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

Isabella R. Palombi, Nicole Lawrence, Andrew M. White, Caitlin L. Gare, David J. Craik, Brendan J. McMorran*, Lara R. Malins*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

4 Citations (Scopus)

Abstract

Malaria continues to impose a global health burden. Drug-resistant parasites have emerged to each introduced small-molecule therapy, highlighting the need for novel treatment approaches for the future eradication of malaria. Herein, targeted drug delivery with peptide-drug conjugates (PDCs) was investigated as an alternative antimalarial therapy, inspired by the success of emerging antibody-drug conjugates utilized in cancer treatment. A synthetic peptide derived from an innate human defense molecule was conjugated to the antimalarial drug 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 identify 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 important to retain activity of the peptide and drug.

Original languageEnglish
Pages (from-to)1105-1113
Number of pages9
JournalBioconjugate Chemistry
Volume34
Issue number6
DOIs
Publication statusPublished - 26 May 2023

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