Small molecule recognition of disease-relevant RNA structures

Meyer, Samantha M.; Williams, Christopher C.; Akahori, Yoshihiro; Tanaka, Toru; Aikawa, Haruo; Tong, Yuquan; Childs‐Disney, Jessica L.; Disney, Matthew D.

doi:10.1039/d0cs00560f

Cited by 121 publications

(126 citation statements)

References 198 publications

(305 reference statements)

Supporting

Mentioning

123

Contrasting

Order By: Relevance

“…An increasing body of evidence suggests that the function of many lncRNAs is largely mediated by their interaction with RBPs or protein complexes. Thus, a promising therapeutic option for targeting lncRNAs is the use of steric hindering antisense oligonucleotides or small molecules that affect these interactions by either (1) blocking the RNA-binding domain of the protein, or (2) directly binding to and disrupting secondary and tertiary structures in the lncRNA molecule ( Meyer et al, 2020 ) ( Figure 4C ).…”

Section: Targeting Lncrnas In Neurological Disorders: Trash or Treasure?mentioning

confidence: 99%

“…Although still early, it has been shown that small molecules can target several classes of RNA besides lncRNAs, including miRNAs , repeat expansion regions, mRNAs encoding for intrinsically disordered proteins, splicing modifiers and motifs located at the 5′- and 3′- untranslated regions (5′- and 3′- UTRs, respectively) ( Meyer et al, 2020 ; Yu et al, 2020 ). Recently, Risdiplam received FDA approval for the treatment of SMA ( U.S. Food & Drug Administration, 2020 ), and Branaplam is undergoing clinical trials as a therapy for the same disease as well as a for HD ( ClinicalTrials.…”

Section: Targeting Lncrnas In Neurological Disorders: Trash or Treasure?mentioning

confidence: 99%

“…gov, 2021 ). Both Risdiplam and Branaplam increase SMN protein levels by acting as SMN2 splicing modulators ( Meyer et al, 2020 ). Other small molecules have been identified as potential therapeutic agents for neurological disorders but are still in early discovery stages.…”

Section: Targeting Lncrnas In Neurological Disorders: Trash or Treasure?mentioning

confidence: 99%

See 2 more Smart Citations

From Junk to Function: LncRNAs in CNS Health and Disease

Policarpo

Sierksma

Strooper

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

Recent advances in RNA sequencing technologies helped to uncover the existence of tens of thousands of long non-coding RNAs (lncRNAs) that arise from the dark matter of the genome. These lncRNAs were originally thought to be transcriptional noise but an increasing number of studies demonstrate that these transcripts can modulate protein-coding gene expression by a wide variety of transcriptional and post-transcriptional mechanisms. The spatiotemporal regulation of lncRNA expression is particularly evident in the central nervous system, suggesting that they may directly contribute to specific brain processes, including neurogenesis and cellular homeostasis. Not surprisingly, lncRNAs are therefore gaining attention as putative novel therapeutic targets for disorders of the brain. In this review, we summarize the recent insights into the functions of lncRNAs in the brain, their role in neuronal maintenance, and their potential contribution to disease. We conclude this review by postulating how these RNA molecules can be targeted for the treatment of yet incurable neurological disorders.

show abstract

Section: Targeting Lncrnas In Neurological Disorders: Trash or Treasure?mentioning

confidence: 99%

Section: Targeting Lncrnas In Neurological Disorders: Trash or Treasure?mentioning

confidence: 99%

See 1 more Smart Citation

From Junk to Function: LncRNAs in CNS Health and Disease

Policarpo

Sierksma

Strooper

et al. 2021

Front. Mol. Neurosci.

View full text Add to dashboard Cite

show abstract

“…The action mechanism of cisplatin involves DNA binding, halting of replication, and induction of apoptosis [ 1 ]. In order to treat human diseases such as microorganism infections and genetic disorders, which rank among the most difficult diseases to tackle, the paradigm has recently shifted to RNA targeting with small molecules [ 2 , 3 , 4 , 5 ].…”

Section: Introductionmentioning

confidence: 99%

Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes

et al. 2021

View full text Add to dashboard Cite

Nucleic acids are essential biomolecules in living systems and represent one of the main targets of chemists, biophysics, biologists, and nanotechnologists. New small molecules are continuously developed to target the duplex (ds) structure of DNA and, most recently, RNA to be used as therapeutics and/or biological tools. Stimuli-triggered systems can promote and hamper the interaction to biomolecules through external stimuli such as light and metal coordination. In this work, we report on the interaction with ds-DNA and ds-RNA of two aza-macrocycles able to coordinate Zn2+ metal ions and form binuclear complexes. The interaction of the aza-macrocycles and the Zn2+ metal complexes with duplex DNA and RNA was studied using UV thermal and fluorescence indicator displacement assays in combination with theoretical studies. Both ligands show a high affinity for ds-DNA/RNA and selectivity for ds-RNA. The ability to interact with these duplexes is blocked upon Zn2+ coordination, which was confirmed by the low variation in the melting temperature and poor displacement of the fluorescent dye from the ds-DNA/RNA. Cell viability assays show a decrease in the cytotoxicity of the metal complexes in comparison with the free ligands, which can be associated with the observed binding to the nucleic acids.

show abstract

“…Still, highly speci c RNA/ligand pairs can nd broad use in diverse applications. As interest in RNA as a target for small molecule drugs has increased, so has the need for information about the design of RNA-targeting probes [22][23][24] . Understanding the chemical features that impact RNA crosslinking e ciency would in uence probe design, as well inform interpretation of results from experiments that use these probes.…”

Section: Introductionmentioning

confidence: 99%

A Chemical Probe Based on the PreQ1 Metabolite Enables Transcriptome-wide Mapping of Binding Sites

Balaratnam¹,

Rhodes²,

Bume³

et al. 2021

Preprint

View full text Add to dashboard Cite

The role of metabolite-responsive riboswitches in regulating gene expression in bacteria is well known and makes them useful systems for the study of RNA-small molecule interactions. Here, we study the PreQ1 riboswitch system, assessing sixteen diverse PreQ1-derived probes for their ability to selectively modify the riboswitch aptamer covalently. For the most active probe, a diazirine-based photocrosslinker, X-ray crystallography and gel-based competition assays demonstrated the mode of binding of the ligand to the aptamer, and functional assays demonstrated that the probe retains activity against the full riboswitch. Transcriptome-wide mapping using Chem-CLIP revealed a highly selective interaction between the bacterial aptamer and the small molecule. In addition, a small number of RNA targets in endogenous human transcripts were found to bind specifically to PreQ1, providing evidence for candidate PreQ1 aptamers in human RNA. This work demonstrates a stark influence of linker chemistry and structure on the ability of molecules to crosslink RNA, reveals that the PreQ1 aptamer/ligand pair are broadly useful for chemical biology applications, and provides insights into how PreQ1 interacts with human RNAs.

show abstract

Small molecule recognition of disease-relevant RNA structures

Abstract: Targeting RNAs with small molecules, a new frontier in drug discovery and development.

Cited by 121 publications

References 198 publications

From Junk to Function: LncRNAs in CNS Health and Disease

From Junk to Function: LncRNAs in CNS Health and Disease

Ditopic Aza-Scorpiand Ligands Interact Selectively with ds-RNA and Modulate the Interaction upon Formation of Zn2+ Complexes

A Chemical Probe Based on the PreQ1 Metabolite Enables Transcriptome-wide Mapping of Binding Sites

Contact Info

Product

Resources

About