New anti-malarial medicines are urgently needed. Groundbreaking and award-winning discoveries in active substance research from the Institute of Pharmacy at Kiel University.
Professor Eric Beitz has been researching possible ways to combat malaria pathogens for around 20 years. "We are trying to find new points of attack against malaria," explained Beitz, head of the Department of Pharmaceutical Chemistry at Kiel University. By points of attack he means protein molecules of the pathogen that it needs to survive. Beitz is focusing here on transporters that convey, for example, nutrients or water into the pathogen or remove metabolic products. A breakthrough came a few years ago with the discovery of lactic acid transporters. According to Beitz: "Decades have been spent looking for this transport protein. But no one has found it because it looks significantly different from the transporter that humans have for this purpose. We discovered this transport protein by lucky coincidence. We can functionally produce it in our test systems and test active substances against it."
The weak point of the parasite
The transport molecule is so interesting for research because the pathogen, a parasite of the genus Plasmodium, needs it for its energy metabolism. In order to gain energy, the parasite uses human blood sugar, which it breaks down to the level of lactic acid (lactate). It has to remove this so as not to become too acidic. And this is exactly why it needs the lactic acid transporter. "The lactate transporter is essential to the pathogen’s existence. We have tried to deactivate the gene, but were not successful. This is a strong indication that it cannot survive without the transporter," reported Beitz. The scientist has been researching the malaria pathogen for years in close collaboration with the working group led by Dr Tobias Spielmann of the Bernhard Nocht Institute for Tropical Medicine in Hamburg. The working group has cultures of the malaria pathogen and provides Beitz and his team with the DNA of the pathogen. "We reproduce the DNA and transfer the gene into our test systems using baker’s yeast. The yeast then produces the transport protein of the malaria pathogen." At the end of 2021 the Kiel-based pharmacy professor won the PHOENIX Pharmacy Science Award 2021 in the category of pharmaceutical chemistry for a recent publication on a promising active substance candidate.
Beitz and his team use the yeast test systems to determine which substances are able to inhibit the transporter. To do this, they use what are known as substance libraries of companies or organisations like the Medicines for Malaria Venture (MMV). MMV is a charitable public-private partnership that funds, among other things, the development of anti-malarial active substances. The register includes substances that are known to be effective against malaria pathogens but with modes of action that are unknown. "We have used the substance library of MMV and found two substances that block lactate transporters."
Effective in the animal model
The substances found this way were further developed in the working group and also tested on infected mice. "By using a test substance we were able to kill up to 99.9 percent of the malaria pathogen in the mice," explained the pharmacist. The successful active substance candidate now needs to be further optimised so that it remains stable for longer in the blood. The aim is to further improve the potency of the substance. It should bind more strongly to the transporter in order to remain effective for longer. At the same time, of course, safety and tolerability are also important. The study in the animal model was encouraging in this respect too. "Of course, the protein structure plays an important role here," said Beitz. "Because people do not have this type of protein at all, we can target this pathogen protein very selectively and not the human proteins." In further studies the inhibitor was adapted to mutations of the pathogen in order to prevent resistance.
The promising anti-malarial active substance class is patented under the designation BH276meta. Cooperation with a pharmaceuticals company would be ideal now for further development to produce a drug. There is, however, little interest from industry in the expensive development of anti-malarial drugs. "This is not a project that will earn you lots of money," explained Beitz. His working group will continue in any case and has applied for more funding from Medicines for Malaria Venture.
Author: Kerstin Nees
Malaria – the world's most common infectious disease
In 2020, around 240 million people were infected with malaria worldwide, predominantly in Africa. 627,000 people died from it. Pathogens of the tropical disease are parasites known as Plasmodium. They are transmitted by mosquito bites. The symptoms of malaria include high, recurrent fever alternating with periods without fever, chills and complaints of the gastrointestinal tract. The illness is often fatal for children under five years in particular.
Although extensive research has already been conducted on malaria, the burden of the disease is still extremely high. Pathogens that vary from region to region and genetic differences in affected population groups, co-infections with other germs and increasing resistance to available drugs make the research work more difficult. (ne)