Immune Responses - Project C2

Utilization of platelet-derived peptides to explore Plasmodium biology and develop antimalarial drug leads.

Host lab:  BRENDAN McMORRAN (John Curtin School of Medical Research ANU, Canberra) 

Partner labs:  TBA (Humboldt University Berlin)
                           ADELE LEHANE, ALEX MAIER (Research School of Biology, ANU, Canberra) and IAN COCKBURN (John Curtin School of
                           Medical Research ANU, Canberra) 

The human platelet defense protein, platelet factor 4 (PF4), has intrinsic antiplasmodial activity (McMorran, Wieczorski et al. 2012) but also undesirable chemokine properties. My group has engineered a peptide containing the isolated PF4 antiplasmodial domain, which through cyclization, retains the critical structure of the parent protein. The peptide, cPF4PD, kills cultured blood-stage Plasmodium falciparum with low micromolar potency by specific disruption of the parasite digestive vacuole. Its mechanism of action involves selective penetration and accumulation inside the intraerythrocytic parasite without damaging the host cell or parasite membranes; it does not accumulate in uninfected cells. This selective activity is accounted by the peptide’s specific binding and penetration of membranes with exposed negatively charged phospholipid headgroups (Lawrence, Dennis et al. 2018). Unpublished data indicate the peptide also selectively accumulates in the digestive vacuole of gametocytes (in collaboration with Daniela Cihalova and Alex Maier, IRTG, ANU), and the cytosol of sporozoites (in collaboration with Kai Pohl and Ian Cockburn, IRTG, ANU). We hypothesize the peptide can be used as a scaffold onto which molecules (peptides or small molecules) may be conjugated to enable their selective and targeted delivery to parasites residing in host erythrocytes, or the free-living sporozoite. Such a peptide-molecule conjugate approach could be advantageous for various applications, including targeted delivery of antimalarial drugs that have undesirable side effects when administered systemically (eg. primaquine in G6PD-deficient individuals), improving lead antimalarial compounds that have poor cell uptake activity, and enable intraparasite delivery of probes or enzymes to explore different aspects of parasite biology (eg. proximity labelling for mass spectrometry). I would be interested in exploring any of these applications in collaboration with other IRTG members.

References: (IRTG members underlined)

1.  Lawrence, N., A. S. M. Dennis, A. M. Lehane, A. Ehmann, P. J. Harvey, A. H. Benfield, O. Cheneval, S. T. Henriques, D. J. Craik and B. J. McMorran (2018). "Defense Peptides Engineered from Human Platelet Factor 4 Kill Plasmodium by Selective Membrane Disruption." Cell Chem Biol 25(9): 1140-1150.e1145.

2. McMorran, B. J., L. Wieczorski, K. E. Drysdale, J. A. Chan, H. M. Huang, C. Smith, C. Mitiku, J. G. Beeson, G. Burgio and S. J. Foote (2012). "Platelet factor 4 and Duffy antigen required for platelet killing of Plasmodium falciparum." Science 338(6112): 1348-1351.