biostudies-literatureRichardson LWAustralian Cancer Research FoundationWellcome Truste202200306https://www.ebi.ac.uk/biostudies/studies/S-EPMC9804387biostudies-literatureUnknown17(18)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 asexual P. falciparum parasites at the schizChemMedChemSubstrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity.PMC9804387UNS19392Hodder ANJarman KETriglia TAshton TDDans MGNguyen NFavuzza PRichardson LWNgo ACowman AFSleebs BEfalseSubstrate Peptidomimetic Inhibitors of P. falciparum Plasmepsin X with Potent Antimalarial Activity.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 asexual P. falciparum parasites at the schiz2022-01-01T00:00:00Z2022 Sep2026-05-28T06:20:58.781Z2025-04-06T09:03:17.821ZS-EPMC98043873590674410.1002/cmdc.202200306