Researchers determined that the compound (+)-SJ733 uses a novel mechanism to kill the parasite by recruiting the immune system to eliminate malaria-infected red blood cells. In a mouse model of malaria, a single dose of (+)-SJ733 killed 80 per cent of malaria parasites within 24 hours. After 48 hours the parasite was undetectable.
Planning has begun for safety trials of the compound in healthy adults, researchers said. Laboratory evidence suggests that the compound’s speed and mode of action work together to slow and suppress development of drug-resistant parasites.
“Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose,” said corresponding author R Kiplin Guy, from the St Jude Children’s Research Hospital in US.
Whole genome sequencing of the Plasmodium falciparum, the deadliest of the malaria parasites, showed that (+)-SJ733 disrupted activity of the ATP4 protein in the parasites. The protein functions as a pump that the parasites depend on to maintain the proper sodium balance by removing excess sodium.
Investigators used the laboratory technique to determine the makeup of the DNA molecule in different strains of the malaria parasite. Researchers showed that inhibiting ATP4 triggered a series of changes in malaria-infected red blood cells that marked them for destruction by the immune system. The infected cells changed shape and shrank in size.
They also became more rigid and exhibited other alterations typical of ageing red blood cells. The immune system responded using the same mechanism the body relies on to rid itself of ageing red blood cells.
“The data suggest that compounds targeting ATP4 induce physical changes in the infected red blood cells that allow the immune system or erythrocyte quality control mechanisms to recognise and rapidly eliminate infected cells,” said co-author Joseph DeRisi, a Howard Hughes Medical Institute investigator.
“This rapid clearance response depends on the presence of both the parasite and the investigational drug. That is important because it leaves uninfected red blood cells, also known as erythrocytes, unharmed,” said DeRisi.
Laboratory evidence also suggests that the mechanism will slow and suppress development of drug-resistant strains of the parasite, researchers said. Planning has begun to move (+)-SJ733 from the laboratory into the clinic beginning with a safety study of the drug in healthy adults, they said.