Poster Presentation International Peptide Symposium 2023

Antiplasmodial peptide–drug conjugates incorporating a platelet-derived cell-penetrating peptide (#330)

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

Malaria is an infectious parasitic disease spread by mosquitoes that continues to devastate communities in Africa and Southeast Asia.1 With drug-resistant parasites rapidly emerging to each introduced small molecule therapy, a novel treatment approach is required for the future eradication of malaria. Peptide drugs are a promising and unprecedented avenue for malaria treatment, due to their high selectivity for specific intracellular targets.2 An antimicrobial peptide lead, platelet factor 4-derived internalisation peptide (PDIP), designed from an innate human defence protein3 can selectively target and kill the malaria parasite in red blood cells. Attaching promising small molecule antimalarial drugs onto PDIP to form peptide–drug conjugates (PDCs) presents a novel strategy to deliver drugs directly to the parasite and thereby prevent their interaction with healthy tissues. Further, the combination of the peptide and drug, each with their own mechanism of action, provides the potential to evade the formation of drug resistant parasites.

This poster will focus on the design, chemical synthesis and biological evaluation of antimalarial PDCs, inspired by the emerging success of antibody drug conjugates in cancer therapeutics.4 Azide-alkyne cycloaddition click chemistry5-7 was utilised to attach antimalarial drugs onto PDIP, to produce a library of PDCs with alternative peptide conjugation sites and linker properties, such as length, hydrophilicity and cleavability.8 The constructs were evaluated using parasite growth assays, which established that the activity of antimalarial PDCs was inextricably linked to conjugate design, as it played a critical role in allowing each PDC component to carry out its intended killing mechanism. The biological activity of these PDCs will be used to inform the synthesis and design of future PDCs and the elucidation of their mechanism of action.

  1. Siciliano, G.; Alano, P. Front. Microbiol. 2015, 6, 391.
  2. He, R.; Finan, B.; Mayer, J. P.; DiMarchi, R. D. Molecules 2019, 24, 1855.
  3. Lawrence, N.; Dennis, A. S.; Lehane, A. M.; Ehmann, A.; Harvey, P. J.; Benfield, A. H.; Cheneval, O.; Henriques, S. T.; Craik, D. J.; McMorran, B. J. Cell Chem. Biol. 2018, 25, 1140–1150. (Note: PDIP was formally known as cPF4PD)
  4. Tsuchikama, K.; An, Z. Protein Cell 2018, 9, 33–46.
  5. Rostovtsev, V. V.; Green, L. G.; Fokin, V. V.; Sharpless, K. B. Angew. Chem. Int. Ed. 2002, 41, 2596–2599.
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  7. Agard, N. J.; Prescher, J. A.; Bertozzi, C. R. J. Am. Chem. Soc. 2004, 126, 15046-15047.
  8. Palombi, I. R.; Lawrence, N.; White, A. M.; Gare, C. L.; Craik, D. J.; McMorran, B. J.; Malins, L. R. Bioconjugate Chem. 2023, doi: 10.1021/acs.bioconjchem.3c00147.