title: A chemical rescue screen identifies a Plasmodium falciparum apicoplast inhibitor targeting MEP isoprenoid precursor biosynthesis.
abstract: The apicoplast is an essential plastid organelle found in Plasmodium parasites which contains several clinically validated antimalarial-drug targets. A chemical rescue screen identified MMV-08138 from the "Malaria Box" library of growth-inhibitory antimalarial compounds as having specific activity against the apicoplast. MMV-08138 inhibition of blood-stage Plasmodium falciparum growth is stereospecific and potent, with the most active diastereomer demonstrating a 50% effective concentration (EC50) of 110 nM. Whole-genome sequencing of 3 drug-resistant parasite populations from two independent selections revealed E688Q and L244I mutations in P. falciparum IspD, an enzyme in the MEP (methyl-d-erythritol-4-phosphate) isoprenoid precursor biosynthesis pathway in the apicoplast. The active diastereomer of MMV-08138 directly inhibited PfIspD activity in vitro with a 50% inhibitory concentration (IC50) of 7.0 nM. MMV-08138 is the first PfIspD inhibitor to be identified and, together with heterologously expressed PfIspD, provides the foundation for further development of this promising antimalarial drug candidate lead. Furthermore, this report validates the use of the apicoplast chemical rescue screen coupled with target elucidation as a discovery tool to identify specific apicoplast-targeting compounds with new mechanisms of action.
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Wesley
authors.initials: W
authors.lastname: Wu
authors.affiliation: Department of Biochemistry, Stanford Medical School, Stanford, California, USA.
authors.forename: Zachary
authors.initials: Z
authors.lastname: Herrera
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Danny
authors.initials: D
authors.lastname: Ebert
authors.affiliation: Department of Biochemistry, Stanford Medical School, Stanford, California, USA.
authors.forename: Katie
authors.initials: K
authors.lastname: Baska
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Seok H
authors.initials: SH
authors.lastname: Cho
authors.affiliation: Department of Biochemistry and Biophysics, University of California, San Francisco, San Francisco, California, USA Howard Hughes Medical Institute, Chevy Chase, Maryland, USA joe@derisilab.ucsf.edu ellenyeh@stanford.edu.
authors.forename: Joseph L
authors.initials: JL
authors.lastname: DeRisi
authors.affiliation: Department of Biochemistry, Stanford Medical School, Stanford, California, USA Department of Pathology, Stanford Medical School, Stanford, California, USA Department of Microbiology and Immunology, Stanford Medical School, Stanford, California, USA joe@derisilab.ucsf.edu ellenyeh@stanford.edu.
authors.forename: Ellen
authors.initials: E
authors.lastname: Yeh
mesh_terms: D019747:Aldose-Ketose Isomerases / Q000037:antagonists & inhibitors / Q000235:genetics; D000962:Antimalarials / Q000494:pharmacology*; D063546:Apicoplasts / Q000187:drug effects*; D001483:Base Sequence; D002243:Carbolines / Q000494:pharmacology*; D016054:DNA, Protozoan / Q000235:genetics; D004896:Erythritol / Q000031:analogs & derivatives*; D004912:Erythrocytes / Q000469:parasitology; D006801:Humans; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D021261:Parasitic Sensitivity Tests; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development; D017422:Sequence Analysis, DNA; D013729:Terpenes / Q000737:chemistry / Q000378:metabolism
chemical_list: D000962:Antimalarials; D002243:Carbolines; D016054:DNA, Protozoan; C000600811:MMV-08138; D013729:Terpenes; D019747:Aldose-Ketose Isomerases; D004896:Erythritol