Substrate peptidomimetic inhibitors of P. falciparum plasmepsin X with potent antimalarial activity
- Author(s)
- Richardson, L; Ashton, TD; Dans, MG; Nguyen, N; Favuzza, P; Triglia, T; Hodder, A; Ngo, A; Jarman, KE; Cowman, AF; Sleebs, BE;
- Journal Title
- ChemMedChem
- Publication Type
- epub ahead of print
- 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, SF h E ( h = hydrophobic amino acid). Peptidomimetics reflecting the P 3 -P 1 positions of the consensus motif were designed and showed potent and selective inhibition of PMX. It was established that PMX prefers Phe in the P 1 position, di-substitution at the β-carbon of the P 2 moiety and a hydrophobic P 3 group which was supported by modelling of the peptidomimetics in complex with PMX. The peptidomimetics were shown to arrest asexual P. falciparum parasites at the schizont stage by impairing PMX substrate processing. Overall, the peptidomimetics described will assist in further understanding PMX substrate specificity and have the potential to act as a template for future antimalarial design.
- Publisher
- Wiley
- Keywords
- Malaria; Plasmodium; aspartyl protease; peptidomimetic; plasmepsin
- Research Division(s)
- Ubiquitin Signalling; Chemical Biology; Infectious Diseases And Immune Defence
- PubMed ID
- 35906744
- Publisher's Version
- https://doi.org/10.1002/cmdc.202200306
- Open Access at Publisher's Site
https://doi.org/10.1002/cmdc.202200306- NHMRC Grants
- NHMRC/1135421, NHMRC/2014427, NHMRC/2001284,
- Terms of Use/Rights Notice
- Refer to copyright notice on published article.
Creation Date: 2022-08-08 09:15:56
Last Modified: 2022-08-25 09:11:02