Biological functions and structural biology of Plasmodium falciparum autophagy-related proteins: the under-explored options for novel antimalarial drug design.

Abstract

Malaria remains a threat to global public health and the available antimalarial drugs are undermined by side effects and parasite resistance, suggesting an emphasis on new potential targets. Amongst the novel targets, Plasmodium falciparum autophagy-related proteins (PfAtg) remain a priority. In this paper, we reviewed the existing knowledge on the functions and structural biology of PfAtg including the compounds with inhibitory activity toward P. falciparum Atg8-Atg3 protein-protein interaction (PfAtg8-PfAtg3 PPI). A total of five PfAtg (PfAtg5, PfAtg8, PfAtg12, PfAtg18, and Rab7) were observed to have autophagic and/or non-autophagic roles. Moreover, available data showed that PfAtg8 has conserved hydrophobic pockets, which allows it to interact with PfAtg3 to form PfAtg8-PfAtg3 PPI. Additionally, 2-bromo-N-(4-pyridin-2-yl-1,3-thiazol-2-yl) benzamide was identified as the most powerful inhibitor of PfAtg8-PfAtg3 PPI. Due to the dearth of knowledge in this field, we hope that the article would open an avenue to further research on the remaining PfAtg as possible drug candidates.