Fluorescent trimethylated naphthyridine derivative with an aminoalkyl side chain as the tightest non-aminoglycoside ligand for the bacterial A-site RNA
Fluorescent trimethylated naphthyridine derivative with an aminoalkyl side chain as the tightest non-aminoglycoside ligand for the bacterial A-site RNA
复制标题
荧光三甲基化萘啶衍生物，具有氨烷基侧链作为细菌 A 位 RNA 最紧密的非氨基糖苷配体
DOI：
10.1002/chem.201802320
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
and S. Nishizawa
中科院分区：
文献类型：
--
作者：
Y. Sato;M. Rokugawa;S. Ito;S. Yajima;H. Sugawara;N. Teramae;and S. Nishizawa
细菌核糖体解码区的氨基酰基-tRNA位点(A-Site)是抗生素类药物最有效的靶向RNA之一。虽然天然氨基糖苷类化合物是A位结合配体，但高度的非靶点效应和细菌对氨基糖苷类药物耐药性的日益增加限制了它们的临床应用。为了避免氨基糖苷家族的这些担忧，非氨基糖苷A位结合配体作为抗细菌感染的新型抗生素具有巨大的潜力。本工作描述了一类新的基于细菌(大肠杆菌)A位的2-氨基-5，6，7-三甲基-1，8-萘啶(ATMND)结构的小杂环配体。具有氨乙基侧链的ATMND与A位的内环有很强的选择性结合(Kd=0.44 μm；pH 7.0，I=0.06m，5 °C)。值得注意的是，该配体显示了迄今为止报道的非氨基糖苷类配体中最紧密的结合。基于热力学和分子模拟的结合研究揭示了ATMND-C2-NH2与A-位点高亲和力的关键分子相互作用。该配体还可用于评价配体/A位相互作用的荧光指示剂置换分析。
The bacterial ribosomal decoding region of the aminoacyl‐tRNA site (A‐site) is one of the most validated target RNAs for antibiotic agents. Although natural aminoglycosides are well‐characterized A‐site binding ligands, high off‐target effects and the growing emergence of bacterial resistance against aminoglycosides limit their clinical use. To circumvent these concerns with the aminoglycoside family, non‐aminoglycoside A‐site binding ligands have great potential as novel antibiotics against bacterial infections. This work describes a new class of small heterocyclic ligands based on the 2‐amino‐5,6,7‐trimethyl‐1,8‐naphthyridine (ATMND) structure for the bacterial (Escherichia coli) A‐site. ATMND possessing an aminoethyl side chain is found to strongly and selectively bind to the internal loop of the A‐site (Kd=0.44 μm; pH 7.0,I=0.06m, 5 °C). Significantly, this ligand shows the tightest binding reported to date among non‐aminoglycoside ligands. The binding study based on the thermodynamics and molecular modelling reveals key molecular interactions of ATMND‐C2‐NH2for high affinity to the A‐site. This ligand is also demonstrated to be applicable to the fluorescence indicator displacement assay for assessing ligand/A‐site interactions.