Mon9 Apr05:30pm(15 mins)
Stream 2 - Llandinam A6
Macroautophagy is an evolutionarily conserved survival process of eukaryotes that supports cellular survival during stress, an exemplar being during nutrient limitation. A key marker of this process is the lipidation of Atg8 with phosphatidylethanolamine (PE) by the E2-conjugating enzyme Atg3 and inclusion of Atg8-PE into autophagososmes that deliver cytoplasmic cargo to lysosomes for degradation and recycling of macromolecules. The cascade of the canonical regulatory and effector proteins for macroautophagy is incomplete in Plasmodium falciparum, leading to speculation around whether canonical autophagy exists in this parasite. PfAtg8 has, however, been implicated in recycling of specialist organelles, vesicular trafficking and apicoplast function.
A screen of a library of compounds that act as modulators of macroautophagy in human cell lines as inhibitors of the Atg8-Atg3 interaction have been evaluated here for their potential as antiplasmodial agents. We identify SK1.47 and SK1.49 as having a rapid cytocidal activity against trophozoite-stage intraerythroctic parasites with a potency (EC50) in the 1µM range. Both compounds show selectivity against parasites compared to the human HepG2 line. Proof-of-concept as inhibitors of autophagy was shown when both compounds inhibit the formation and distribution of PfAtg8-labelled vesicles on induction of starvation. We also report molecular modelling and structure activity relationship studies that describe a key scaffold to be developed in follow on work. Whilst not a lead for development at this stage - SK1.49, the more potent of these two compounds, is available as a chemical probe to explore the potential of autophagy-related processes in the parasite as a novel drug target.