dies from malaria every two minutes.

There are five species of Plasmodium parasite that can infect humans, but two – Plasmodium falciparum and Plasmodium vivax – cause almost all cases worldwide.

Much like antibiotic resistance, malaria resistance is an emerging crisis. Effective antimalarial drugs aren't just critical for the infected individual, they are also critical for breaking the cycle of infection and an important way for us to reach our goal of eliminating malaria from highly endemic regions.

"WM382 targets plasmepsin IX (PMIX) and plasmepsin X (PMX), two 'master regulators' that are critical for parasite survival.

"PMIX and PMX are involved in multiple stages of the parasite lifecycle including red blood cell invasion. Because the compound hits both these targets, it is harder for parasites to develop resistance," Professor Cowman says.

Research project that never sleeps

The development of WM382 started five years ago when Dr David Olsen, the head of the MSD US team, contacted Professor Cowman to ask if he was interested in a collaboration to develop new antimalarial drugs. This began an exciting research project that 'never sleeps'.

"In the US, when scientists at MSD finished their work day, our team at the Walter and Eliza Hall Institute would take up the baton, fast-tracking the discovery and development of these exciting novel antimalarial compounds," says Professor Cowman.

In recent years, the focus of international efforts to develop new malaria drugs have centred on two criteria; they must target a novel process or pathway to avoid pre-existing resistance to current drugs; and they must be active at multiple stages of the parasite lifecycle.

Professor Cowman said WM382 successfully met both of these criteria.

"A major problem with current antimalarial drugs is that malaria parasites evolve and develop resistance to the drugs over time," says Professor Cowman.

"An exciting feature of WM382 is that it kills the malaria parasite in a very different way to current antimalarial drugs. In preclinical testing, malaria parasites that were resistant to the lethal effects of current antimalarial drugs were fully susceptible to WM382," Professor Cowman says.

"It was also very difficult to induce resistance to this compound in malaria parasites in the lab. This is uncommon in drug discovery, and is a positive sign, suggesting it will be harder for malaria parasites to acquire resistance in the field."

Research at the Walter and Eliza Hall Institute was led by Professor Cowman, with Dr Paola Favuzza, Associate Professor Justin Boddey, Dr Brad Sleebs and colleagues. The MSD team in the US was headed by Dr David Olsen, with Dr Manuel de la Ruiz and colleagues. The research was funded by the Wellcome Trust (UK), Australian National Health and Medical Research Council and the Victorian Government.

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