title: A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.
abstract: Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against Plasmodium falciparum laboratory-adapted strains (mean IC5032 nM), Ugandan field isolates (mean ex vivo IC5064 nM), and murine P. berghei and P. falciparum infections (day 4 ED900.34 and 0.57 mg kg-1, respectively). Multiple P. falciparum lines selected in vitro for resistance to AN3661 harboured point mutations in pfcpsf3, which encodes a homologue of mammalian cleavage and polyadenylation specificity factor subunit 3 (CPSF-73 or CPSF3). CRISPR-Cas9-mediated introduction of pfcpsf3 mutations into parental lines recapitulated AN3661 resistance. PfCPSF3 homology models placed these mutations in the active site, where AN3661 is predicted to bind. Transcripts for three trophozoite-expressed genes were lost in AN3661-treated trophozoites, which was not observed in parasites selected or engineered for AN3661 resistance. Our results identify the pre-mRNA processing factor PfCPSF3 as a promising antimalarial drug target.
authors.affiliation: Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.|Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, 293 University Hall, 2199 Addison Street, Berkeley, California 94720-7360, USA.
authors.forename: Ebere
authors.initials: E
authors.lastname: Sonoiki
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Caroline L
authors.initials: CL
authors.lastname: Ng
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Marcus C S
authors.initials: MC
authors.lastname: Lee
authors.affiliation: Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.
authors.forename: Denghui
authors.initials: D
authors.lastname: Guo
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
authors.forename: Yong-Kang
authors.initials: YK
authors.lastname: Zhang
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
authors.forename: Yasheen
authors.initials: Y
authors.lastname: Zhou
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
authors.forename: M R K
authors.initials: MR
authors.lastname: Alley
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, Box 2542, 1700 4th Street, 403C, San Francisco, California 94158, USA.
authors.forename: Vida
authors.initials: V
authors.lastname: Ahyong
authors.affiliation: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline, c/Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Laura M
authors.initials: LM
authors.lastname: Sanz
authors.affiliation: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline, c/Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Maria Jose
authors.initials: MJ
authors.lastname: Lafuente-Monasterio
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
authors.forename: Chen
authors.initials: C
authors.lastname: Dong
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
authors.forename: Patrick G
authors.initials: PG
authors.lastname: Schupp
authors.affiliation: Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.
authors.forename: Jiri
authors.initials: J
authors.lastname: Gut
authors.affiliation: Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.
authors.forename: Jenny
authors.initials: J
authors.lastname: Legac
authors.affiliation: Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, California 94901, USA.
authors.forename: Roland A
authors.initials: RA
authors.lastname: Cooper
authors.affiliation: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline, c/Severo Ochoa 2, Tres Cantos 28760, Spain.
authors.forename: Francisco-Javier
authors.initials: FJ
authors.lastname: Gamo
authors.affiliation: Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, Box 2542, 1700 4th Street, 403C, San Francisco, California 94158, USA.
authors.forename: Joseph
authors.initials: J
authors.lastname: DeRisi
authors.affiliation: Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
authors.forename: Yvonne R
authors.initials: YR
authors.lastname: Freund
authors.affiliation: Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.|Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
authors.forename: David A
authors.identifier: 0000-0001-6753-8938
authors.initials: DA
authors.lastname: Fidock
authors.affiliation: Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.
authors.forename: Philip J
authors.initials: PJ
authors.lastname: Rosenthal
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000962:Antimalarials / Q000138:chemical synthesis / Q000494:pharmacology*; D001896:Boron Compounds / Q000138:chemical synthesis / Q000494:pharmacology*; D064113:CRISPR-Cas Systems; D020134:Catalytic Domain; D039223:Cleavage And Polyadenylation Specificity Factor / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D004351:Drug Resistance / Q000235:genetics; D004912:Erythrocytes / Q000187:drug effects / Q000469:parasitology; D000072669:Gene Editing / Q000379:methods; D006801:Humans; D008288:Malaria / Q000188:drug therapy / Q000469:parasitology; D016778:Malaria, Falciparum / Q000188:drug therapy / Q000469:parasitology; D051379:Mice; D062105:Molecular Docking Simulation; D009154:Mutation; D010962:Plasmodium berghei / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000235:genetics / Q000254:growth & development / Q000378:metabolism; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs; D017433:Protein Structure, Secondary; D015800:Protozoan Proteins / Q000037:antagonists & inhibitors / Q000737:chemistry* / Q000235:genetics / Q000378:metabolism; D012333:RNA, Messenger / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment; D017386:Sequence Homology, Amino Acid; D053058:Trophozoites / Q000187:drug effects / Q000235:genetics / Q000254:growth & development / Q000378:metabolism
chemical_list: D000962:Antimalarials; D001896:Boron Compounds; D039223:Cleavage And Polyadenylation Specificity Factor; D015800:Protozoan Proteins; D012333:RNA, Messenger