Global malaria deaths declined for years, stabilizing to over 400,000 per year as of 2015
Monday 25 April was World Malaria Day. The disease is still a major health problem worldwide, which has been exacerbated by the corona pandemic. Researchers at Radboudumc have developed a new drug that effectively kills the malaria parasite and blocks the transmission of the parasite to the mosquito. The drug is ready for clinical studies in humans.
The worldwide number of deaths from malaria declined for years, until it stabilized to more than 400,000 per year as of 2015. Then came the corona pandemic and the number of deaths rose alarmingly: almost 630,000 in the year 2020. The disease therefore remains a major problem. All drugs that have been marketed to date have developed resistance to the drugs. Therefore, the development of new resources is still very important.
turning pills
Researchers at Radboudumc have been working for years on new substances that work against malaria. Years ago, biologist Joost Schalkwijk came across old literature from the 1940s stating that substances he was working on for skin conditions could also be effective against malaria. He initiated further research into these agents. The result: a new drug that works well, meets all requirements, and is ready for testing in humans.
The substance was not immediately suitable as a remedy for malaria. ‘We have done a lot of work on it’, says molecular microbiologist Taco Kooij. ‘The first version worked excellently, but was liquid and therefore less suitable for drug production. Of all the chemical variations, we finally selected the substance called MMV693183. This is a solid, which makes it possible to make pills. The new variant also meets other needs for use in humans, such as an easy preparation process and high effectiveness with the expectation that a single dose will suffice.’
Mechanism of action
The drug is similar to pantothenate, or vitamin B5. Kooij: ‘Our variant of this substance blocks the action of a crucial enzyme in the parasite. We show that our drug kills the malaria parasite very effectively in this way, both in animal models and on parasites that we isolated from patients. In addition, the drug also blocks the transfer of parasites from humans to mosquitoes. The agent therefore has a double effect and can thus prevent the spread of the parasite.’
During her PhD, Laura de Vries unraveled the precise mechanism of action of the new antimalarial drug. ‘We use four different research methods to show that the substance interferes with a molecular process in the malaria parasite. As a result, the parasite is deficient in a substance that plays a central role in various biological functions, such as the production of fatty acids and the regulation of the functioning of proteins. These processes are crucial for survival’, explains De Vries. ‘We also show that the drug does not work directly, but is first converted into an active form in the parasite.’
Smart combinations
This drug is the first antimalarial drug that intervenes in this specific molecular process in the malaria parasite. ‘That is important news’, Kooij explains. ‘Because of resistance, it is good to disrupt a completely different process in the malaria parasite than other drugs do. I think we need to cleverly combine our drug with other drugs. The advantage of this agent is that it also blocks transmission to mosquitoes, so that resistance is less easily spread.’
The drug has been developed preclinically and is ready for translation to patients. Kooij: ‘The Malaria Medicine Venture is now further developing the substance and will set up clinical studies. They also own the patent. Hopefully this drug will find a place in the fight against malaria and we can reduce the number of deaths from malaria.’
This research is published in Nature Communications: Preclinical characterization and target validation of the antimalarial pantothenamide MMV693183
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