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5
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Chemical Matter That Binds RNA
Emily G. Swanson Hay, Zhengguo Cai, and Amanda E. Hargrove
Duke University, Department of Chemistry, 124 Science Drive, Durham, NC 27705, USA
5.1 Introduction
Therapeutic drugs act on specic molecular targets to impact or alter the corresponding biological pathways, thus delivering pharmacological eects toward the disease
phenotypes of interest. Most of the small-molecule drugs in clinical use target proteins. In total <700 proteins are currently targeted, representing merely 0.05% of the
human genome [1]. In contrast, over 70% of the human genome is transcribed into
RNA, and RNA-targeted therapies could greatly expand the range of drug development. Interest in RNAs as potential drug targets has been increasing in part due to
the mounting evidence that non-coding RNAs (ncRNAs) pervasively regulate gene
expression and protein function in cells, participating in disease development and
viral infections. The feasibility of RNA-targeted therapies has been demonstrated
by the successful deployment of multiple modalities, including antisense oligonucleotides, small interfering RNAs, and RNA aptamers [2].
There is also growing interest in developing small-molecule-based therapies
because of improved oral administration and cell permeability, as well as to expand
the number of targets to include highly structured RNAs that might not be readily
targeted by antisense-based strategies. Many RNAs bear structural motifs that could
form binding pockets or clefts suitable for selective small-molecule binding [1].
The chemical nature of RNA, including the dynamic structure and densely charged
backbone, requires ligands with specic physiochemical properties that might be
limited in current screening libraries. Many eorts have been made to understand
what types of molecular design could favor RNA targeting based on cheminformatic
analysis, which led to multiple collections of literature-reported ligands, such as the
RNA-Targeting BIoactive LigaNd Database (R-BIND), [3–5], Nucleic Acid Ligand
Database (NALDB) [6] and Small Molecule Modulators of RNA (SMMRNA) [7],
as well as curated libraries to increase hit rates of screening, such as Inforna [8, 9]
and the Duke RNA-Targeted Library (DRTL) [10]. The increasing pool of reported
RNA-targeted small molecules with diverse chemical structures provides a reliable
data source for such analysis and elicits a distinguished chemical space occupied
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RNA as a Drug Target: The Next Frontier for Medicinal Chemistry, First Edition.
Edited by John Schneekloth and Martin Pettersson.
© 2024 WILEY-VCH GmbH. Published 2024 by WILEY-VCH GmbH.
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by ligands that are able to bind to RNA, which can be further rened by those
demonstrating biological activity.
In this chapter, we focus on RNA ligands and discuss what type of chemical entities should be pursued for RNA targeting. We will rst review common chemical
scaolds and their structural features with varied RNA-binding properties, from naturally discovered ligands to synthetic small molecules. Representative works on the
construction of focused libraries will be introduced to explain library curation methods and the improved hit rates this strategy can achieve, followed by the discussion
of methods to explore novel chemical space, a case study highlighting classes of ligands presented in this chapter, and future directions for the eld of small-molecule
RNA targeting.
5.2 Natural Ligands
Many of the early insights into RNA–small-molecule targeting came from exploring naturally occurring RNA–small-molecule interactions. From antibiotics to
riboswitch ligands, there are many examples of how diverse and complex small
molecules can bind RNA to regulate biological systems. Additionally, by utilizing
the chemical diversity of ligands generated through complex biosynthetic pathways,
new RNA-binding molecules can be identied. Disney and coworkers recently
performed a screen with the Scripps Research Natural Products Discovery Center
collections and identied a natural product, nocathiacin I, that selectively targeted
pre-miR-18a and had bioactivity in a prostate cancer cell line [11]. This work
exemplies how the potential of natural products may be harnessed for targeting
RNA, and how expanding beyond common antibiotic scaolds may aord more
selective ligands. Further examination of the functional binding interactions
that have evolved for RNA and small molecules, alongside investigating novel
RNA–natural product interactions, may help inform future ligand design for novel
RNA targets.
5.2.1 Aminoglycosides
Aminoglycosides represent a major class of RNA-binding natural products consisting of oligosaccharides that contain amine groups, giving the molecules
hydrogen-bonding capability as well as positive charge(s) that drive electrostatic
interactions with RNA molecules [12–14]. In fact, aminoglycosides were among the
rst known small molecules to aect biology through RNA binding [15]. Extracted
from various bacteria, aminoglycosides serve as antibiotics through a variety of
mechanisms that result in the disruption of protein synthesis through binding to
ribosomal RNA (rRNA), often in the aminoacyl-transfer RNA (tRNA) site (A-site),
thereby interfering with bacterial function [12, 16]. Due to aminoglycosides containing oligosaccharide units, they often have much higher stereocenter and oxygen
counts than other RNA-targeting ligands, while their positive charge can make them
promiscuous RNA binders [3, 17]. Many naturally occurring aminoglycosides have
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