Issue 20, 2020

Design of small molecules targeting RNA structure from sequence

Abstract

The design and discovery of small molecule medicines has largely been focused on a small number of druggable protein families. A new paradigm is emerging, however, in which small molecules exert a biological effect by interacting with RNA, both to study human disease biology and provide lead therapeutic modalities. Due to this potential for expanding target pipelines and treating a larger number of human diseases, robust platforms for the rational design and optimization of small molecules interacting with RNAs (SMIRNAs) are in high demand. This review highlights three major pillars in this area. First, the transcriptome-wide identification and validation of structured RNA elements, or motifs, within disease-causing RNAs directly from sequence is presented. Second, we provide an overview of high-throughput screening approaches to identify SMIRNAs as well as discuss the lead identification strategy, Inforna, which decodes the three-dimensional (3D) conformation of RNA motifs with small molecule binding partners, directly from sequence. An emphasis is placed on target validation methods to study the causality between modulating the RNA motif in vitro and the phenotypic outcome in cells. Third, emergent modalities that convert occupancy-driven mode of action SMIRNAs into event-driven small molecule chemical probes, such as RNA cleavers and degraders, are presented. Finally, the future of the small molecule RNA therapeutics field is discussed, as well as hurdles to overcome to develop potent and selective RNA-centric chemical probes.

Graphical abstract: Design of small molecules targeting RNA structure from sequence

Supplementary files

Article information

Article type
Tutorial Review
Submitted
29 Apr 2020
First published
16 Sep 2020

Chem. Soc. Rev., 2020,49, 7252-7270

Author version available

Design of small molecules targeting RNA structure from sequence

A. Ursu, J. L. Childs-Disney, R. J. Andrews, C. A. O’Leary, S. M. Meyer, A. J. Angelbello, W. N. Moss and M. D. Disney, Chem. Soc. Rev., 2020, 49, 7252 DOI: 10.1039/D0CS00455C

To request permission to reproduce material from this article, please go to the Copyright Clearance Center request page.

If you are an author contributing to an RSC publication, you do not need to request permission provided correct acknowledgement is given.

If you are the author of this article, you do not need to request permission to reproduce figures and diagrams provided correct acknowledgement is given. If you want to reproduce the whole article in a third-party publication (excluding your thesis/dissertation for which permission is not required) please go to the Copyright Clearance Center request page.

Read more about how to correctly acknowledge RSC content.

Social activity

Spotlight

Advertisements