Systematically Studying the Effect of Small Molecules Interacting with RNA in Cellular and Preclinical Models

Bush, Jessica A.; Williams, Christopher C.; Meyer, Samantha M.; Tong, Yuquan; Haniff, Hafeez S.; Childs‐Disney, Jessica L.; Disney, Matthew D.

doi:10.1021/acschembio.1c00014

Cited by 11 publications

(7 citation statements)

References 163 publications

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“…50 Therefore, QSTR should be beneficial for understanding intracellular replication. Since the systematic study of ligand screening is powerful for finding ligands that regulate the function of structured nucleic acids, 51 QSTR analysis of large ligand libraries is required.…”

Section: ■ Discussionmentioning

confidence: 99%

Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

et al. 2021

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Ligands that bind to and stabilize guaninequadruplex (G4) structures to regulate DNA replication have therapeutic potential for cancer and neurodegenerative diseases. Because there are several G4 topologies, ligands that bind to their specific types may have the ability to preferentially regulate the replication of only certain genes. Here, we demonstrated that binding ligands stalled the replication of template DNA at G4, depending on different topologies. For example, naphthalene diimide derivatives bound to the G-quartet of G4 with an additional interaction between the ligand and the loop region of a hybrid G4 type from human telomeres, which efficiently repressed the replication of the G4. Thus, these inhibitory effects were not only stability-dependent but also topology-selective based on the manner in which G4 structures interacted with G4 ligands. Our original method, referred to as a quantitative study of topologydependent replication (QSTR), was developed to evaluate correlations between replication rate and G4 stability. QSTR enabled the systematic categorization of ligands based on topology-dependent binding. It also demonstrated accuracy in determining quantitatively how G4 ligands control the intermediate state of replication and the kinetics of G4 unwinding. Hence, the QSTR index would facilitate the design of new drugs capable of controlling the topology-dependent regulation of gene expression.

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Section: ■ Discussionmentioning

confidence: 99%

Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

et al. 2021

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“…The reader is referred to ref. 127 for a review on the validation of phenotypic screens of RNA targets.…”

Section: Strategies To Identify Small-molecule Rna Bindersmentioning

confidence: 99%

Targeting RNA structures with small molecules

Childs‐Disney

Yang

Gibaut

et al. 2022

Nat Rev Drug Discov

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256

219

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RNA adopts 3D structures that confer varied functional roles in human biology and dysfunction in disease. Approaches to therapeutically target RNA structures with small molecules are being actively pursued, aided by key advances in the field including the development of computational tools that predict evolutionarily conserved RNA structures, as well as strategies that expand mode of action and facilitate interactions with cellular machinery. Existing RNA-targeted small molecules use a range of mechanisms including directing splicing — by acting as molecular glues with cellular proteins (such as branaplam and the FDA-approved risdiplam), inhibition of translation of undruggable proteins and deactivation of functional structures in noncoding RNAs. Here, we describe strategies to identify, validate and optimize small molecules that target the functional transcriptome, laying out a roadmap to advance these agents into the next decade.

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“…Small molecules able to produce the desired phenotype are selected for further validation. It can be performed in vivo in suitable animal models or in cell lines. , In cell-based phenotypic screening, luciferase or any other fluorescent protein is utilized as a reporter. The luciferase assay is the most extensively used method for validating targets in cell lines.…”

Section: Crucial Steps In Rna-targeted Drug Discoverymentioning

confidence: 99%

RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag

Kaur,

Sharma,

Mundlia

et al. 2024

J. Med. Chem.

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RNA targeting, specifically with small molecules, is a relatively new and rapidly emerging avenue with the promise to expand the target space in the drug discovery field. From being "disregarded" as an "undruggable" messenger molecule to FDA approval of an RNA-targeting small-molecule drug Risdiplam, a radical change in perspective toward RNA has been observed in the past decade. RNAs serve important regulatory functions beyond canonical protein synthesis, and their dysregulation has been reported in many diseases. A deeper understanding of RNA biology reveals that RNA molecules can adopt a variety of structures, carrying defined binding pockets that can accommodate smallmolecule drugs. Due to its functional diversity and structural complexity, RNA can be perceived as a prospective target for therapeutic intervention. This perspective highlights the proof of concept of RNA−small-molecule interactions, exemplified by targeting of various transcripts with functional modulators. The advent of RNA-oriented knowledge would help expedite drug discovery. ■ SIGNIFICANCE• This Perspective highlights the importance of RNA as a drug target to solve the issues such as lack of therapeutic treatments for several diseases, increasing resistance against conventional drugs, and tackling the undruggability of various protein targets. • In-depth analysis of various aspects, i.e., small-moleculebinding modes, and current trends required to dig deep into this area of drug discovery are discussed. • The research discussed herein would aid in the development of small-molecule therapeutics.

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Systematically Studying the Effect of Small Molecules Interacting with RNA in Cellular and Preclinical Models

Cited by 11 publications

References 163 publications

Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

Chemical Modulation of DNA Replication along G-Quadruplex Based on Topology-Dependent Ligand Binding

Targeting RNA structures with small molecules

RNA–Small-Molecule Interaction: Challenging the “Undruggable” Tag

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