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August 30, 2026Expert Opinion on Therapeutic TargetsOpen Access

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

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Authors

AOAdeshina I. OdugbemiSouth African Medical Research CouncilWMWendy MthembuStellenbosch UniversityTZTawanda ZiningaUniversity of Johannesburg

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Overview

Narrative review reveals protein disulfide isomerases as selective drug targets in Plasmodium falciparum, suggesting novel combination strategies to overcome artemisinin resistance.

Key Points

  • To evaluate Plasmodium falciparum protein disulfide isomerases as selective antimalarial therapeutic targets capable of overcoming artemisinin resistance through disruption of endoplasmic reticulum proteostasis.
  • Reviewed structural architecture, catalytic mechanisms, and chaperone holdase functions of Plasmodium falciparum protein disulfide isomerases (PfPDIs) compared to human orthologs.
  • Assessed existing covalent and non-covalent chemotypes, medicinal chemistry constraints for endoplasmic reticulum penetration, and target-validation strategies including chemoproteomics.
  • PfPDIs play essential roles in parasite blood-stage survival and transmission, possessing structural divergences from human PDIs that offer viable pockets for selective drug design.
  • Current small-molecule inhibitors lack proven on-target intracellular selectivity in parasites, indicating a critical need for non-catalytic surface binders and activity-based profiling.
  • Targeting endoplasmic reticulum proteostasis can qualitatively enhance susceptibility to protein-damaging agents, highlighting PfPDI inhibition as an attractive partner for artemisinin combination regimens.

Cite This Study

Odugbemi et al. (2026) studied this question.

synapsesocial.com/papers/6a93f14b6c1a8fb52e79e2fahttps://doi.org/10.1080/14728222.2026.2723486
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