A new way to fight malaria turns the disease against itself

A new method of fighting malaria that sees the disease turning on itself could provide effective treatment for the hundreds of millions of people infected each year around the world, as the effectiveness of current antimalarial drugs wanes.

Research led by the University of Melbourne published today in Science identified an anti-malarial compound, ML901, which inhibits the malaria parasite but does not damage cells in mammals – humans or other mammals.

Co-lead author Professor Leann Tilley, from the University of Melbourne’s Bio21 Institute, said the compound ML901 effectively made the parasite the agent of its own demise, which underlies its potency and its selectivity.

ML901 works by an unusual reaction diversion mechanism.


Imagine a stealth weapon that can be used to launch a self-destruct attack on your vehicle – slamming on the brakes and cutting out the engine. ML901 finds a particular flaw in the machinery that the malaria parasite uses to generate the proteins necessary for its reproduction and prevents it from doing so.


Although there is a lot of work to be done to refine what we have discovered, these results are really encouraging in the search for new antimalarials.”


Professor Leann Tilley, Bio21 Institute, University of Melbourne

In collaboration with Takeda Pharmaceuticals, Medicines for Malaria Medicine – the leading international organization for the development of antimalarial drugs – and research laboratories on five continents, tests were carried out using molecules provided by Takeda, in during which compound ML901 was identified.

Once ML901 entered the parasite, it attached itself to an amino acid and attacked the protein synthesis machinery from within, quickly immobilizing the parasite. The molecular structure of human cells means that they are not susceptible to attack by ML901.

In tests using both human blood cultures and an animal model of malaria, the team found that ML901 killed malaria parasites resistant to currently used drugs and showed rapid and prolonged action resulting in excellent parasite clearance.

Professor Tilley said the compound has shown activity against all stages of the life cycle, meaning it could be used to prevent malaria infections as well as treat the disease.

“It also shows potential for preventing infected people from transmitting the disease to others, which is critical to stopping the spread of malaria.”

Each year, at least 200 million new malaria infections are diagnosed worldwide, causing more than 600,000 deaths in Africa and Southeast Asia. Over the past 50 years, ever-increasing levels of antimalarial drug resistance have led to a looming crisis, with breakthrough drugs desperately needed.

Professor Tilley said that based on these findings, the team was ready to pursue the development of new antimalarial drug candidates.

“We believe this is just the beginning. We now have the potential to find drugs, similar to ML901, that target a range of deadly infectious diseases, including multidrug-resistant bacterial infections. The work opens up several new avenues of drug discovery.

Source:

Journal reference:

Xie, SC, et al. (2022) Tyrosine tRNA synthetase reaction hijacking as a new life cycle antimalarial strategy. Science. doi.org/10.1126/science.abn0611.

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