Self-destructing parasites -- New weapon against drug-resistant malaria
[June 5, 2022: Harriet Edmund, University of Melbourne]
To help save lives and improve quality of life, breakthrough drugs that hit new targets are desperately needed. (CREDIT: Getty Images)
A new method to combat malaria which sees the disease turn against itself could offer an effective treatment for the hundreds of millions of people infected globally each year, as the efficacy of current antimalarial drugs weakens.
The University of Melbourne-led research published today in Science has identified an anti-malarial compound, ML901, which inhibits the malaria parasite but does not harm mammalian – human or other mammals’ – cells.
Co-lead author Professor Leann Tilley, from the Bio21 Institute at the University of Melbourne, said the ML901 compound effectively made the parasite the agent of its own demise, underpinning it potency and selectivity.
“ML901 works by an unusual reaction-hijacking mechanism,” Professor Tilley said.
“Imagine a stealth weapon that can be used to launch a self-destruct attack on your vehicle – slamming on the brakes and cutting the engine. ML901 finds a particular chink in the machinery that the malaria parasite uses to generate the proteins needed to reproduce itself and stops it doing so.
Plasmodium falciparum (pictured inside red blood cells) is the most lethal of all malaria parasites. (CREDIT: Getty Images)
“While there is much work to be done to fine tune what we’ve discovered, these results are really encouraging in the search for new antimalarials.”
In the collaboration with Takeda Pharmaceuticals, Medicines for Malaria Medicine – the peak international body for antimalarial drug development – and research labs across five continents, tests were conducted using molecules provided by Takeda, during which the ML901 compound was identified.
Once ML901 entered the parasite, it attached itself to an amino acid and attacked the protein synthesis machinery from the inside, rapidly grinding the parasite to a halt. The molecular structure of human cells means they are not susceptible to attack by ML901.
Diagrammatic representation of the target of a new antimalarial compound, ML901 (coloured structure), that shows highly specific and potent inhibition of the malaria parasite but is non-toxic to mammalian cells. ML901 finds a particular chink in an enzyme called tyrosine tRNA synthetase (depicted in pink), part of the machinery that the malaria parasite uses to generate the proteins needed to reproduce itself. The parasite rapidly grinds to a halt and can’t cause disease or be transmitted to other people via mosquitoes (purple).
In tests using both human blood cultures and an animal model of malaria, the team found ML901 killed malaria parasites that had resistance to currently used drugs and showed rapid and prolonged action resulting in excellent parasite killing.
Professor Tilley said the compound showed it was active against all stages of the lifecycle, meaning it could be used to prevent malaria infections as well as to treat the disease.
“It also shows potential for preventing infected people from transmitting the disease to others, which is critical to stop the spread of malaria.”
Every 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 resistance to antimalarials has led to an impending crisis, with breakthrough drugs desperately needed.
Professor Tilley said 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 possibility of finding drugs, similar to ML901, that target a range of deadly infectious diseases, including multi-drug resistant bacterial infections. ”
“This opens up several important new drug discovery avenues to help address the deadly impact of malaria and other infectious diseases - particularly in developing nations. It could also be used to target other diseases like cancer, neurodegenerative disease, metabolic syndromes including, diabetes and autoimmune disorders.”
According to Professor Tilley, the next step for the team is to tweak the chemical structure to improve the drug-like properties to optimise the absorption and distribution of the compound in the body.
“A particularly exciting part of the work is the ability to work with a large, talented and highly collaborative team, bringing together scientists from academia, the pharmaceutical industry and the not-for-profit sector.”
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Note: Materials provided above by University of Melbourne. Content may be edited for style and length.
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