Journal article

Enhanced antimalarial activity of plasmepsin V inhibitors by modification of the P-2 position of PEXEL peptidomimetics

William Nguyen, Anthony N Hodder, Richard Bestel de Lezongard, Peter E Czabotar, Kate E Jarman, Matthew T O'Neill, Jennifer K Thompson, Helene Jousset Sabroux, Alan F Cowman, Justin A Boddey, Brad E Sleebs



Plasmepsin V is an aspartyl protease that plays a critical role in the export of proteins bearing the Plasmodium export element (PEXEL) motif (RxLxQ/E/D) to the infected host erythrocyte, and thus the survival of the malaria parasite. Previously, development of transition state PEXEL mimetic inhibitors of plasmepsin V have primarily focused on demonstrating the importance of the P3 Arg and P1 Leu in binding affinity and selectivity. Here, we investigate the importance of the P2 position by incorporating both natural and non-natural amino acids into this position and show disubstituted beta-carbon amino acids convey the greatest potency. Consequently, we show analogues with either cyclohexylg..

View full abstract


Awarded by National Health and Medical Research Council of Australia

Awarded by CASS Foundation Science and Medicine Grant

Awarded by NHMRC Research Fellows

Funding Acknowledgements

This work was funded by the National Health and Medical Research Council of Australia (Development Grant 1113712 to B.E.S. Project Grant 1092789 and Program Grant 1092789 to A.F.C.), a CASS Foundation Science and Medicine Grant SM/15/6430 to J.A.B., the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. A.F.C. is a Howard Hughes International Scholar. P.E.C and J.A.B are NHMRC Research Fellows (1079700 and 1123727, respectively). X-ray diffraction data was collected on the MX2 beamline at the Australian Synchrotron and made use of the ACRF Detector.