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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 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.

journal_name

Nat Commun

journal_title

Nature communications

authors

Sonoiki E,Ng CL,Lee MC,Guo D,Zhang YK,Zhou Y,Alley MR,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

doi

10.1038/ncomms14574

subject

Has Abstract

pub_date

2017-03-06 00:00:00

pages

14574

issn

2041-1723

pii

ncomms14574

journal_volume

8

pub_type

杂志文章

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