Host red enzymes as targets for host-directed antimalarial therapy

During its residence in the red blood cell, the Plasmodium parasite scavenges and co-opts many host cell molecules to sustain its own growth requirements. The aim of this project is to develop drugs that ‘starve’ parasite of these molecules, and thereby act as host-directed antimalarial therapies. Amongst these molecules are enzymes used by progenitor red cells to synthesise haem. We have discovered, using a combination of genetics, bioinformatics and molecular biology that these host enzymes are essential for the parasite. Inhibiting their functions by genetic targeting or small molecule inhibitors produces a potent anti-malarial effect. Our current work aims to evaluate which enzymes are most suited as targets for host-directed therapy, and to develop novel inhibitors as lead antimalarial compounds.

Relevant papers

  • Smith, CM, Jerkovic, A, Puy, H, Winship, I, Deybach, JC, Gouya, L, van Dooren, G, Goodman, CD, Sturm, A, Manceau, H, McFadden, GI, David, P, Mercereau-Puijalon, O, Burgio, G, McMorran, BJ, Foote, SJ., 2015 Red cells from ferrochelatase-deficient erythropoietic protoporphyria patients are resistant to growth of malarial parasites. Blood 125:534-541.

Project funding

  • Foote and McMorran. Griseofulvin, a novel host-directed drug. NHMRC Project Grant APP104090
  • Foote, McMorran and Burgio. ENU Mutagenesis and malaria chemotherapy. NHMRC Project Grant APP1047082.