title: Validation of the proteasome as a therapeutic target in Plasmodium using an epoxyketone inhibitor with parasite-specific toxicity.
abstract: The Plasmodium proteasome has been suggested to be a potential antimalarial drug target; however, toxicity of inhibitors has prevented validation of this enzyme in vivo. We report a screen of a library of 670 analogs of the recent US Food and Drug Administration-approved inhibitor, carfilzomib, to identify compounds that selectively kill parasites. We identified one compound, PR3, that has significant parasite killing activity in vitro but dramatically reduced toxicity in host cells. We found that this parasite-specific toxicity is not due to selective targeting of the Plasmodium proteasome over the host proteasome, but instead is due to a lack of activity against one of the human proteasome subunits. Subsequently, we used PR3 to significantly reduce parasite load in Plasmodium berghei infected mice without host toxicity, thus validating the proteasome as a viable antimalarial drug target.
authors.affiliation: Graduate Program in Chemical and Systems Biology, Stanford University School of Medicine, 300 Pasteur Drive, Stanford, CA 94305-5324, USA.
authors.forename: Hao
authors.initials: H
authors.lastname: Li
authors.forename: Elizabeth L
authors.initials: EL
authors.lastname: Ponder
authors.forename: Martijn
authors.initials: M
authors.lastname: Verdoes
authors.forename: Kristijana H
authors.initials: KH
authors.lastname: Asbjornsdottir
authors.forename: Edgar
authors.initials: E
authors.lastname: Deu
authors.forename: Laura E
authors.initials: LE
authors.lastname: Edgington
authors.forename: Jeong Tae
authors.initials: JT
authors.lastname: Lee
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Kirk
authors.forename: Susan D
authors.initials: SD
authors.lastname: Demo
authors.forename: Kim C
authors.initials: KC
authors.lastname: Williamson
authors.forename: Matthew
authors.initials: M
authors.lastname: Bogyo
mesh_terms: D000818:Animals; D000962:Antimalarials / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008807:Mice, Inbred BALB C; D009842:Oligopeptides / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use / Q000633:toxicity; D010961:Plasmodium / Q000187:drug effects* / Q000201:enzymology*; D010962:Plasmodium berghei / Q000187:drug effects / Q000201:enzymology; D046988:Proteasome Endopeptidase Complex / Q000378:metabolism*; D061988:Proteasome Inhibitors / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000962:Antimalarials; D009842:Oligopeptides; D061988:Proteasome Inhibitors; C524865:carfilzomib; D046988:Proteasome Endopeptidase Complex