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.