The new weapon against malaria resistance

So far, the malaria parasite has had a response to every control method we’ve thrown at it.

Despite significant advances in the fight against it — including a vaccine rollout that showed promise but only showed about 30 percent effectiveness against serious diseases — and dozens of drugs — the parasite always makes a comeback†

Currently, the recommended treatment for malaria infection is a artemisinin combination therapya mix of fast-acting and slower-acting drugs designed to treat malaria infections and prevent transmission.

However, combination therapies do not heal in more than 50 percent of patients in some Southeast Asian regions. In addition, there is now also resistance to artemisinins detected in Africawhere most of the 600,000 deaths per year occur from malaria.

To help save lives and improve quality of life, breakthrough drugs that achieve new goals and use new modes of action are desperately needed.

Professor Leann Tilley, of the Department of Biochemistry and Pharmacologyis part of an international research team working on global concerns that current antimalarial treatments are rapidly losing their effectiveness.

Professor Tilley and colleagues have published a world’s first discovery in the news Science showing that a previously overlooked class of chemicals — known as nucleoside sulfamates or “nukes” — can cause enzymes from the malaria parasite involved in protein synthesis to self-destruct.

These new targets are highly effective because protein synthesis enzymes play a critical role in the maintenance and growth of cells.

Of particular note, inhibitors of this pathway are expected to be active against all stages of the malaria parasite – effective for both treating and preventing transmission to new victims.

In particular, the nucleoside sulfamates were found to hijack the parasite’s own cell machinery, causing enzymes involved in protein production to create their own inhibitors — stopping processes essential to the parasite’s survival.

This mechanism was not previously reported for protein synthesis enzymes.

“Basically, we’ve discovered a new way of tackling pathogens — making them the instrument of their own demise,” says Professor Tilley. “Preventing transmission is very exciting because it will slow the development of resistance.”

Go Global

Working with the top body for malaria drug development, Medicines for Malaria Venture and Takeda Pharmaceuticalsas well as research labs from five continents, the large international team began their investigation of compounds Takeda was investigating to treat cancer.

The team identified a series of compounds that affect the malaria parasite, but not human cells — but the mechanism of toxicity was not understood.

“We were fortunate to have access to the array of biochemical and structural biology platforms at the University of Melbourne” Bio21 Institute of Molecular Sciences and Biotechnologylike The Australian Synchrotron”, says Professor Michael Parker, director of Bio21.

“That allowed us to set up a multiple study on the mechanism of action.”

Through further work by Dr. Stanley Xie and Dr. Elyse Dunn, of the Department of Biochemistry and Pharmacology, working closely with colleagues from Takeda Pharmaceuticals, the team was able to discover that nucleoside sulfamates hijack protein synthesis enzymes to form covalent inhibitor-amino acid conjugates — a bit like supergluing a key into a lock so that it can lock no longer works.

“Excitingly, we discovered a particular compound, ML901, in the Takeda compound library that targets a single plasmodium enzyme and was non-toxic to mammalian cells,” says Professor Tilley.

Colleagues from the Department of Biochemistry and Pharmacology Dr. Riley Metcalf, Dr. Craig Morton and associate professor Mike Griffin have solved the structure of the protein.

“We discovered a protein flap that is located where the inhibitor conjugate binds,” explains associate professor Griffin. “The flap appears to hold the working enzyme in an intermediate state ready for attack by ML901.

“The human enzyme has a much more open active site, meaning it is less susceptible to reaction hijacking by ML901. Our 3D renderings of the active site were very important in understanding why ML901 is so powerful and selective.”

The next phase was the testing of ML901 in a series of malaria assays provided by the Medicines for Malaria Venture† These tests are designed to ensure that drug candidates meet the criteria for further development.

The team showed that ML901 is active against all stages and strains of the tested malaria parasite. Importantly, ML901 exhibits rapid and sustained activity causing potent parasite kill in an animal model of human malaria that meets the criteria for rapid and effective treatment of malaria patients.

“The team is now ready to continue the development of ML901 as a new antimalarial drug candidate,” said Professor Tilley.

New avenues for drug discovery await

With at least 200 million new malaria infections diagnosed every year, it is hoped that this class of nucleoside sulfamates will have the same success as other nucleoside sulfamates that target a different class of enzymes called ubiquitin-activating (E1) enzymes.

These compounds have been used by Takeda to develop several new clinical cancer-fighting candidates†

“We believe our work here is just the beginning,” said Dr. Larry Dick, Honorary Fellow in the Department of Biochemistry and Pharmacology and co-lead author.

“This opens up several important new ways to discover drugs to address the deadly impact of malaria and other infectious diseases, especially in developing countries. It can also be used to target other diseases such as cancer, neurodegenerative diseases, metabolic syndromes including diabetes and autoimmune diseases.”

According to Professor Tilley, the next step for the team is to modify the chemical structure to enhance the drug-like properties to optimize the absorption and distribution of the compound in the body.

“A particularly exciting part of the job is the ability to work with a large, talented and highly collaborative team, bringing together scientists from academia, the pharmaceutical industry and the non-profit sector.”

This research is funded by the Global Health Innovative Technology (GHIT) fund. The program has received approval from the Medicine for Malaria Venture to enter the lead optimization phase and the team will now seek funding from GHIT for the next phase of development.

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