Aminopeptidase Inhibition in Drug-Resistant Plasmodium falciparum: Structural, Functional, and Pharmacological...

Malaria remains a significant global health burden, increasingly threatened by the emergence of artemisinin-resistant Plasmodium falciparum strains that compromise the efficacy of frontline combination therapies. Hemoglobin digestion constitutes a central metabolic pathway sustaining intraerythrocytic parasite growth, in which the terminal processing of hemoglobin-derived peptides and liberation of free amino acids are mediated by two zinc-dependent metalloaminopeptidases, PfA-M1 (M1 alanyl aminopeptidase) and PfA-M17 (M17 leucyl aminopeptidase). This review synthesizes current evidence supporting PfA-M17 and PfA-M1 as validated antimalarial targets, with particular emphasis on the structural biology, catalytic regulation, and cellular essentiality of PfA-M17. We discuss how the oligomerization-dependent activation of PfA-M17, governed by metal-ion-mediated quaternary assembly and a dynamic regulatory loop (L13), imposes structural constraints that may limit resistance evolution. We further evaluate selective and dual-target inhibitors, including MMV1557817 and compound 26, that demonstrate cross-species antiplasmodial efficacy with substantial fitness costs on resistant parasites. The mechanistic interplay between aminopeptidase inhibition and established antimalarial drug classes, including quinolines and artemisinins, is also examined. This review supports dual PfA-M1/PfA-M17 inhibition as a promising approach for next-generation antimalarial drug development.