title: Transition state mimetics of the Plasmodium export element are potent inhibitors of Plasmepsin V from P. falciparum and P. vivax.
abstract: Following erythrocyte invasion, malaria parasites export a catalogue of remodeling proteins into the infected cell that enable parasite development in the human host. Export is dependent on the activity of the aspartyl protease, plasmepsin V (PMV), which cleaves proteins within the Plasmodium export element (PEXEL; RxL↓xE/Q/D) in the parasite's endoplasmic reticulum. Here, we generated transition state mimetics of the native PEXEL substrate that potently inhibit PMV isolated from Plasmodium falciparum and Plasmodium vivax. Through optimization, we identified that the activity of the mimetics was completely dependent on the presence of P1 Leu and P3 Arg. Treatment of P. falciparum-infected erythrocytes with a set of optimized mimetics impaired PEXEL processing and killed the parasites. The striking effect of the compounds provides a clearer understanding of the accessibility of the PMV active site and reaffirms the enzyme as an attractive target for the design of future antimalarials.
authors.affiliation: The Walter and Eliza Hall Institute of Medical Research , 1G Royal Parade, Parkville 3052, Victoria, Australia.
authors.forename: Brad E
authors.initials: BE
authors.lastname: Sleebs
authors.forename: Michelle
authors.initials: M
authors.lastname: Gazdik
authors.forename: Matthew T
authors.initials: MT
authors.lastname: O'Neill
authors.forename: Pravin
authors.initials: P
authors.lastname: Rajasekaran
authors.forename: Sash
authors.initials: S
authors.lastname: Lopaticki
authors.forename: Kurt
authors.initials: K
authors.lastname: Lackovic
authors.forename: Kym
authors.initials: K
authors.lastname: Lowes
authors.forename: Brian J
authors.initials: BJ
authors.lastname: Smith
authors.forename: Alan F
authors.initials: AF
authors.lastname: Cowman
authors.forename: Justin A
authors.initials: JA
authors.lastname: Boddey
mesh_terms: D016282:Aspartic Acid Endopeptidases / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D040761:Biomimetic Materials / Q000494:pharmacology*; D002460:Cell Line; D055808:Drug Discovery; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D006801:Humans; D008958:Models, Molecular; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology*; D010966:Plasmodium vivax / Q000187:drug effects* / Q000201:enzymology*; D011480:Protease Inhibitors / Q000494:pharmacology*; D011487:Protein Conformation; D059748:Proteolysis / Q000187:drug effects; D013329:Structure-Activity Relationship
chemical_list: D011480:Protease Inhibitors; D016282:Aspartic Acid Endopeptidases; C089643:plasmepsin