Exploiting ER proteostasis in malaria: protein disulphide isomerases as selective antimalarial targets.

INTRODUCTION: The emergence of partial resistance to artemisinin-based therapies has intensified the search for antimalarial targets beyond classical kinases and proteases. Protein disulfide isomerases (PDIs) have emerged as attractive candidates due to their roles in endoplasmic reticulum (ER) oxidative folding, redox homeostasis, and survival under proteotoxic stress. Several Plasmodium falciparum PDI family members are essential during asexual blood stages and contribute to parasite transmission. AREAS COVERED: We summarize PfPDI architecture, catalytic and holdase functions, and their integration within the parasite ER folding network, highlighting structural divergence from human PDIs that may enable selective inhibition. We review PDI-directed chemotypes, including covalent active-site binders and non-covalent/allosteric modulators, and highlight the absence of PfPDI-selective probes with validated intracellular mechanisms. We further discuss approaches for target validation, including chemoproteomics, activity-based profiling, and chemical genetics, alongside medicinal chemistry considerations for achieving exposure to an intracellular ER target. Finally, we examine PfPDIs within a proteostasis-stress framework and discuss combination strategies with protein-damaging agents such as artemisinin derivatives. EXPERT OPINION: Progress will depend on structure-guided targeting of divergent non-catalytic surfaces, optimization of intracellular and ER exposure, and rigorous in-parasite target-engagement studies. PfPDI inhibitors are most likely to succeed as components of resistance-robust combination therapies.