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

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.

Enhancing the Intrinsic Antiplasmodial Activity and Improving the Stability and Selectivity of a Tunable Peptide Scaffold Derived from Human Platelet Factor 4

“…We had previously demonstrated similar properties between 1 and 2 and proposed that the shorter scaffold would be more desirable for drug development. In other work, we added a Gly to the N-terminus to produce disulfide macrocyclic peptide 3 , with improved ability to use the Cys residue for covalent bridge formation if required (e.g., acetone staple) . Therefore, we maintained N-terminal Gly in the newly designed C-terminally truncated, disulfide macrocyclic analogues.…”

“…Studies on drug-resistant strains will be required, but we anticipate similar activity against drug-sensitive and -resistant strains due to the differences in the mechanism of action between PDIP and small-molecule antimalarial drugs , and because the parental PF4 protein, which acts on parasites via the same membrane-active mechanism, is equally active on drug sensitive and resistant strains . In other work (unpublished), we are examining the effect of PDIP and PDIP-drug conjugates on the development of sexual-stage gametocytes and maturation into macrogametes . Measuring resistance risk is a challenging undertaking, requiring culture of P.…”

Development of New Leishmanicidal Compounds via Bioconjugation of Antimicrobial Peptides and Antileishmanial Guanidines

“…The conjugates utilized in peptide therapeutics may comprise poly(ethylene glycol), ferrocene, lipids, or other molecular types. Our group has leveraged this conjugation to augment the activity of AMP against cancer, , bacteria, fungus, and viruses. , Furthermore, peptide–drug conjugates have been instrumental in the development of antiplasmodial compounds. , …”