Researchers led by the University of Glasgow have unveiled a new drug designed to combat treatment-resistant malaria.
The breakthrough development is the first to adapt an approach from cancer treatments to tackle malaria. It works by permanently disabling a protein that Plasmodium falciparum, one of the mosquito-borne parasites which spreads malaria, uses to duplicate itself inside the human body.
Chemists and bioscientists from the University of Glasgow led the development of the new drug. In a paper published in the Journal of Medicinal Chemistry, they 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 around the world every year, killing more than 600,000 people annually. The new drug could help to overcome the growing problem of Plasmodium falciparum’s resistance to artemisinin, the current frontline treatment for malaria infections.
Andrew Jamieson, Professor of Chemical Biology at the University of Glasgow’s School of Chemistry, is one of the paper’s corresponding authors. He said: “During the pandemic, global progress against malaria stalled as access to treatment became more difficult, while parasites simultaneously developed increasing resistance to current drugs.
“We wanted to see whether a type of drug called a covalent kinase inhibitor, which has been used successfully in some cancer treatments, could provide an entirely new way to tackle malaria parasites. A fresh approach to medication could help us shore up our defences against malaria in the years to come.”
The new drug works by targeting a protein called PfCLK3, which plays a vital role in the parasite’s ability to splice RNA. By firmly attaching itself to the protein, the drug molecule essentially turns off the parasite’s method of replicating itself in the bloodstream, killing it before it can spread.
The development of the drug was part of doctoral research by PhD student Skye Brettell, also of the School of Chemistry, who is the paper’s first author.
She said: “Covalent kinase inhibitors are commonly used in oncology, but a frequent drawback is that, while targeting cancer proteins, these drugs often affect other proteins as well, leading to side effects. The molecule we’ve developed is much more focused on its target – it has a special chemical ‘grappling hook’ that ensures it sticks only to the PfCLK3 protein, which could help it treat malaria without causing unwanted effects in humans.”
The researchers ran the drug through an extensive battery of tests of its properties. Colleagues at the University of Edinburgh helped them test the drug on isolated proteins. Using mass spectrometry, they showed that the drug was permanently binding to its targets. Further tests on live samples of Plasmodium falciparumdemonstrated that washing the parasites after six hours did not remove the effect of the drug.
In collaboration with Columbia University in New York, they also demonstrated that parasites were unable to develop resistance to the drug over time.
Skye added: “These are really robust results, which show that the drug can withstand the challenges it might face inside the parasite, and that the parasite is unlikely to develop resistance to it. That’s very exciting, because preventing resistance is a high barrier to clear for anti-malarial drugs.
“Although more testing is required, we’d expect from what we’ve seen so far that the molecule would be effective at all stages of the parasite’s life cycle, which is something that isn’t possible with artemisinin. Our hope is that this molecule could be the basis of a one-shot cure for malaria in the future.”
The researchers are now seeking additional funding to conduct advanced toxological studies – the next step in establishing that the drug may be safely administered to patients – and to work on stabilising the drug for use in the human body.
Developing the next generation of malaria treatments is one of the aims of Keltic Pharma, a spinout from the University of Glasgow founded by Professor Jamieson and colleagues Professor Andrew Tobin and Professor Graeme Milligan.
The Glasgow researchers acknowledge the importance of the University’s Mazumdar-Shaw Advanced Research Centre (ARC), which opened in 2022, in making the research possible.
Professor Jamieson added: “One of the big things in academic science at the moment is breaking down the silos of chemistry, biology and physics to create new multidisciplinary research projects with real world impact. In the ARC, researchers from different disciplines work in close proximity on a daily basis, and this project is a great example of the impact this approach can generate. This project would’ve taken much longer and been much more difficult without us being in the same building, where we can solve problems together.”
The team’s paper, titled ‘Targeting Pf CLK3 with Covalent Inhibitors: A Novel Strategy for Malaria Treatment’, is published in Journal of Medicinal Chemistry. The research was supported by funding from the Engineering and Physical Sciences Research Council (EPSRC), Biotechnology and Biological Sciences Research Council (BBSRC) and the Bill and Melinda Gates Foundation (BMGF).