Targeting a parasite-specific enzyme offers new hope for malaria treatment

Research published in The FEBS Journal may help overcome challenges to the treatment of malaria-a tropical disease caused by infection of red blood cells with Plasmodium parasites, which are transmitted through infected mosquito bites. The research is based on a strategy that targets an enzyme specific to the parasite, Falcipain-2 (FP2), which is essential for parasite survival and growth within the host.

FP2 allows the parasite to digest human hemoglobin so that it can replicate inside red blood cells, which leads to severe malaria symptoms, including red blood cell destruction. Although FP2 is parasite-specific, it is highly similar to a class of human enzymes called cathepsins. This study therefore sought to determine the detailed structural and functional characterizations of FP2 so that it could be targeting without harming cathepsins.

Previously, the researchers identified that polyethylene glycol (PEG) can form stable interactions with FP2. In this latest study, they focused on how different PEG molecules bind to FP2 and its target, hemoglobin. Their computational analyses identified a binding region, or pocket, of a particular PEG called PEG400 with FP2. This pocket exhibits minimal conservation in human cathepsins. PEG400 was capable of binding FP2 and affecting its digestion of hemoglobin.

"The findings pave the way for designing and incorporating new small molecule inhibitors of FP2 activity, suggesting opportunities for selective antimalarial therapies with a cumulative benefit of reducing off-target specificity," said corresponding author Sampa Biswas, PhD, who conducted this work while at the Saha Institute of Nuclear Physics, in India, and is currently at InBOL (Indian Barcode of Life) Health Care.