New drug could help fight treatment-resistant malaria

An international team of researchers has developed a promising new drug that could help combat the spread of treatment-resistant malaria.

The groundbreaking development is the first to adapt an approach from cancer treatments to combat malaria. It works by permanently deactivating a protein that Plasmodium falciparum, one of the mosquito-borne parasites that spread malaria, uses to replicate in the human body.

Chemists and life scientists from the University of Glasgow led the development of the new drug. In an article titled “Targeting PfCLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment,” published in the Journal of Medicinal ChemistryThey outline how the treatment could be more effective than current medications at all stages of malaria infection. It could also work as a single-dose treatment, the researchers say.

Nearly a quarter of a billion cases of malaria are reported worldwide each year, killing more than 600,000 people each year. The new drug could help overcome the growing problem of Plasmodium falciparum resistance to artemisinin, the current first-line treatment for malaria infections.

Andrew Jamieson, Professor of Chemical Biology at the School of Chemistry at the University of Glasgow, is one of the paper's corresponding authors. He said: “During the pandemic, global progress in the fight against malaria stalled as access to treatment became more difficult, while at the same time parasites developed increasing resistance to current medicines.”

“We wanted to see whether a drug called a covalent kinase inhibitor, which has been used successfully in some cancer treatments, could provide an entirely new way to combat malaria parasites. A new drug approach could help us strengthen our defenses against malaria in the coming years.

The new drug works by targeting a protein called PfCLK3, which plays a crucial role in the parasite's ability to splice RNA. By binding tightly to the protein, the drug molecule essentially stops the parasite's method of reproducing in the bloodstream, killing it before it can spread.

The development of the drug was part of Ph.D. student Skye Brettell, also from the School of Chemistry, the first author of the paper.

She said: “Covalent kinase inhibitors are widely used in oncology, but a common drawback is that although these drugs target cancer proteins, they often also affect other proteins, leading to side effects. The molecule we developed is much more focused.” Its goal: It has a special chemical “attacker” that ensures that it only sticks to the PfCLK3 protein, which could help it treat malaria without causing undesirable effects in humans to have an impact.”

The researchers subjected the drug to an extensive series of tests on its properties. Colleagues at the University of Edinburgh helped them test the drug on isolated proteins. Using mass spectrometry, they showed that the drug binds permanently to its targets. Further testing on live samples of Plasmodium falciparum showed that washing the parasites after six hours did not reverse the drug's effects.

In collaboration with Columbia University in New York, they also showed that parasites could not develop resistance to the drug over time.

Skye added: “These are really robust results, showing that the drug can withstand the challenges it might face inside the parasite and that the parasite is unlikely to develop resistance to it. This is very exciting because preventing resistance is a high hurdle for antimalarial drugs.

“Although further testing is needed, from what we have seen so far we believe the molecule would be effective at all stages of the parasite's life cycle, which is not possible with artemisinin. Our hope is that this is the case.” The molecule could be the basis for a unique cure for malaria in the future.

Researchers are now seeking additional funding to conduct advanced toxicology studies — the next step in determining whether the drug can be safely administered to patients — and to work on stabilizing the drug for use in the human body.

Developing the next generation of malaria treatments is one of the goals of Keltic Pharma, a University of Glasgow spin-out founded by Professor Jamieson and his colleagues Professor Andrew Tobin and Professor Graeme Milligan.

Glasgow researchers recognize the importance of the university's Mazumdar-Shaw Advanced Research Center (ARC), opening in 2022, in enabling research.

Professor Jamieson added: “One of the big things in academic science right now is breaking down the silos of chemistry, biology and physics to create new multidisciplinary research projects with real-world impact. At ARC, researchers from different disciplines work closely together every day, and this project is a great example of the impact this approach can have. This project would have taken much longer and been much more difficult if we were not in the same building where we can solve problems together.