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首页> 外文期刊>Journal of the American Chemical Society >Targeting RNA with Small Molecules To Capture Opportunities at the Intersection of Chemistry, Biology, and Medicine
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Targeting RNA with Small Molecules To Capture Opportunities at the Intersection of Chemistry, Biology, and Medicine

机译：用小分子靶向RNA以捕获化学，生物学和医学交叉口的机会

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摘要

The biology of healthy and disease-affected cells is often mediated by RNA structures, desirable targets for small molecule chemical probes and lead medicines. Although structured regions are found throughout the transcriptome, some even with demonstrated functionality, human RNAs are considered recalcitrant to small molecule targeting. However, targeting structured regions with small molecules provides an important alternative to oligonucleotides that target sequence. In this Perspective, we describe challenges and progress in developing small molecules interacting with RNA (SMIRNAs) to capture their significant opportunities at the intersection of chemistry, biology, and medicine. Key to establishing a new paradigm in chemical biology and medicine is the development of methods to obtain, preferably by design, bioactive compounds that modulate RNA targets and companion methods that validate their direct effects in cells and pre-clinical models. While difficult, demonstration of direct target engagement in the complex cellular milieu, along with methods to establish modes of action, is required to push this field forward. We also describe frameworks for accelerated advancements in this burgeoning area, their implications, key new technologies for development of SMIRNAs, and milestones that have led to broader acceptance of RNA as a small molecule druggable target.
机译：健康和受疾病影响的细胞的生物学通常由RNA结构介导，RNA结构是小分子化学探针和先导药物的理想靶标。尽管在整个转录组中都发现了结构化区域，有些甚至具有已证明的功能，但人类RNA被认为对小分子靶向具有顽固性。然而，用小分子靶向结构化区域提供了靶向序列的寡核苷酸的重要替代。在此观点中，我们描述了开发与RNA（SMIRNA）相互作用的小分子以捕获其在化学，生物学和医学交叉领域的重大机遇的挑战和进展。建立化学生物学和医学新范式的关键是开发一些方法，最好是通过设计获得可调节RNA靶标的生物活性化合物，以及证实其在细胞和临床前模型中具有直接作用的伴随方法。虽然很困难，但需要证明直接靶标参与复杂的细胞环境以及建立作用方式的方法，才能推动这一领域的发展。我们还描述了在这个新兴领域加速发展的框架，它们的含义，开发SMIRNA的关键新技术以及使RNA作为小分子可药物化靶标的更广泛接受的里程碑。

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  • 来源
    《Journal of the American Chemical Society》 |2019年第17期|6776-6790|共15页
  • 作者

    Disney Matthew D.;

  • 作者单位

    Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA;

  • 收录信息 美国《科学引文索引》(SCI);美国《工程索引》(EI);美国《生物学医学文摘》(MEDLINE);美国《化学文摘》(CA);
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  • 正文语种 eng
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