Journal article
Substrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity
LW Richardson, TD Ashton, MG Dans, N Nguyen, P Favuzza, T Triglia, AN Hodder, A Ngo, KE Jarman, AF Cowman, BE Sleebs
Chemmedchem | Published : 2022
Abstract
Plasmepsin X (PMX) is an aspartyl protease that processes proteins essential for Plasmodium parasites to invade and egress from host erythrocytes during the symptomatic asexual stage of malaria. PMX substrates possess a conserved cleavage region denoted by the consensus motif, SFhE (h=hydrophobic amino acid). Peptidomimetics reflecting the P3-P1 positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P1 position, di-substitution at the β-carbon of the P2 moiety and a hydrophobic P3 group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest ..
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Awarded by Wellcome Trust
Funding Acknowledgements
This work was funded by the National Health and Medical Research Council of Australia (Development Grants 1135421, 2014427 to B.E.S. and A.F.C.; Ideas Grant 2001284 to T.D.A.) and the Wellcome Trust (Grant UNS19392 to B.E.S. and A.F.C.), the Australian Cancer Research Foundation, the Victorian State Government Operational Infrastructure Support and Australian Government NHMRC IRIISS. We thank and acknowledge the Australian Red Cross Blood Bank for the provision of fresh red blood cells, without which this research could not have been performed. A.F.C. is a Howard Hughes International Scholar and an Australia Fellow of the NHMRC, and B.E.S. is a Corin Centenary Fellow. We thank Wilhemus Kersten and Janni Christensen from the Walter and Eliza Hall Institute of Medical Research for technical support. Open access publishing facilitated by The University of Melbourne, as part of the Wiley - The University of Melbourne agreement via the Council of Australian University Librarians.