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Benzoxaboroles are effective against bacterial, fungal and protozoan pathogens. We report potent activity of the benzoxaborole AN3661 against  Plasmodium falciparum  laboratory-adapted strains (mean IC 50  32 nM), Ugandan field isolates (mean  ex vivo  IC 50  64 nM), and murine  P. berghei  and  P. falciparum  infections (day 4 ED 90  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.

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