Department of Chemistry , The Scripps Research Institute , Jupiter , Florida 33458 , United States.
J Am Chem Soc. 2019 May 1;141(17):6776-6790. doi: 10.1021/jacs.8b13419. Epub 2019 Apr 19.
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.
健康细胞和病变细胞的生物学特性通常由 RNA 结构介导，这些 RNA 结构是小分子化学探针和先导药物的理想靶标。尽管结构域存在于整个转录组中，有些甚至具有已证实的功能，但人们认为人类 RNA 不易受到小分子的靶向作用。然而，用小分子靶向结构域为靶向序列的寡核苷酸提供了一个重要的替代方案。在本观点中，我们描述了开发与 RNA 相互作用的小分子（SMIRNAs）的挑战和进展，以捕捉它们在化学、生物学和医学交叉点的重要机会。在化学生物学和医学中建立新范式的关键是开发获得生物活性化合物的方法，最好是通过设计来获得，这些化合物可以调节 RNA 靶标，以及验证其在细胞和临床前模型中直接作用的配套方法。虽然这很困难，但需要在复杂的细胞环境中证明直接的靶标结合，以及建立作用模式的方法，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、它们的影响、开发 SMIRNAs 的关键新技术，以及导致更广泛接受 RNA 作为小分子药物靶标的里程碑。
