Characterization of therapeutically important proteases of malaria parasites

Malarial proteases are considered as potential drug targets because of their crucial role at erythrocytic and exoerythrocytic stages of malaria parasite and feasibility of designing inhibitors against them. Plasmodium falciparum serine proteases belonging to subtilisin superfamily and a group of cysteine proteases called serine repeat antigens (SERAs) are crucial for merozoite release (egress) and invasion of red blood cells during asexual blood stages. 
 We have done the initial characterization of P. falciparum subtilisin-like protease 3 (PfSUB3); the other two members PfSUB1 and PfSUB2 have been known to be involved in merozoite egress and invasion. PfSUB3 possesses PMSF-sensitive serine protease activity in its C-terminal region. It is expressed at late asexual blood stages and cleaves parasite proinflammatory molecule profilin, suggesting the role of protease in immune evasion. 
   	Among SERA proteases, SERA5 possessing chymotrypsin-like activity, is the most highly expressed member and involved in merozoite egress. We found that the prodomain of SERA5 has a regulatory function for the enzyme, as a 7-residue peptide derived from its C-terminus was inhibitory to the enzyme activity. Incubation of recombinant prodomain and the peptide with parasite culture caused a significant delay in schizont rupture. Our study demonstrated that the prodomain is crucial for the enzyme activity of SERA5 and small molecule inhibitors based on the design of prodomain sequences could be developed as future antimalarials.