Malaria kills over 550,000 children each year; nearly one every minute. The disease is transmitted through four species of Plasmodium parasite that travels through a mosquito vector. Though concerted efforts have cut the number of malaria cases in half since 2001, there is still a lot of work to be done to achieve complete eradication. A new molecule called (+)-SJ733 has been shown to effectively kill the malaria parasite in mice within 48 hours. R. Kiplin Guy of St. Jude Children’s Research Hospital is senior author on the paper, which has been published in the Proceedings of the National Academy of Sciences.
Using a mouse model, a single dose of SJ733 was able to eliminate 80% of the parasite within 24 hours, and bring it to undetectable levels by 48 hours. Attempts at using other drugs to combat malaria have been difficult, due to increased levels of drug resistance. However, SJ733 works quickly enough that this might not become a problem.
"Our goal is to develop an affordable, fast-acting combination therapy that cures malaria with a single dose," Guy said in a press release. "These results indicate that SJ733 and other compounds that act in a similar fashion are highly attractive additions to the global malaria eradication campaign, which would mean so much for the world's children, who are central to the mission of St. Jude.”
Previous work by St. Jude’s led to the development of SJ733. This new study identified the mechanism the compound uses to trigger the immune system and attack infected red blood cells, while leaving healthy cells unharmed. For cells infected with the parasite, SJ733 interferes with the ATP4 protein, which operates a pump that regulates cellular sodium level.
Without a functional pump, the sodium level in the cell gets too high. Not only does the cell change shape and shrink, but it also becomes more rigid. These are normal characteristics of aging cells, which the immune system is easily able to discard. This way, the drug isn’t necessarily attacking the parasite itself, but rather using it as a marker to destroy the entire infected cell. SJ733 isn’t the only drug that operates in this way. ATP4 is also targeted by a class of drugs called spiroindolones. A spiroindolone known as NITD246 has already begun human trials with other institutions.
"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 recognize and rapidly eliminate infected cells," added co-author Joseph DeRisi of the University of California, San Francisco. "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.”
Following the success of this study, the researchers are now going forward and planning the first human clinical trials.