Transition state mimetics of the plasmodium export element are potent inhibitors of plasmepsin v from P. falciparum and P. Vivax

BE Sleebs; M Gazdik; MT O'Neill; P Rajasekaran; S Lopaticki; K Lackovic; K Lowes; BJ Smith; AF Cowman; JA Boddey

Journal article

Transition state mimetics of the plasmodium export element are potent inhibitors of plasmepsin v from P. falciparum and P. Vivax

BE Sleebs, M Gazdik, MT O'Neill, P Rajasekaran, S Lopaticki, K Lackovic, K Lowes, BJ Smith, AF Cowman, JA Boddey

Journal of Medicinal Chemistry | Published : 2014

DOI: 10.1021/jm500797g

Abstract

Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; RxL"xE/Q/D) in the parasite's endoplasmic reticulum. Here, we generated transition state mimetics of the native PEXEL substrate that potently inhibit PMV isolated from Plasmodium falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics was completely dependent on the presence of P1Leu and P3Arg. Treatment of P. falciparum-infected eryt..

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University of Melbourne Researchers

Brad Sleebs Author

Sash Lopaticki Author

Kym Lowes Author

Alan Cowman Author

Grants

Awarded by National Health and Medical Research Council of Australia

Awarded by Human Frontiers Science Program

Awarded by Ramaciotti Foundation

Awarded by CASS Foundation Science and Medicine

Funding Acknowledgements

This work was funded by the National Health and Medical Research Council of Australia (project grant 1010326 to JAB.), the Human Frontiers Science Program (RGY0073/2012 to JAB.), the Ramaciotti Foundation (establishment grant 3197/2010 to JAB.), a CASS Foundation Science and Medicine grant (SM.12.4348 to JAB.), the Australian Cancer Research Foundation, and a Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank the University of Melbourne for the provision of a postgraduate scholarship awarded to M.G. A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC. JAB. is a QEII Fellow of the Australian Research Council. We thank Dr Guillaume Lessene and Prof. David Huang for their helpful discussions.