Scientists from the Heidelberg University Hospital and the German Center for Infection Research (DZIF) have developed a new substance that has cured severe malaria in humanised mice.
Severe malaria, caused by the Plasmodium falciparum parasite, causes dangerous circulatory disorders and neurological complications. If the affected person is not treated immediately, the disease will inevitably lead to death. On the one hand, the currently used drugs artesunate and quinine have unwanted side effects and, on the other, more and more plasmodia are becoming resistant to them. Developing new drugs with other mechanisms of action is therefore essential.
"New drugs for treating severe malaria are indeed urgently needed," emphasizes Prof Michael Lanzer, DZIF scientist at the Heidelberg University Hospital. In a DZIF project, he developed the first promising candidate together with his research team: SC83288, the promising substance with a somewhat prosaic name has the required properties, and has already been successfully used to treat severe malaria in humanised mice.
Animal tests successful
The starting point of the drug development was benzamidine derivatives, which had been effective against different parasites in veterinary medicine but were not used as they have severe side effects. The scientists have now tried to modify these substances so that they become suitable to treat severe malaria. The substance was chemically modified to make it more tolerable without forfeiting its effect against parasites. "The new chemical structure is very well tolerated, is metabolised rapidly in the body and the crucial factor: in animal models, it can kill the severe malaria parasites in a short period of time," explains Lanzer.
For their tests, the scientists used mice with human blood cells and that had been infected with severe malaria. In this model system, SC83288 was effective in the late stages of malaria, during which the parasites are in the blood cells where they cause severe damage. Detailed preclinical studies on pharmacokinetics and toxicology showed consistent positive results for the substance which is to be administered intravenously. "We are now in the process of conducting the regulatory preclinical procedures and hope to initiate the clinical trials in 2018," says Lanzer.
Malaria parasites (plasmodia) are transmitted to humans by bites from infected anopheles mosquitoes. Once in the body, they reproduce in the liver cells and then target red blood cells. In these red blood cells, they reproduce once again and finally destroy them. The blood cells burst open, causing the characteristic intermittent fever and anaemia. Tropical malaria, the severe form of malaria, is one of five types of malaria and is caused by Plasmodium falciparum. It accounts for an estimated two thirds of all malaria cases. According to the World Health Organisation, there were 214 million new cases of malaria worldwide in 2015 and almost half a million people died of malaria.
Pegoraro S et al.
SC83288 is a clinical development candidate for the treatment of severe malaria
Nature Communications 8:14193 (2017). Doi: 10.1038/NCOMMS14193