A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
Copyright policy )A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue
AbstractBenzoxaboroles 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.
- Howard Hughes Medical Institute United States
- Columbia University United States
- Pfizer (United States) United States
- Anacor Pharmaceuticals Inc. United States
- Seton Hill University United States
Secondary, Erythrocytes, Plasmodium berghei, Messenger, Protozoan Proteins, Drug Resistance, Sequence Homology, Protein Structure, Secondary, Mice, name=General, Catalytic Domain, name=General Biochemistry,Genetics and Molecular Biology, /dk/atira/pure/subjectarea/asjc/1000, Malaria, Falciparum, Immunology and Infectious Disease, Gene Editing, /dk/atira/pure/subjectarea/asjc/1300/1300, Q, Cleavage And Polyadenylation Specificity Factor, Molecular Docking Simulation, Amino Acid, Infectious Diseases, name=General Physics and Astronomy, 5.1 Pharmaceuticals, HIV/AIDS, Development of treatments and therapeutic interventions, Infection, /dk/atira/pure/subjectarea/asjc/1600/1600, Protein Binding, Falciparum, Boron Compounds, 570, Protein Structure, Science, Plasmodium falciparum, Article, Antimalarials, Rare Diseases, Genetics, Animals, Humans, Protein Interaction Domains and Motifs, RNA, Messenger, Trophozoites, Amino Acid Sequence, Sequence Homology, Amino Acid, 500, 540, Malaria, Vector-Borne Diseases, Orphan Drug, Emerging Infectious Diseases, Good Health and Well Being, Mutation, RNA, /dk/atira/pure/subjectarea/asjc/3100/3100, CRISPR-Cas Systems, name=General Chemistry, Sequence Alignment
Secondary, Erythrocytes, Plasmodium berghei, Messenger, Protozoan Proteins, Drug Resistance, Sequence Homology, Protein Structure, Secondary, Mice, name=General, Catalytic Domain, name=General Biochemistry,Genetics and Molecular Biology, /dk/atira/pure/subjectarea/asjc/1000, Malaria, Falciparum, Immunology and Infectious Disease, Gene Editing, /dk/atira/pure/subjectarea/asjc/1300/1300, Q, Cleavage And Polyadenylation Specificity Factor, Molecular Docking Simulation, Amino Acid, Infectious Diseases, name=General Physics and Astronomy, 5.1 Pharmaceuticals, HIV/AIDS, Development of treatments and therapeutic interventions, Infection, /dk/atira/pure/subjectarea/asjc/1600/1600, Protein Binding, Falciparum, Boron Compounds, 570, Protein Structure, Science, Plasmodium falciparum, Article, Antimalarials, Rare Diseases, Genetics, Animals, Humans, Protein Interaction Domains and Motifs, RNA, Messenger, Trophozoites, Amino Acid Sequence, Sequence Homology, Amino Acid, 500, 540, Malaria, Vector-Borne Diseases, Orphan Drug, Emerging Infectious Diseases, Good Health and Well Being, Mutation, RNA, /dk/atira/pure/subjectarea/asjc/3100/3100, CRISPR-Cas Systems, name=General Chemistry, Sequence Alignment
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