Target Identification of an Antimalarial Oxaborole Identifies AN13762 as an Alternative Chemotype for Targeting CPSF3 in Apicomplexan Parasites.
Target Identification of an Antimalarial Oxaborole Identifies AN13762 as an Alternative Chemotype for Targeting CPSF3 in Apicomplexan Parasites.
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DOI：
10.1016/j.isci.2020.101871
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发表时间：
2020-12-18
期刊：
影响因子：
5.8
通讯作者：
Bougdour A
中科院分区：
文献类型：
--
作者：
Bellini V;Swale C;Brenier-Pinchart MP;Pezier T;Georgeault S;Laurent F;Hakimi MA;Bougdour A
含硼化合物代表了一类有前途的分子，已证明其对广泛的病原体（包括顶复门寄生虫）有效。在先导化合物优化后，苯并氧杂硼杂环戊烯AN 13762被确定为抗人类疟疾寄生虫的临床前候选药物，但其分子靶点仍不确定。在这里，我们通过将正向遗传学与转录组测序和计算突变发现相结合，并使用弓形虫作为顶复虫的相关模型，揭示了AN 13762的杀寄生虫机制。AN 13762显示靶向TgCPSF 3，前体mRNA切割和聚腺苷酸化复合物的催化亚基，作为抗泛-apicomplexan苯并氧杂硼杂环戊烯化合物AN 3661。然而，TgCPSF 3催化位点内的独特突变赋予对AN 13762的抗性，但不赋予对AN 3661的交叉保护，这表明存在不同的抗性机制。最后，与弓形虫和隐孢子虫之间CPSF 3的高度序列保守性一致，AN 13762在隐孢子虫病小鼠模型中显示出口服有效性，这种疾病的新药开发是高度优先的。AN 13762对弓形虫有活性对AN 13762有抗性的寄生虫携带TgCPSF 3内的突变TgCPSF 3内的突变赋予对AN 13762的抗性AN 13762提供了一种在弓形虫和隐孢子虫中靶向CPSF 3的替代方法分子生物学;分子医学;微生物学;微生物学寄生虫
Boron-containing compounds represent a promising class of molecules with proven efficacy against a wide range of pathogens, including apicomplexan parasites. Following lead optimization, the benzoxaborole AN13762 was identified as a preclinical candidate against the human malaria parasite, yet the molecular target remained uncertain. Here, we uncovered the parasiticidal mechanisms of AN13762, by combining forward genetics with transcriptome sequencing and computational mutation discovery and using Toxoplasma gondii as a relevant model for Apicomplexa. AN13762 was shown to target TgCPSF3, the catalytic subunit of the pre-mRNA cleavage and polyadenylation complex, as the anti-pan-apicomplexan benzoxaborole compound, AN3661. However, unique mutations within the TgCPSF3 catalytic site conferring resistance to AN13762 do not confer cross-protection against AN3661, suggesting a divergent resistance mechanism. Finally, in agreement with the high sequence conservation of CPSF3 between Toxoplasma and Cryptosporidium, AN13762 shows oral efficacy in cryptosporidiosis mouse model, a disease for which new drug development is of high priority. AN13762 is active against T. gondii parasites Parasites resistant to AN13762 harbor mutations within TgCPSF3 Mutations within TgCPSF3 confer resistance to AN13762 AN13762 offers an alternative for targeting CPSF3 in Toxoplasma and Cryptosporidium Molecular Biology; Molecular Medicine; Microbiology; Microbiology Parasite
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影响因子：
64.8
作者：
De Rycker M;Baragaña B;Duce SL;Gilbert IH
通讯作者：
Gilbert IH
影响因子：
11.1
作者：
Palencia A;Bougdour A;Brenier-Pinchart MP;Touquet B;Bertini RL;Sensi C;Gay G;Vollaire J;Josserand V;Easom E;Freund YR;Pelloux H;Rosenthal PJ;Cusack S;Hakimi MA
通讯作者：
Hakimi MA
影响因子：
10.5
作者：
Shi Y;Manley JL
通讯作者：
Manley JL
影响因子：
7.7
作者：
He H;Brenier-Pinchart MP;Braun L;Kraut A;Touquet B;Couté Y;Tardieux I;Hakimi MA;Bougdour A
通讯作者：
Bougdour A
影响因子：
28.3
作者：
Farhat, Dayana C.;Swale, Christopher;Hakimi, Mohamed-Ali
通讯作者：
Hakimi, Mohamed-Ali