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Atomic Resolution Analyses of Isocoumarin Derivatives for Inhibition of Lysyl-tRNA Synthetase.
ACS Chemical Biology ( IF 4 ) Pub Date : 2020-03-26 , DOI: 10.1021/acschembio.0c00032
Jintong Zhou 1 , Li Zheng 1 , Zhoufei Hei 1 , Wei Li 2 , Jing Wang 1, 3 , Biao Yu 1, 3 , Pengfei Fang 1, 3
Affiliation  

Aminoacyl-tRNA synthetases, the essential enzyme family for protein translation, are attractive targets for developing antibacterial, antifungal, and antiparasitic agents and for treating other human diseases. The antimalarial natural product cladosporin was discovered recently as a novel lysyl-tRNA synthetase (LysRS) specific inhibitor. Here, we report a thorough analysis of cladosporin derivatives using chemical synthesis, biophysical, and biochemical experiments. A series of isocoumarin derivatives with only one nonhydrogen atom/bond change per compound was synthesized. These changes include replacements of methyltetrahydropyran moiety by methylcyclohexane or cyclohexane, lactone by lactam, hydroxyl groups by methoxyl groups, and dismission of the chiral center at C3 with a Δ3,4 double bond. We evaluated these compounds by thermal shift assays and enzymatic experiments and further studied their molecular recognition by the Plasmodium falciparum LysRS through total five high-resolution crystal structures. Our results showed that the methyltetrahydropyran moiety of cladosporin could be replaced by a more stable methylcyclohexane without reducing binding ability. Removing the methyl group from the methylcyclohexane moiety slightly decreased the interaction with LysRS. Besides, the replacement with a lactam group or a conjugated Δ3,4 double bond within the scaffold could be two more options to optimize the compound. Lastly, the two phenolic hydroxyl groups were critical for the compounds to bind LysRS. The detailed analyses at atomic resolution in this study provide a foundation for the further development of new antibiotics from cladosporin derivatives.

中文翻译:

异香豆素衍生物的赖氨酸-tRNA合成酶抑制作用的原子分辨率分析。

氨酰基-tRNA合成酶是蛋白质翻译所必需的酶家族,是开发抗菌,抗真菌和抗寄生虫剂以及治疗其他人类疾病的诱人靶标。最近发现抗疟疾天然产物clasporporin是新型的赖氨酰-tRNA合成酶(LysRS)特异性抑制剂。在这里,我们报告了使用化学合成,生物物理和生化实验对clasporsporin衍生物进行的全面分析。合成了每个化合物仅具有一个非氢原子/键变化的一系列异香豆素衍生物。这些变化包括用甲基环己烷或环己烷取代甲基四氢吡喃部分,用内酰胺取代内酯,用甲氧基取代羟基,以及在C3上以Δ3,4双键释放手性中心。我们通过热位移分析和酶促实验评估了这些化合物,并通过总的五个高分辨率晶体结构进一步研究了恶性疟原虫LysRS的分子识别作用。我们的结果表明,cladosporin的甲基四氢吡喃部分可被更稳定的甲基环己烷取代,而不会降低结合能力。从甲基环己烷部分除去甲基稍微降低了与LysRS的相互作用。此外,在支架内用内酰胺基或共轭的Δ3,4双键取代可能是优化化合物的两个选择。最后,两个酚羟基对于化合物结合LysRS至关重要。
更新日期:2020-04-23
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