Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei.
Structure-guided discovery of selective methionyl-tRNA synthetase inhibitors with potent activity against Trypanosoma brucei.
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以结构为指导发现对布氏锥虫具有有效活性的选择性甲硫氨酰-tRNA 合成酶抑制剂。
DOI：
10.1039/d0md00057d
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发表时间：
2020
影响因子：
4.1
通讯作者：
Buckner,Fre
中科院分区：
文献类型：
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作者：
Zhang,Zhongsheng;Barros-Álvarez,Ximena;Gillespie,JRobert;Ranade,RanaeM;Huang,Wenlin;Shibata,Sayaka;Molasky,NoraMR;Faghih,Omeed;Mushtaq,Aisha;Choy,RobertKM;deHostos,Eugenio;Hol,WimGJ;Verlinde,ChristopheLMJ;Buckner,Fre
基于布氏锥虫甲硫氨酰-tRNA合成酶（TbMetRS）抑制剂的晶体结构，设计、合成并评价了两个系列针对该寄生虫酶的新型TbMetRS抑制剂。一个系列具有含1，3-二氢-咪唑-2-酮的接头，另一个系列在接头中具有刚性稠合芳环。对于这两个系列的化合物，有效抑制寄生虫生长，达到EC 50 < 10 nM and most compounds exhibited low general toxicity to mammalian cells with CC50s >20 000 nM。还使用基于细胞的线粒体蛋白质合成测定评价了对人线粒体甲硫氨酰tRNA合成酶的选择性，并且实现了20-200倍范围内的选择性。这些抑制剂表现出较差的血脑屏障渗透性，需要进一步努力优化用于晚期人类非洲锥虫病的化合物。
Based on crystal structures of Trypanosoma brucei methionyl-tRNA synthetase (TbMetRS) bound to inhibitors, we designed, synthesized, and evaluated two series of novel TbMetRS inhibitors targeting this parasite enzyme. One series has a 1,3-dihydro-imidazol-2-one containing linker, the other has a rigid fused aromatic ring in the linker. For both series of compounds, potent inhibition of parasite growth was achieved with EC50 < 10 nM and most compounds exhibited low general toxicity to mammalian cells with CC50s > 20 000 nM. Selectivity over human mitochondrial methionyl tRNA synthetase was also evaluated, using a cell-based mitochondrial protein synthesis assay, and selectivity in a range of 20–200-fold was achieved. The inhibitors exhibited poor permeability across the blood brain barrier, necessitating future efforts to optimize the compounds for use in late stage human African trypanosomiasis.