重新发现PF-3845作为抑制结核分枝杆菌中苯丙氨酰-tRNA合成酶的新型化学支架,Journal of Biological Chemistry

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重新发现PF-3845作为抑制结核分枝杆菌中苯丙氨酰-tRNA合成酶的新型化学支架
Journal of Biological Chemistry ( IF 4.0 ) Pub Date : 2021-01-04 , DOI: 10.1074/jbc.ra120.016477
Heng Wang, Min Xu, Curtis A. Engelhart, Xi Zhang, Baohua Yan, Miaomiao Pan, Yuanyuan Xu, Shilong Fan, Renhe Liu, Lan Xu, Lan Hua, Dirk Schnappinger, Shawn Chen

结核分枝杆菌（Mtb）仍然是全世界最致命的致病菌。寻找新的抗生素来治疗药物敏感性和耐药性结核病已成为当务之急。必需的酶苯丙氨酰-tRNA合成酶（PheRS）是抗菌药物的靶标，因为细菌和人类PheRS对应物之间存在很大差异。在对2148种生物活性化合物的高通量筛选中，已知PF-3845（一种已知的人类脂肪酸酰胺水解酶（FAAH）抑制剂）在Ki〜0.73±0.06 µM时抑制Mtb PheRS。与所述的苯基-噻唑基脲-磺酰胺类的PheRS抑制剂相比，通过酶动力学，蛋白质结构模型和晶体学研究了抑制机理。2。Mtb PheRS与PF-3845配合形成的3-Å晶体结构揭示了其新颖的结合方式，其中三氟甲基-吡啶基苯基占据了Phe的口袋，而哌啶-哌嗪脲基团则通过由Pc增强的相互作用网络结合到ATP口袋中。硫酸根离子。它代表了细菌PheRS的第一个非核苷双底物竞争性抑制剂。PF-3845在〜24 µM时抑制了Mtb H37Rv的体外生长，并且PF-3845对Mtb pheS-FDAS的效力增强，表明分枝杆菌全细胞具有靶标活性。PF-3845在生化分析中不抑制人的细胞质或线粒体PheRS，这可以从晶体结构上解释。

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Re-discovery of PF-3845 as a new chemical scaffold inhibiting phenylalanyl-tRNA synthetase in Mycobacterium tuberculosis

Mycobacteria tuberculosis (Mtb) remains the deadliest pathogenic bacteria worldwide. The search for new antibiotics to treat drug-sensitive as well as drug-resistant tuberculosis has become a priority. The essential enzyme phenylalanyl-tRNA synthetase (PheRS) is an antibacterial drug target because of the large differences between bacterial and human PheRS counterparts. In a high-throughput screening of 2148 bioactive compounds, PF-3845, which is a known inhibitor of human fatty acid amide hydrolase (FAAH), was identified inhibiting Mtb PheRS at Ki ~0.73 ± 0.06 µM. The inhibition mechanism was studied with enzyme kinetics, protein structural modelling and crystallography, in comparison to a PheRS inhibitor of the noted phenyl-thiazolylurea-sulfonamide class. The 2.3-Å crystal structure of Mtb PheRS in complex with PF-3845 revealed its novel binding mode, in which a trifluoromethyl-pyridinylphenyl group occupies the Phe pocket while a piperidine-piperazine urea group binds into the ATP pocket through an interaction network enforced by a sulfate ion. It represents the first non-nucleoside bi-substrate competitive inhibitor of bacterial PheRS. PF-3845 inhibits the in vitro growth of Mtb H37Rv at ~24 µM, and the potency of PF-3845 increased against Mtb pheS-FDAS, suggesting on target activity in mycobacterial whole cells. PF-3845 does not inhibit human cytoplasmic or mitochondrial PheRS in biochemical assay, which can be explained from the crystal structures. Further medicinal chemistry efforts focused on the piperidine-piperazine urea moiety may result in the identification of a selective antibacterial lead compound.

更新日期：2021-01-05

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