A Modular Approach to Synthetic RNA Binders of the Hepatitis C Virus Internal Ribosome Entry Site
A Modular Approach to Synthetic RNA Binders of the Hepatitis C Virus Internal Ribosome Entry Site
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DOI：
10.1002/cbic.201000177
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发表时间：
2010-07-05
期刊：
影响因子：
3.2
通讯作者：
Hermann, Thomas
中科院分区：
文献类型：
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作者：
Carnevali, Maia;Parsons, Jerod;Hermann, Thomas
以细菌核糖体的 RNA 成分为靶点的天然产物，从而充当关闭微生物蛋白质合成的抗生素，为针对 RNA 靶标的小分子配体的设计和合成提供了丰富的灵感来源。[1, 2] 天然氨基糖苷类抗生素中发生的 RNA 识别的特殊支架的一个突出例子是 2-脱氧链霉胺 (2-DOS)，[3]，它包含氢键供体的刚性框架，其中刚性 cis-1, 3 排列氨基负责与 RNA 靶标中的结构基序选择性相互作用（图 1）。[4]在降低涉及高度功能化 2-DOS 支架的化学文库合成复杂性的方法中，我们最近开发了 3, 5-二氨基哌啶杂环 (DAP)，作为 2-DOS 支架的 RNA 识别药效团的结构模拟物（图 1）。结构引导设计已被应用于发现一系列抗菌 DAP-三嗪衍生物，它们与天然氨基糖苷类抗生素作用于相同的核糖体 RNA 靶标，这最初是 DAP 化合物概念的灵感。[5, 6]在这里，我们描述了一类新型模块化配体 (1) 的合成，其中包含 DAP 支架作为非核糖体靶标中 RNA 识别的关键部分（图 1）。[7]针对子结构域 IIa（丙型肝炎病毒 (HCV) 内部核糖体进入位点 (IRES) 中的 RNA 靶标）（图 1）筛选模块化 DAP 配体，揭示了一组 N-酰胺基取代的 DAP (2) α-氨基酸缀合物作为该 RNA 的微摩尔结合物。我们之前已经证明，配体诱导的子域 IIa RNA 构象变化会破坏 IRES 的功能并阻止病毒蛋白合成，最终导致受感染细胞中 HCV 的抑制。 [8]
Natural products that target the RNA components of bacterial ribosomes, and thereby act as antibiotics that shut down microbial protein synthesis, have provided a rich source of inspiration for the design and synthesis of small molecule ligands directed at RNA targets.[1, 2] A prominent example of a privileged scaffold for RNA recognition occurring in natural aminoglycoside antibiotics is 2-deoxystreptamine (2-DOS),[3] which contains a rigid framework of hydrogen bond donors among which the rigid cis-1, 3 arrangement of amino groups is responsible for selective interaction with structural motifs in RNA targets (Figure 1).[4] In an approach to reduce the complexity of chemical library synthesis involving the highly functionalized 2-DOS scaffold, we have recently developed the 3, 5-diaminopiperidine heterocycle (DAP) as a structural mimetic of the RNA-recognizing pharmacophore of the 2-DOS scaffold (Figure 1). Structure-guided design had been applied to discover a series of antibacterial DAP-triazine derivatives that act on the same ribosomal RNA target as the natural aminoglycoside antibiotics which initially served as the inspiration for the conception of the DAP compounds.[5, 6]Here, we describe the synthesis of a novel class of modular ligands (1) that contain the DAP scaffold as the key moiety for RNA recognition in nonribosomal targets (Figure 1).[7] Screening of modular DAP ligands against the subdomain IIa, an RNA target in the internal ribosome entry site (IRES) of hepatitis C virus (HCV)(Figure 1), revealed a set of N-amido substituted α-amino acid conjugates of DAP (2) as micromolar binders of this RNA. We had previously shown that ligand-induced conformational change in the subdomain IIa RNA disrupts the function of the IRES and blocks viral protein synthesis, which ultimately leads to inhibition of HCV in infected cells.[8]