Journal article

Exploration of the P-3 region of PEXEL peptidomimetics leads to a potent inhibitor of the Plasmodium protease, plasmepsin V

Michelle Gazdik, Kate E Jarman, Matthew T O'Neill, Anthony N Hodder, Kym N Lowes, Helene Jousset Sabroux, Alan F Cowman, Justin A Boddey, Brad E Sleebs



The use of arginine isosteres is a known strategy to overcome poor membrane permeability commonly associated with peptides or peptidomimetics that possess this highly polar amino acid. Here, we apply this strategy to peptidomimetics that are potent inhibitors of the malarial protease, plasmepsin V, with the aim of enhancing their activity against Plasmodium parasites, and exploring the structure-activity relationship of the P3 arginine within the S3 pocket of plasmepsin V. Of the arginine isosteres trialled in the P3 position, we discovered that canavanine was the ideal and that this peptidomimetic potently inhibits plasmepsin V, efficiently blocks protein export and inhibits parasite growth..

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Awarded by National Health and Medical Research Council of Australia

Funding Acknowledgements

This work was funded by the National Health and Medical Research Council of Australia ( Project Grant 1010326 to J. A. B., Program Grant 1092789 to A. F. C.), the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank the University of Melbourne for the provision of an Australian Postgraduate Award to M. G. A. F. C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC. J. A. B. is an Australian Research Council QEII Fellow.