The new weapon against malaria drug resistance

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

Despite significant advances in the fight against this disease – including a vaccine rollout that was promising but only shows around 30% effectiveness against severe disease – and dozens of drugs – the the parasite always comes back.

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

To help save lives and improve quality of life, breakthrough drugs that reach new targets are desperately needed. Photo: Getty Images

However, combination therapies fail to cure infections in more than 50% of patients in parts of Southeast Asia. In addition, resistance to artemisinins has also been detected in Africawhere most of the 600,000 annual deaths caused by malaria occur.

To help save lives and improve quality of life, breakthrough drugs that reach new targets and use new mechanisms of action are desperately needed.

Professor Leann Tilley, of Department of Biochemistry and Pharmacologyis part of an international research team working to address global concerns about the rapid loss of effectiveness of current antimalarial treatments.

Professor Tilley and his colleagues have published a world first discovery in the magazine Science showing that a hitherto ignored class of chemicals – known as nucleoside sulfamates or “nucleosides” – can cause malaria parasite enzymes involved in protein synthesis to self-destruct.

These new targets are very effective because protein synthesis enzymes play an essential role in the maintenance and growth of cells.

It is particularly important that inhibitors of this pathway are active against all stages of the malaria parasite – effective both for treatment and for preventing transmission to new victims.

Specifically, nucleoside sulfamates have been found to hijack the parasite’s own cellular machinery, inducing enzymes involved in protein production to create their own inhibitors, thereby halting processes essential for parasite survival.

This mechanism had not been previously reported for protein synthesis enzymes.

“In short, we have discovered a new way to target pathogens – to get them to be the instrument of their own demise,” says Professor Tilley. “Preventing transmission is very exciting because it will help slow the development of resistance.”

Plasmodium falciparum (pictured inside red blood cells) is the deadliest of all malaria parasites. Photo: Getty Images

Go global

Work with the leading body for the development of antimalarial drugs, Malaria drugs and Takeda Pharmaceuticalsas well as research laboratories on five continents, the large international team began research with compounds that Takeda was studying to treat cancer.

The team identified a series of compounds that affect the malaria parasite but not human cells – but the mechanism of toxicity has not been understood.

“We were fortunate to have access to the University of Melbourne’s suite of biochemical and structural biology platforms. Bio21 Institute of Molecular Sciences and Biotechnologyas good as The Australian synchrotron“, explains Professor Michael Parker, director of Bio21.

“This allowed us to mount a multi-pronged investigation into the mechanism of action.”

Further work by Dr. Stanley Xie and Dr. Elyse Dunn of the Department of Biochemistry and Pharmacology, working closely with colleagues at Takeda Pharmaceuticals, led the team to discover that sulfamate nucleosides hijack synthetic enzymes of proteins to form covalent inhibitor-amino acid conjugates – much like super-gluing a key into a lock so that the lock no longer works.

“Excitingly, we discovered a particular compound, ML901, in the Takeda compound library that targets a single plasmodium enzyme and was not 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 solved the structure of the protein.

Schematic representation of the target of a new antimalarial compound, ML901 (shaded structure), which shows highly specific and potent inhibition of the malaria parasite but is not toxic to mammalian cells. ML901 finds a particular flaw in an enzyme called tyrosine tRNA synthetase (shown in pink), part of the machinery that the malaria parasite uses to generate the proteins necessary for its reproduction. The parasite stops quickly and cannot cause disease or be transmitted to other people by mosquitoes (purple).

“We discovered a flap of protein that sits at the site where the inhibitor conjugate binds,” says Associate Professor Griffin. “The flap appears to keep the working enzyme in an intermediate state ready for attack by ML901.

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

The next phase was to test ML901 in a malaria test suite provided by the Malaria drugs. 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 malaria parasite tested. Importantly, ML901 exhibits rapid and prolonged activity that provides potent parasite clearance 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 pursue the development of ML901 as a novel antimalarial drug candidate,” says Professor Tilley.

New avenues of 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 similar success to other nucleoside sulfamates that target a different class of enzymes called ubiquitin-activating (E1) enzymes.

These compounds have been leveraged by Takeda to develop several novel cancer clinics candidates.

The research team will now pursue ML901 as a new antimalarial drug candidate. Photo: Getty Images

“We believe our work here is just the beginning,” says Dr. Larry Dick, honorary member of the Department of Biochemistry and Pharmacology and co-lead author.

“This opens up several important avenues for the discovery of new drugs to help combat the deadly impact of malaria and other infectious diseases, especially in developing countries. It could also be used to target other diseases like 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 improve 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 not-for-profit sector.”

This research is funded by the Innovative Technology in Global Health (GHIT). The received approval from 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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