NIH Investigates Two New Targets for Anti-Malaria Drugs
Responsible for approximately 212 million cases in 2015, malaria causes fever, chills, and flu-like illness. If untreated, the mosquito-borne parasitic disease can lead to death. In fact, almost 430,000 individuals succumbed to the infection in 2015. Most of these individuals lived in sub-Saharan Africa or South Asia.
Proteases of the malaria parasite Plasmodium falciparum have long been investigated as drug targets. The P. falciparum genome encodes 10 aspartic proteases called plasmepsins, which are involved in diverse cellular processes. Most have been studied extensively but the functions of plasmepsins IX and X (PMIX and PMX) were unknown.
Now, the investigators at the NIH, have found plasmepsin IX in rhoptries, specialized cell structures inside the parasite, which help it invade red blood cells. Parasites lacking plasmepsin IX had defective rhoptries.
In addition, the team observed plasmepsin X in exonemes — small vesicles (balloon-like structures) that help malaria parasites exit infected cells. The team also discovered that plasmepsin X processes an important protein called SUB1. When deprived of plasmepsin X, the parasites couldn’t process SUB1 and couldn’t infect red blood cells or exit these cells after multiplying.
The team expects that the parasites lacking the plasmepsins could be used for screening
of drug candidates in order to identify new anti-malaria compounds.The researchers currently identified three experimental malaria drugs that could potentially target plasmepsin X.
Out of the three drugs, CWHM-117 has been evaluated in a mouse model of malaria and the researchers intend to use this data to alter the drug for obtaining better efficacy.
The new findings may help researchers modify CWHM-117 to make it more effective. Furthermore, parasites lacking the plasmepsins could potentially be used to screen candidate drugs to identify additional anti-malaria compounds.
