Targeting RNA with Small Molecules To Capture Opportunities at the Intersection of Chemistry, Biology, and Medicine

被引:147
作者
Disney, Matthew D. [1 ]
机构
[1] Scripps Res Inst, Dept Chem, Jupiter, FL 33458 USA
基金
美国国家卫生研究院;
关键词
BIOACTIVE SMALL MOLECULES; SEQUENCE-BASED DESIGN; 16S RIBOSOMAL-RNA; SECONDARY STRUCTURE; INTERVENING SEQUENCE; ROSEOFLAVIN; BINDING; ANTIBIOTICS; RESISTANCE; INHIBITION;
D O I
10.1021/jacs.8b13419
中图分类号
O6 [化学];
学科分类号
0703 ;
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.
引用
收藏
页码:6776 / 6790
页数:15
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