Poster Presentation 8th Modern Solid Phase Peptide Synthesis & Its Applications Symposium 2022

Peptide drug conjugates as novel antimalarials (#133)

Isabella Palombi 1 , Nicole Lawrence 2 , Brendan McMorran 3 , Lara R Malins 1
  1. Research School of Chemistry, Australian National University, Acton, ACT, Australia
  2. Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD, Australia
  3. 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 intramolecular targets.2 An antimicrobial peptide lead, platelet derived internalisation peptide (PDIP), designed from a protein in the immune system3 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 synthesis and biological evaluation of antimalarial PDCs, inspired by the emerging success of antibody drug conjugates in cancer therapeutics.4 The use of copper(I)-catalysed azide-alkyne cycloaddition (CuAAC)5 to attach antimalarial drugs onto PDIP will be detailed, along with the synthetic techniques required to modify the peptide and drug components for CuAAC conjugation. This includes the construction of PDIP and incorporation of an azide functional group using solid phase peptide synthesis, and the modification of small molecule drugs to contain an alkyne handle. Various cleavable and non-cleavable linkers—comprising the region between the drug and the peptide—will be explored to understand the effect of drug release in the parasite on the activity of the conjugate. 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.