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

Ebere Sonoiki, Caroline L. Ng, Marcus C.S. Lee, Denghui Guo, Yong Kang Zhang, Yasheen Zhou, M. R.K. Alley, Vida Ahyong, Laura M. Sanz, Maria Jose Lafuente-Monasterio, Chen Dong, Patrick G. Schupp, Jiri Gut, Jenny Legac, Roland A. Cooper, Francisco Javier Gamo, Joseph Derisi, Yvonne R. Freund, David A. Fidock, Philip J. Rosenthal

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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.

Original languageEnglish (US)
Article number14574
JournalNature communications
Volume8
DOIs
StatePublished - Mar 6 2017

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Cleavage And Polyadenylation Specificity Factor
Clustered Regularly Interspaced Short Palindromic Repeats
RNA Precursors
Antimalarials
Pathogens
Plasmodium falciparum
mutations
cleavage
Trophozoites
Genes
Inhibitory Concentration 50
Processing
parasites
Mutation
pathogens
homology
infectious diseases
preprocessing
Point Mutation
genes

ASJC Scopus subject areas

  • Chemistry(all)
  • Biochemistry, Genetics and Molecular Biology(all)
  • Physics and Astronomy(all)

Cite this

A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. / Sonoiki, Ebere; Ng, Caroline L.; Lee, Marcus C.S.; Guo, Denghui; Zhang, Yong Kang; Zhou, Yasheen; Alley, M. R.K.; Ahyong, Vida; Sanz, Laura M.; Lafuente-Monasterio, Maria Jose; Dong, Chen; Schupp, Patrick G.; Gut, Jiri; Legac, Jenny; Cooper, Roland A.; Gamo, Francisco Javier; Derisi, Joseph; Freund, Yvonne R.; Fidock, David A.; Rosenthal, Philip J.

In: Nature communications, Vol. 8, 14574, 06.03.2017.

Research output: Contribution to journalArticle

Sonoiki, E, Ng, CL, Lee, MCS, Guo, D, Zhang, YK, Zhou, Y, Alley, MRK, Ahyong, V, Sanz, LM, Lafuente-Monasterio, MJ, Dong, C, Schupp, PG, Gut, J, Legac, J, Cooper, RA, Gamo, FJ, Derisi, J, Freund, YR, Fidock, DA & Rosenthal, PJ 2017, 'A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue', Nature communications, vol. 8, 14574. https://doi.org/10.1038/ncomms14574
Sonoiki, Ebere ; Ng, Caroline L. ; Lee, Marcus C.S. ; Guo, Denghui ; Zhang, Yong Kang ; Zhou, Yasheen ; Alley, M. R.K. ; Ahyong, Vida ; Sanz, Laura M. ; Lafuente-Monasterio, Maria Jose ; Dong, Chen ; Schupp, Patrick G. ; Gut, Jiri ; Legac, Jenny ; Cooper, Roland A. ; Gamo, Francisco Javier ; Derisi, Joseph ; Freund, Yvonne R. ; Fidock, David A. ; Rosenthal, Philip J. / A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue. In: Nature communications. 2017 ; Vol. 8.
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