Targeting Allosteric Site of Enzyme: New Approach to Overcoming Drug Resistance Problem in Malaria

Haemoglobin degradation is essential for parasite growth and development performed by the cascade of proteases. Falcipains, the cysteine protease of malaria parasite, act as major hemoglobinases. They consist of bipartite pro- and mature domains that interact via ‘hot-spot’ and retain the structural integrity of the enzyme in an inactive state. Upon sensing the acidic conditions, the hot-spot interactions dissociate and release mature active enzyme. To inhibit falcipains, several active site compounds exist, however, inhibitors that target it via allosteric mechanism remain unexplored. Recently characterized allosteric inhibitors, NA-01 & NA-03, arrest the parasite growth by specifically blocking the auto-processing event in falcipains. Inhibitors showed high affinity for enzymes in the presence of the prodomain without affecting the secondary structure. Our group published the first report in malaria where allosteric inhibitors blocked the autoprocessing event in parasite proteases. Targeting allosteric sites in falcipains can serve as a new mechanismbased approach in malaria, which could be less vulnerable to the drug resistance.