Structural basis for plasmep sin V inhibition that blocks export of malaria proteins to human erythrocytes
Anthony N Hodder, Brad E Sleebs, Peter E Czabotar, Michelle Gazdik, Yibin Xu, Matthew T O'Neill, Sash Lopaticki, Thomas Nebl, Tony Triglia, Brian J Smith, Kym Lowes, Justin A Boddey, Alan F Cowman
NATURE STRUCTURAL & MOLECULAR BIOLOGY | NATURE PUBLISHING GROUP | Published : 2015
Plasmepsin V, an essential aspartyl protease of malaria parasites, has a key role in the export of effector proteins to parasite-infected erythrocytes. Consequently, it is an important drug target for the two most virulent malaria parasites of humans, Plasmodium falciparum and Plasmodium vivax. We developed a potent inhibitor of plasmepsin V, called WEHI-842, which directly mimics the Plasmodium export element (PEXEL). WEHI-842 inhibits recombinant plasmepsin V with a half-maximal inhibitory concentration of 0.2 nM, efficiently blocks protein export and inhibits parasite growth. We obtained the structure of P. vivax plasmepsin V in complex with WEHI-842 to 2.4-Å resolution, which provides an..View full abstract
Awarded by NHMRC
We thank the Red Cross Blood Service (Melbourne, Australia) for supply of blood and the Australian Synchrotron and Commonwealth Scientific and Industrial Research Organisation Crystallization Facility. This work was supported by the Victorian State Government Operational Infrastructure Support and Australian Government National Health and Medical Research Council (NHMRC) Independent Research Institute Infrastructure Support Scheme, the Australian Cancer Research Foundation and the NHMRC (grants 1057960 (A.F.C.), 637406 (ARC.) and 1010326 (J.A.B.)). We thank the University of Melbourne for the provision of an Australian Postgraduate Award to M.G. A.F.C. is supported as a Howard Hughes International Scholar, P.E.C. is supported as an National Health and Medical Research Council of Australia Senior Research Fellow, and J.A.B. is supported as an Australian Research Council Queen Elizabeth II Fellow. We thank G. Lessens for useful discussions and Jacobus Pharmaceuticals for providing WR99210.