Development of Antiplasmodial Peptide-Drug Conjugates Using a Human Protein-Derived Cell-Penetrating Peptide with Selectivity for Infected Cells

Malaria continues to impose a global health burden. Drug-resistantparasites have emerged to each introduced small-molecule therapy,highlighting the need for novel treatment approaches for the futureeradication of malaria. Herein, targeted drug delivery with peptide-drugconjugates (PDCs) was investigated as an alternative antimalarialtherapy, inspired by the success of emerging antibody-drugconjugates utilized in cancer treatment. A synthetic peptide derivedfrom an innate human defense molecule was conjugated to the antimalarialdrug primaquine (PQ) to produce PDCs with low micromolar potency toward Plasmodium falciparum in vitro.A suite of PDCs with different design features was developed to identifyoptimal conjugation site and investigate linker length, hydrophilicity,and cleavability. Conjugation within a flexible spacer region of thepeptide, with a cleavable linker to liberate the PQ cargo, was importantto retain activity of the peptide and drug.

Automated summary

Targeted drug delivery with peptide-drug conjugates (PDCs) was investigated as an alternative antimalarial therapy. PDCs with low micromolar potency were developed by conjugating a synthetic peptide derived from an innate human defense molecule with the antimalarial drug primaquine (PQ). Various PDCs were designed to identify the optimal conjugation site and investigate linker length, hydrophilicity, and cleavability. Conjugation within a flexible spacer region of the peptide, with a cleavable linker to liberate the PQ cargo, was crucial for retaining the activity of both the peptide and drug.