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Increasing resistance of the causative parasite, <jats:italic>Plasmodium<\/jats:italic>, to existing antimalarial drugs underscores a need for additional compounds with distinct modes of action in the therapeutic development pipeline. Here we showcase peptide\u2010drug conjugates (PDCs) as an attractive compound class, in which therapeutic or lead antimalarials are chemically conjugated to cell\u2010penetrating peptides. This approach aims to enhance selective uptake into <jats:italic>Plasmodium<\/jats:italic>\u2010infected red blood cells and impart additional cytotoxic actions on the intraerythrocytic parasite, thereby enabling targeted drug delivery and dual modes of action. We describe the development of PDCs featuring four compounds with antimalarial activity\u2014primaquine, artesunate, tafenoquine and methotrexate\u2014conjugated to three cell\u2010penetrating peptide scaffolds with varied antiplasmodial activity, including active and inactive analogues of platelet factor 4 derived internalization peptide (PDIP), and a cyclic polyarginine peptide. Development of this diverse set of PDCs featured distinct and adaptable conjugation strategies, to produce conjugates with <jats:italic>in\u2005vitro<\/jats:italic> antiplasmodial activities ranging from low nanomolar to low micromolar potencies according to the drug cargo and bioactivity of the partner peptide. Overall, this study establishes a strategic and methodological framework for the further development of dual mode of action peptide\u2010drug antimalarial therapeutics.<\/jats:p>","DOI":"10.1002\/cmdc.202400637","type":"journal-article","created":{"date-parts":[[2024,10,8]],"date-time":"2024-10-08T22:18:47Z","timestamp":1728425927000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":8,"title":["Exploring the Utility of Cell\u2010Penetrating Peptides as Vehicles for the Delivery of Distinct Antimalarial Drug Cargoes"],"prefix":"10.1002","volume":"20","author":[{"given":"Caitlin L.","family":"Gare","sequence":"first","affiliation":[{"name":"Research School of Chemistry The Australian National University  Canberra, ACT 2601 Australia"},{"name":"Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science The Australian National University  Canberra, ACT 2601 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