A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.
A potent antimalarial benzoxaborole targets a Plasmodium falciparum cleavage and polyadenylation specificity factor homologue.
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DOI：
10.1038/ncomms14574
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发表时间：
2017-03-06
影响因子：
16.6
通讯作者：
Rosenthal PJ
中科院分区：
文献类型：
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作者：
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
苯并氧杂硼杂环戊烯对细菌、真菌和原生动物病原体有效。我们报告了苯并氧杂硼杂环戊烯AN 3661对恶性疟原虫实验室适应株（平均IC 50 32 nM）、乌干达田间分离株（平均离体IC 50 64 nM）以及鼠伯氏疟原虫和恶性疟原虫感染（第4天ED 90分别为0.34和0.57 mg kg−1）的有效活性。在体外选择的对AN 3661具有抗性的多个恶性疟原虫株系在pfcpsf 3中具有点突变，pfcpsf 3编码哺乳动物切割和多聚腺苷酸化特异性因子亚基3（CPSF-73或CPSF 3）的同源物。CRISPR-Cas9介导的将pfcpsf 3突变引入亲本系中重现了AN 3661抗性。PfCPSF 3同源性模型将这些突变置于活性位点，其中AN 3661被预测为结合。在AN 3661处理的滋养体中丢失了三个滋养体表达基因的转录本，这在选择或工程改造为AN 3661抗性的寄生虫中没有观察到。我们的研究结果确定前mRNA加工因子PfCPSF 3作为一个有前途的抗疟药物靶点。苯并氧杂硼杂环戊烯已被证明对不同的病原体具有活性。在这里，作者表明苯并氧杂硼杂环戊烯AN 3661在体外和小鼠模型中抑制恶性疟原虫，并鉴定了哺乳动物切割和多聚腺苷酸化特异性因子的同源物作为药物靶标。
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. Benzoxaboroles have been shown to be active against different pathogens. Here, the authors show that the benzoxaborole AN3661 inhibits Plasmodium falciparum in vitro and in mouse models, and identify a homologue of a mammalian cleavage and polyadenylation specificity factor as a drug target.