Kiaran Kirk (Australian National University)
Lewis Sigler Institute Special Seminar
Australian national university
Kiaran Kirk carried out his PhD in the Department of Biochemistry at the University of Sydney (1985-1988). In 1989 he went to the Oxford University Laboratory of Physiology where he held an Oxford Nuffield Medical Fellowship, the Staines Medical Research Fellowship (Exeter College) and a Lister Institute Senior Research Fellowship. He returned to Australia in 1996 to head the Division of Biochemistry and Molecular Biology in the ANU Faculty of Science, holding this post until taking up his present position as Director of the ANU Research School of Biology in June 2009.
Ion regulation in the malaria parasite: the target of a new generation of antimalarials
The intraerythrocytic malaria parasite maintains a tight control over its internal ion composition. In particular, it maintains an intracellular Na+ concentration some ten-fold less than that in its host cell, extruding Na+ via a Na+-ATPase on its plasma membrane. Bioinformatic analysis of the genome of the human malaria parasite Plasmodium falciparum reveals that the most likely candidate for the parasite’s Na+ ATPase is a protein known as PfATP4. A recent ‘whole cell’ screen of a large compound library for the ability to inhibit the in vitro growth of P. falciparum, has led to the discovery of a group of highly active antimalarial compounds, the spiroindolones (Rottmann et al. (2010) Science 329, 1175-1180), one of which is now in Phase IIa clinical trials. Prolonged exposure of P. falciparum parasites to sub-lethal concentrations of spiroindolones leads to the emergence of spiroindolone-resistant parasites, with the resistance attributable to mutations in PfATP4. For two other (structurally unrelated) candidate antimalarial drug classes, exposure of parasites to sub-lethal concentrations gives rise to resistant parasites that once again have mutations in PfATP4. In this talk I will introduce the cell physiology of the intracellular malaria parasite and present evidence for the hypothesis that the three compound classes – all of which form part of the Medicines for Malaria Venture’s drug development portfolio – exert their antimalarial effect by inhibiting Na+ extrusion via PfATP4, and thereby disrupting parasite Na+ regulation.
Free and open to the university community and the public