title: Identification of potent and selective non-covalent inhibitors of the Plasmodium falciparum proteasome.
abstract: We have identified short N,C-capped peptides that selectively inhibit the proteasome of the malaria-causing pathogen Plasmodium falciparum. These compounds are highly potent in culture with no toxicity in host cells. One cyclic biphenyl ether compound inhibited intraerythrocytic growth of P. falciparum with an IC50 of 35 nM, and we show that even a pulse treatment with this cyclic peptide induced parasite death due to proteasome inhibition. These compounds represent promising new antimalarial agents that target the essential proteasomal machinery of the parasite without toxicity toward the host.
authors.affiliation: Department of Chemical and Systems Biology and ‡ Department of Pathology, Stanford University School of Medicine , 300 Pasteur Drive, Stanford, California 94305-5324, United States.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Christopher
authors.initials: C
authors.lastname: Tsu
authors.forename: Christopher
authors.initials: C
authors.lastname: Blackburn
authors.forename: Gang
authors.initials: G
authors.lastname: Li
authors.forename: Paul
authors.initials: P
authors.lastname: Hales
authors.forename: Lawrence
authors.initials: L
authors.lastname: Dick
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D005347:Fibroblasts / Q000166:cytology / Q000187:drug effects; D006801:Humans; D015394:Molecular Structure; D021261:Parasitic Sensitivity Tests; D010456:Peptides, Cyclic / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology* / Q000254:growth & development; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D010456:Peptides, Cyclic; D061988:Proteasome Inhibitors; D046988:Proteasome Endopeptidase Complex