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 and Philip J. Rosenthal ()
Additional contact information
Ebere Sonoiki: University of California
Caroline L. Ng: Columbia University Medical Center
Marcus C. S. Lee: Columbia University Medical Center
Denghui Guo: University of California
Yong-Kang Zhang: Anacor Pharmaceuticals
Yasheen Zhou: Anacor Pharmaceuticals
M. R. K. Alley: Anacor Pharmaceuticals
Vida Ahyong: Howard Hughes Medical Institute, University of California
Laura M. Sanz: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline
Maria Jose Lafuente-Monasterio: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline
Chen Dong: Anacor Pharmaceuticals
Patrick G. Schupp: Columbia University Medical Center
Jiri Gut: University of California
Jenny Legac: University of California
Roland A. Cooper: Dominican University of California
Francisco-Javier Gamo: Malaria Discovery Performance Unit, Diseases of the Developing World, Tres Cantos Medicines Development Campus,GlaxoSmithKline
Joseph DeRisi: Howard Hughes Medical Institute, University of California
Yvonne R. Freund: Anacor Pharmaceuticals
David A. Fidock: Columbia University Medical Center
Philip J. Rosenthal: University of California

Nature Communications, 2017, vol. 8, issue 1, 1-11

Abstract: 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.

Date: 2017
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DOI: 10.1038/ncomms14574

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