Peptide-drug conjugates as a novel approach to antimalarial therapeutics — ASN Events
  1. Schedule
  2. Poster Session 1 - Wine Tasting
  3. Peptide-drug conjugates as a novel approach to antimalarial therapeutics

Peptide-drug conjugates as a novel approach to antimalarial therapeutics (#241)

Caitlin L Gare 1 2 , Isabella R Palombi 1 2 , Andrew M White 1 2 , Nicole Lawrence 3 4 , David J Craik 3 4 , Brendan J McMorran 5 , Lara R Malins 1 2
  1. Research School of Chemistry, The Australian National University, Canberra, ACT, Australia
  2. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, Australian National University, Canberra, ACT, Australia
  3. Institute for Molecular Bioscience, University of Queensland, Brisbane, QLD, Australia
  4. Australian Research Council Centre of Excellence for Innovations in Peptide and Protein Science, The University of Queensland, Brisbane, QLD, Australia
  5. John Curtain School of Medical Research, Australian National University, Canberra, ACT, Australia

Malaria is a significant global health challenge, with 247 million cases and 619 000 deaths reported in 2021, largely in African countries.1 Plasmodium, the causative parasites, have evolved complete or partial resistance to nearly all current antimalarial therapeutics,2 including to artemisinin derived treatments which are currently the most effective and widely used treatments.2,3,4 Resistance to these therapeutics threatens the ability to prevent mortality associated with malaria and as such, new antimalarial therapeutics with novel modes of action are urgently required.

We have recently published our initial efforts towards the development of antiplasmodial peptide-drug conjugates (PDCs) which utilise a peptide, PDIP, for the targeted delivery of primaquine, a small molecule antimalarial therapeutic.5 Lawrence and McMorran identified that PDIP—a synthetic peptide derived from Platelet Factor 4—is antiplasmodial, cell-penetrating, and selectively targets infected red blood cells and Plasmodium membranes.6 This PDC approach aims to minimise off-target effects and provide a new mechanism of drug delivery that may evade resistance. Through synthesis of a library of PDIP-primaquine conjugates with varying conjugation and linker characteristics, we identified conjugates with low micromolar potency, confirming this as a viable avenue to novel antimalarial therapeutics.5

This poster will highlight our subsequent exploration into the underlying mechanism of these peptide-drug conjugates through synthesis of a second generation of conjugates. Conjugates utilising PDIP and several other cell-penetrating peptides as the peptide scaffold, in combination with common antimalarial therapeutics, including primaquine, tafenoquine and artesunate, were synthesised to elucidate the individual antiplasmodial contribution and role of both the peptide and drug within conjugates. Solid-phase peptide synthesis of azide modified peptides and introduction of alkyne functionality to the antimalarial therapeutics allowed for the combinatorial synthesis of PDCs through either copper-catalysed or strain-promoted azide-alkyne cycloaddition reactions.

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  1. World Health Organisation, World malaria report 2022. Geneva, 2022.
  2. Haldar, K.; Bhattacharjee, S.; Safeukui, I., Nat. Rev. Microbiol., 2018, 16, 156-170.
  3. Uwimana, A. et al., Lancet Infect. Dis., 2021, 21, 1120-1128.
  4. Balikagala, B. et al., New Engl. J. Med., 2021, 385, 1163-1171.
  5. Palombi, I. et al., Bioconjugate Chem., 2023, ASAP article, DOI: 10.1021/acs.bioconjchem.3c00147.
  6. Lawrence, N. et al., Cell Chem. Biol., 2018, 25, 1140-1150.
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