Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space

Rizvi, Noreen F.; Maria, John P. Santa; Nahvi, Ali; Klappenbach, Joel A.; Klein, Daniel; Curran, Patrick J.; Richards, Matthew P.; Chamberlin, Chad; Saradjian, P; Burchard, Julja; Aguilar, Rodrigo; Lee, Jeannie T.; Dandliker, Peter J.; Smith, G. F.; Kutchukian, Peter S.; Nickbarg, Elliott

doi:10.1177/2472555219885373

Cited by 78 publications

(86 citation statements)

References 45 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Rizvi et al (115) recently published a study in which they investigated small-molecule properties that lead to selective RNA binding. They screened a library of 50,000 drug-like and 5100 tool compounds against a variety of RNA structures using a mass spectrometry-based assay and used a machine-learning algorithm on identified binders to build an RNA-biased library, which had a higher hit rate compared with the starting libraries.…”

Section: Rna-biased Librariesmentioning

confidence: 99%

Frameworks for targeting RNA with small molecules

Juru

Hargrove

2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

Since the characterization of mRNA in 1961, our understanding of the roles of RNA molecules has significantly grown. Beyond serving as a link between DNA and proteins, RNA molecules play direct effector roles by binding to various ligands, including proteins, DNA, other RNAs, and metabolites. Through these interactions, RNAs mediate cellular processes such as the regulation of gene transcription and the enhancement or inhibition of protein activity. As a result, the misregulation of RNA molecules is often associated with disease phenotypes, and RNA molecules have been increasingly recognized as potential targets for drug development efforts, which in the past had focused primarily on proteins. Although both small molecule–based and oligonucleotide-based therapies have been pursued in efforts to target RNA, small-molecule modalities are often favored owing to several advantages including greater oral bioavailability. In this review, we discuss three general frameworks (sets of premises and hypotheses) that, in our view, have so far dominated the discovery of small-molecule ligands for RNA. We highlight the unique merits of each framework as well as the pitfalls associated with exclusive focus of ligand discovery efforts within only one framework. Finally, we propose that RNA ligand discovery can benefit from using progress made within these three frameworks to move toward a paradigm that formulates RNA-targeting questions at the level of RNA structural subclasses.

show abstract

Section: Rna-biased Librariesmentioning

confidence: 99%

Frameworks for targeting RNA with small molecules

Juru

Hargrove

2021

Journal of Biological Chemistry

View full text Add to dashboard Cite

show abstract

“…Furthermore, similar to miRNAs, lncRNA activities can be modulated by nucleic acid-based mimics and inhibitors. Once considered undruggable, RNAs, including lncRNAs are now considered druggable with small molecules [133][134][135].…”

Section: Discussionmentioning

confidence: 99%

The Role of Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis

Sharma

Münger

2020

Pathogens

View full text Add to dashboard Cite

Infections with high-risk human papillomaviruses cause ~5% of all human cancers. E6 and E7 are the only viral genes that are consistently expressed in cancers, and they are necessary for tumor initiation, progression, and maintenance. E6 and E7 encode small proteins that lack intrinsic enzymatic activities and they function by binding to cellular regulatory molecules, thereby subverting normal cellular homeostasis. Much effort has focused on identifying protein targets of the E6 and E7 proteins, but it has been estimated that ~98% of the human transcriptome does not encode proteins. There is a growing interest in studying noncoding RNAs as biochemical targets and biological mediators of human papillomavirus (HPV) E6/E7 oncogenic activities. This review focuses on HPV E6/E7 targeting cellular long noncoding RNAs, a class of biologically versatile molecules that regulate almost every known biological process and how this may contribute to viral oncogenesis.

show abstract

“…More recently, Merck's diversity set of *50,000 members and a set of functionally annotated compounds (*5100 compounds) were studied for binding an array of 42 RNA targets, thus probing interactions between drug-like molecules and biologically important RNA structures. 133,199 The binders identified were largely biased toward G quadruplexes (1097 of *1420 compounds, or 77%), and only 119 were selective for one of the 42 RNAs screened. Although the data generated are somewhat limited in scope and predictive power for RNA in general because of the bias for G-quadruplexes, these studies did identify features enriched in selective and general RNA binders as well as differences between RNA and protein binders.…”

Section: Rna-binding Scaffoldsmentioning

confidence: 99%

Target-Directed Approaches for Screening Small Molecules against RNA Targets

et al. 2020

View full text Add to dashboard Cite

RNA molecules have a variety of cellular functions that can drive disease pathologies. They are without a doubt one of the most intriguing yet controversial small-molecule drug targets. The ability to widely target RNA with small molecules could be revolutionary, once the right tools, assays, and targets are selected, thereby defining which biomolecules are targetable and what constitutes drug-like small molecules. Indeed, approaches developed over the past 5–10 years have changed the face of small molecule–RNA targeting by addressing historic concerns regarding affinity, selectivity, and structural dynamics. Presently, selective RNA–protein complex stabilizing drugs such as branaplam and risdiplam are in clinical trials for the modulation of SMN2 splicing, compounds identified from phenotypic screens with serendipitous outcomes. Fully developing RNA as a druggable target will require a target engagement-driven approach, and evolving chemical collections will be important for the industrial development of this class of target. In this review we discuss target-directed approaches that can be used to identify RNA-binding compounds and the chemical knowledge we have today of small-molecule RNA binders.

show abstract

Targeting RNA with Small Molecules: Identification of Selective, RNA-Binding Small Molecules Occupying Drug-Like Chemical Space

Cited by 78 publications

References 45 publications

Frameworks for targeting RNA with small molecules

Frameworks for targeting RNA with small molecules

The Role of Long Noncoding RNAs in Human Papillomavirus-associated Pathogenesis

Target-Directed Approaches for Screening Small Molecules against RNA Targets

Contact Info

Product

Resources

About