Objective

The emergence of resistance to all frontline antimalarial drugs has made the identification of novel therapeutic targets critical. Proteases are attractive drug targets with inhibitors against various protease classes licenced for clinical use. For instance, very effective and well-tolerated inhibitors targeting HIV-1 protease and dipeptidyl peptidase 4 (DPP4) are used for the treatment of AIDS and diabetes, respectively. Surprisingly, proteases from these families have not yet been characterised in P. falciparum, namely the proteasome shuttler Ddi1, which contains a retroviral-like protease domain, and the DPP4-related protein S9C. Using the latest approaches for genetic modification in Plasmodium falciparum, we have investigated the role of S9C and Ddi1 to understand their biological function and assess their potential as antimalarial targets. Our results show that S9C is important for early parasite formation within the red blood cell (RBC). We also show that Ddi1 is essential for invasion of RBCs by the parasite. Complementation studies show that these phenotypes are likely due to the loss of proteolytic activity. Future efforts will involve identification of substrate specificity and screening for selective inhibitors of these putative proteases.