Structure-guided targeting of Plasmodium falciparum aminopeptidase P: exploiting S4' dimer-interface interactions for selective antimalarial drug design.

Abstract

Introduction: Malaria remains a major global infectious disease, and resistance to frontline antimalarial therapies continues to drive the search for novel drug targets. Plasmodium falciparum aminopeptidase P (PfAPP) is emerging as a promising target because it performs a specialized role in hemoglobin-derived peptide metabolism.

Areas covered: This review discusses the biological role of PfAPP within parasite amino acid recycling, its relationship to other malaria metalloaminopeptidases, structural features governing substrate recognition, and recent progress in hydroxamate-based inhibitor development. Particular emphasis is placed on structure-guided discovery of potent PfAPP inhibitors and on the S4' subsite and Tyr617-mediated dimer-interface interaction as the principal currently defined structural determinants of PfAPP inhibitor potency and parasite selectivity.

Expert opinion: PfAPP has strong target credentials because it combines biological essentiality, unique Xaa-Pro substrate specificity, structural tractability and exploitable divergence from human aminopeptidase P homologues. However, current inhibitors remain limited by poor permeability and modest whole-parasite activity. The most promising future direction is the conversion of potent peptide-like hydroxamates into drug-like compounds that preserve S4' engagement while improving parasite exposure.