2. Academic Validation
  3. A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue

  • Nat Commun. 2017 Mar 6;8:14574. doi: 10.1038/ncomms14574.
Ebere Sonoiki 1 2,  Caroline L Ng 3,  Marcus C S Lee 3,  Denghui Guo 1,  Yong-Kang Zhang 4,  Yasheen Zhou 4,  M R K Alley 4,  Vida Ahyong 5,  Laura M Sanz 6,  Maria Jose Lafuente-Monasterio 6,  Chen Dong 4,  Patrick G Schupp 3,  Jiri Gut 1,  Jenny Legac 1,  Roland A Cooper 7,  Francisco-Javier Gamo 6,  Joseph DeRisi 5,  Yvonne R Freund 4,  David A Fidock 3 8,  Philip J Rosenthal 1
Affiliations

Affiliations

  • 1 Department of Medicine, University of California, Box 0811, San Francisco, California 94143, USA.
  • 2 Division of Infectious Diseases and Vaccinology, School of Public Health, University of California, 293 University Hall, 2199 Addison Street, Berkeley, California 94720-7360, USA.
  • 3 Department of Microbiology and Immunology, Columbia University Medical Center, Room 1502 HHSC, 701 West 168th Street, New York, New York 10032, USA.
  • 4 Anacor Pharmaceuticals, Inc., 1020 East Meadow Circle, Palo Alto, California 94303-4230, USA.
  • 5 Department of Biochemistry and Biophysics, Howard Hughes Medical Institute, University of California, Box 2542, 1700 4th Street, 403C, San Francisco, California 94158, USA.
  • 6 Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline, c/Severo Ochoa 2, Tres Cantos 28760, Spain.
  • 7 Department of Natural Sciences and Mathematics, Dominican University of California, 50 Acacia Avenue, San Rafael, California 94901, USA.
  • 8 Division of Infectious Diseases, Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA.
PMID: 28262680 DOI: 10.1038/ncomms14574
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 IC50 32 nM), Ugandan field isolates (mean ex vivo IC50 64 nM), and murine P. berghei and P. falciparum infections (day 4 ED90 0.34 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.

Figures
Products
  • Cat. No.
    Product Name
    Description
    Target
    Research Area
  • HY-128204
    99.89%, PfCPSF3 Inhibitor