Identification and optimisation of small molecule inhibitors of PfAPP as novel therapeutics

Malaria is a parasitic disease which affects millions of people every year and, due to the rapid development of resistance to existing treatments, presents an area of urgent medical need. PfAPP is a malarial X-prolyl aminopeptidase which is thought to be involved in the catabolism of host cell haemoglobin and has been proven vital for the survival of the parasite. As a result of this, PfAPP has been highlighted as being a potential target for novel anti-malarial therapeutics. Herein is presented the current SAR data which has been collected surrounding various isoforms of APP across a range of species, alongside a library of analogues which have been synthesised to further extend the current SAR knowledge, particularly in regard to PfAPP. Alongside this, details of the expression and purification of the PfAPP protein have been outlined. The recombinant protein was used in biochemical assays and crystallisation trials with the aim of identifying small molecule inhibitors of PfAPP to be used as novel anti-malarial therapies.