Browse
Submit Data
Databases
API
Help

Dataset Information

18 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Small molecule recognition of disease-relevant RNA structures.

ABSTRACT: Targeting RNAs with small molecules represents a new frontier in drug discovery and development. The rich structural diversity of folded RNAs offers a nearly unlimited reservoir of targets for small molecules to bind, similar to small molecule occupancy of protein binding pockets, thus creating the potential to modulate human biology. Although the bacterial ribosome has historically been the most well exploited RNA target, advances in RNA sequencing technologies and a growing understanding of RNA structure have led to an explosion of interest in the direct targeting of human pathological RNAs. This review highlights recent advances in this area, with a focus on the design of small molecule probes that selectively engage structures within disease-causing RNAs, with micromolar to nanomolar affinity. Additionally, we explore emerging RNA-target strategies, such as bleomycin A5 conjugates and ribonuclease targeting chimeras (RIBOTACs), that allow for the targeted degradation of RNAs with impressive potency and selectivity. The compounds discussed in this review have proven efficacious in human cell lines, patient-derived cells, and pre-clinical animal models, with one compound currently undergoing a Phase II clinical trial and another that recently garnerd FDA-approval, indicating a bright future for targeted small molecule therapeutics that affect RNA function.

SUBMITTER: Meyer SM

PROVIDER: S-EPMC7717589 | biostudies-literature |

REPOSITORIES: biostudies-literature

ACCESS DATA

Json Xml

Similar Datasets

Selective Small Molecule Recognition of RNA Base Pairs.

Project description:Many types of RNAs exist in the human transcriptome, yet only the bacterial ribosome has been exploited as a small molecule drug target. Aside from rRNA, other cellular RNAs such as noncoding RNAs have primarily secondary structure and limited tertiary structure. Within these secondary structures of noncanonically paired and unpaired regions, more than 50% are base paired, with most efforts to target these structures focused on looped regions. A void exists in the availability of small molecules capable of targeting RNA base pairs. Using chemoinformatics, an RNA-focused library enriched for nitrogen-containing heterocycles was developed and tested for binding RNA base pairs, leading to the identification of six selective and previously unknown binders. While all binders were derivatives of benzimidazoles, those with expanded aromatic polycycles bound selectively to AU pairs, while those with flexible urea side chains bound selectively to GC pairs. Two of the three selective GC pair binders can distinguish between two different orientations, 5'GG/3'CC and 5'GC/3'CG pairs. Furthermore, all six molecules showed >50-fold selectivity for RNA over DNA. These studies provide foundational knowledge to better exploit RNA as targets for small molecule chemical probes or lead therapeutics by using modules that target RNA base pairs.

| S-EPMC6325646 | biostudies-literature

Small molecule ligands for bulged RNA secondary structures.

Project description:A class of wedge-shaped small molecules has been designed, synthesized, and shown to bind bulged RNA secondary structures. These minimally cationic ligands exhibit good affinity and selectivity for certain RNA bulges as demonstrated in a fluorescent intercalator displacement assay.

| S-EPMC4975938 | biostudies-literature

Small Molecule-Based Pattern Recognition To Classify RNA Structure.

Project description:Three-dimensional RNA structures are notoriously difficult to determine, and the link between secondary structure and RNA conformation is only beginning to be understood. These challenges have hindered the identification of guiding principles for small molecule:RNA recognition. We herein demonstrate that the strong and differential binding ability of aminoglycosides to RNA structures can be used to classify five canonical RNA secondary structure motifs through principal component analysis (PCA). In these analyses, the aminoglycosides act as receptors, while RNA structures labeled with a benzofuranyluridine fluorophore act as analytes. Complete (100%) predictive ability for this RNA training set was achieved by incorporating two exhaustively guanidinylated aminoglycosides into the receptor library. The PCA was then externally validated using biologically relevant RNA constructs. In bulge-stem-loop constructs of HIV-1 transactivation response element (TAR) RNA, we achieved nucleotide-specific classification of two independent secondary structure motifs. Furthermore, examination of cheminformatic parameters and PCA loading factors revealed trends in aminoglycoside:RNA recognition, including the importance of shape-based discrimination, and suggested the potential for size and sequence discrimination within RNA structural motifs. These studies present a new approach to classifying RNA structure and provide direct evidence that RNA topology, in addition to sequence, is critical for the molecular recognition of RNA.

| S-EPMC5465965 | biostudies-literature

Small molecule targeting of RNA structures in neurological disorders.

Project description:Aberrant RNA structure and function operate in neurological disease progression and severity. As RNA contributes to disease pathology in a complex fashion, that is, via various mechanisms, it has become an attractive therapeutic target for small molecules and oligonucleotides. In this review, we discuss the identification of RNA structures that cause or contribute to neurological diseases as well as recent progress toward the development of small molecules that target them, including small molecule modulators of pre-mRNA splicing and RNA repeat expansions that cause microsatellite disorders such as Huntington's disease and amyotrophic lateral sclerosis. The use of oligonucleotide-based modalities is also discussed. There are key differences between small molecule and oligonucleotide targeting of RNA. The former targets RNA structure, while the latter prefers unstructured regions. Thus, some targets will be preferentially targeted by oligonucleotides and others by small molecules.

| S-EPMC6785366 | biostudies-literature

Recognition of small molecule-RNA binding sites using RNA sequence and structure.

Project description:MotivationRNA molecules become attractive small-molecule drug targets to treat disease in recent years. Computer-aided drug design can be facilitated by detecting the RNA sites that bind small molecules. However, very limited progress has been reported for the prediction of small molecule-RNA binding sites.ResultsWe developed a novel method RNAsite to predict small molecule-RNA binding sites using sequence profile- and structure-based descriptors. RNAsite was shown to be competitive with the state-of-the-art methods on the experimental structures of two independent test sets. When predicted structure models were used, RNAsite outperforms other methods by a large margin. The possibility of improving RNAsite by geometry-based binding pocket detection was investigated. The influence of RNA structure's flexibility and the conformational changes caused by ligand binding on RNAsite were also discussed. RNAsite is anticipated to be a useful tool for the design of RNA-targeting small molecule drugs.Availability and implementationhttp://yanglab.nankai.edu.cn/RNAsite.Supplementary informationSupplementary data are available at Bioinformatics online.

| S-EPMC8034527 | biostudies-literature

Systematic analysis of the interactions driving small molecule-RNA recognition.

Project description:RNA molecules are becoming an important target class in drug discovery. However, the principles for designing RNA-binding small molecules are yet to be fully uncovered. In this study, we examined the Protein Data Bank (PDB) to highlight privileged interactions underlying small molecule-RNA recognition. By comparing this analysis with previously determined small molecule-protein interactions, we find that RNA recognition is driven mostly by stacking and hydrogen bonding interactions, while protein recognition is instead driven by hydrophobic effects. Furthermore, we analyze patterns of interactions to highlight potential strategies to tune RNA recognition, such as stacking and cation-π interactions that favor purine and guanine recognition, and note an unexpected paucity of backbone interactions, even for cationic ligands. Collectively, this work provides further understanding of RNA-small molecule interactions that may inform the design of small molecules targeting RNA.

| S-EPMC7549050 | biostudies-literature

Precise small-molecule recognition of a toxic CUG RNA repeat expansion.

Project description:Excluding the ribosome and riboswitches, developing small molecules that selectively target RNA is a longstanding problem in chemical biology. A typical cellular RNA is difficult to target because it has little tertiary, but abundant secondary structure. We designed allele-selective compounds that target such an RNA, the toxic noncoding repeat expansion (r(CUG)exp) that causes myotonic dystrophy type 1 (DM1). We developed several strategies to generate allele-selective small molecules, including non-covalent binding, covalent binding, cleavage and on-site probe synthesis. Covalent binding and cleavage enabled target profiling in cells derived from individuals with DM1, showing precise recognition of r(CUG)exp. In the on-site probe synthesis approach, small molecules bound adjacent sites in r(CUG)exp and reacted to afford picomolar inhibitors via a proximity-based click reaction only in DM1-affected cells. We expanded this approach to image r(CUG)exp in its natural context.

| S-EPMC5290590 | biostudies-literature

Structures of active-state orexin receptor 2 rationalize peptide and small-molecule agonist recognition and receptor activation.

Project description:Narcolepsy type 1 (NT1) is a chronic neurological disorder that impairs the brain's ability to control sleep-wake cycles. Current therapies are limited to the management of symptoms with modest effectiveness and substantial adverse effects. Agonists of the orexin receptor 2 (OX2R) have shown promise as novel therapeutics that directly target the pathophysiology of the disease. However, identification of drug-like OX2R agonists has proven difficult. Here we report cryo-electron microscopy structures of active-state OX2R bound to an endogenous peptide agonist and a small-molecule agonist. The extended carboxy-terminal segment of the peptide reaches into the core of OX2R to stabilize an active conformation, while the small-molecule agonist binds deep inside the orthosteric pocket, making similar key interactions. Comparison with antagonist-bound OX2R suggests a molecular mechanism that rationalizes both receptor activation and inhibition. Our results enable structure-based discovery of therapeutic orexin agonists for the treatment of NT1 and other hypersomnia disorders.

| S-EPMC7864924 | biostudies-literature

Covalent small-molecule-RNA complex formation enables cellular profiling of small-molecule-RNA interactions.

Project description:Won't let you go! A strategy is described to design small molecules that react with their cellular RNA targets. This approach not only improves the activity of compounds targeting RNA in cell culture by a factor of about 2500 but also enables cell-wide profiling of its RNA targets.

| S-EPMC3876275 | biostudies-literature

Aptamer Recognition of Multiplexed Small-Molecule-Functionalized Substrates.

Project description:Aptamers are chemically synthesized oligonucleotides or peptides with molecular recognition capabilities. We investigated recognition of substrate-tethered small-molecule targets, using neurotransmitters as examples, and fluorescently labeled DNA aptamers. Substrate regions patterned via microfluidic channels with dopamine or ??l-tryptophan were selectively recognized by previously identified dopamine or l-tryptophan aptamers, respectively. The on-substrate dissociation constant determined for the dopamine aptamer was comparable to, though, slightly greater than the previously determined solution dissociation constant. Using prefunctionalized neurotransmitter-conjugated oligo(ethylene glycol) alkanethiols and microfluidics patterning, we produced multiplexed substrates to capture and to sort aptamers. Substrates patterned with l-3,4-dihydroxyphenylalanine, l- threo-dihydroxyphenylserine, and l-5-hydroxytryptophan enabled comparison of the selectivity of the dopamine aptamer for different targets via simultaneous determination of in situ binding constants. Thus, beyond our previous demonstrations of recognition by protein binding partners (i.e., antibodies and G-protein-coupled receptors), strategically optimized small-molecule-functionalized substrates show selective recognition of nucleic acid binding partners. These substrates are useful for side-by-side target comparisons and future identification and characterization of novel aptamers targeting neurotransmitters or other important small molecules.

| S-EPMC6087467 | biostudies-literature

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data