Approaches for the Discovery of Small Molecule Ligands Targeting microRNAs

Lorenz, Daniel A.; Garner, Amanda L.

doi:10.1007/7355_2017_3

Cited by 14 publications

(11 citation statements)

References 156 publications

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“…40 The repression of aberrantly upregulated miRNAs by inhibiting Dicer cleavage of targeted pre-miRNAs has been postulated as a possible intervention point in miRNA biogenesis, and several assays to identify putative inhibitors have been described. 41 These assays have all employed light-based detection methods, that is, fluorescence or chemiluminescence. A functional MS-based assay would provide several notable advantages, including the elimination of fluorescence interference, the detection of noncanonical cleavage by Dicer, and the ability to multiplex through the addition of several pre-miRNAs.…”

Section: Resultsmentioning

confidence: 99%

High-Throughput Amenable MALDI-MS Detection of RNA and DNA with On-Surface Analyte Enrichment Using Fluorous Partitioning

et al. 2021

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Section: Resultsmentioning

confidence: 99%

High-Throughput Amenable MALDI-MS Detection of RNA and DNA with On-Surface Analyte Enrichment Using Fluorous Partitioning

et al. 2021

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“…19 MicroRNAs (miRNAs) are a class of small RNAs that play key roles in the regulation of gene expression, and alteration of miRNA levels has been linked to many human diseases. 68–70 In order to be active, miRNAs undergo two maturation steps, one in the nucleus (pri-miRNA to pre-miRNA) and one in the cytoplasm (pre-miRNA to mature miRNA), mediated by the RNase III enzymes Drosha and Dicer, respectively. 68 Since cat-ELCCA is a functional biochemical assay, the team developed a method by which to monitor Dicer-mediated pre-miRNA maturation and discover small molecule inhibitors of this process.…”

Section: Application Of Click Chemistry For Biochemical Assay Devementioning

confidence: 99%

“…With respect to RNA assays, most are binding-based and do not measure functional inhibition. 70 Moreover, they are often constructed using small molecule microarray, which utilizes immobilized compounds, thereby limiting the number and structural diversity of molecules that can be tested. 70, 71 Because cat-ELCCA uses immobilized RNA and is not subject to compound interference, it should enable HTS of any chemical library.…”

Section: Application Of Click Chemistry For Biochemical Assay Devementioning

confidence: 99%

“…70 Moreover, they are often constructed using small molecule microarray, which utilizes immobilized compounds, thereby limiting the number and structural diversity of molecules that can be tested. 70, 71 Because cat-ELCCA uses immobilized RNA and is not subject to compound interference, it should enable HTS of any chemical library. Of greater significance for RNA targeting, cat-ELCCA enables the possibility of multi-dimensional screening, as any biotinylated pre-miRNA could be used as a substrate.…”

Section: Application Of Click Chemistry For Biochemical Assay Devementioning

confidence: 99%

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cat-ELCCA: catalyzing drug discovery through click chemistry

Garner

2018

Chem. Commun.

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Click chemistry has emerged as a powerful tool in our arsenal for unlocking new biology. This includes its utility in both chemical biology and drug discovery. An emerging application of click chemistry is in the development of biochemical assays for high-throughput screening to identify new chemical probes and drug leads. This Feature Article will discuss the advancements in click chemistry that were necessary for the development of a new class of biochemical assay, catalytic enzyme-linked click chemistry assay or cat-ELCCA. Inspired by enzyme immunoassays, cat-ELCCA was designed as a click chemistry-based amplification assay where bioorthogonally-tagged analytes and enzymes are used in place of the enzyme-linked secondary antibodies used in immunoassays. The result is a robust assay format with demonstrated applicability in several important areas of biology and drug discovery, including post-translational modifications, pre-microRNA maturation, and protein-protein and RNA-protein interactions. Through the use of cat-ELCCA and other related click chemistry-based assays, new chemical probes for interrogating promising drug targets have been discovered. These examples will be discussed, in addition to a future outlook on the impact of this approach in probe and drug discovery.

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“…For miRNAs, the complexity of miRNA-mRNA networks and their critical roles in human diseases require proper and efficient tools for elucidation of these networks and regulation of miRNAs for therapeutic treatments. Even though RNAs have long been considered as undruggable targets for small molecules, recent work indicate that miRNAs can be targeted by small molecules obtained from high-throughput screening or appropriate design [30][31][32][33][34][35][36]. In this review paper, we will summarize current strategies for discovery of small molecule modifiers of miRNAs, their mechanisms of action and their use in probing miRNA-mRNA network and miRNA-targeted therapeutics.…”

Section: Introductionmentioning

confidence: 99%

Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics

Fan¹,

Xiao²,

Wan

et al. 2019

RNA Biology

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MicroRNAs (miRNAs) are small, non-coding RNAs that post-transcriptionally regulate gene expression. Aberrant miRNA expression or function have close links with various human diseases. Therefore, therapeutic treatments with disease-associated miRNAs as targets are emerging. However, the intracellular miRNA networks are extremely complicated and poorly understood, which thus hinder the development of miRNA-targeted therapeutics. Small molecules that are able to regulate endogenous miRNAs hold great potential in both elucidation of miRNA networks and treatment of miRNA-related diseases. Herein, we summarize current strategies for discovery of small molecule modifiers of miRNAs, and we highlight aspects of miRNA cellular biology elucidated by using these small molecules and miRNAtargeted therapeutics realized by these small molecules. We envision that this area will expand dramatically in the near future and will ultimately contribute to a better understanding of miRNAinvolved cellular processes and development of therapeutic agents for miRNA-associated diseases.

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Approaches for the Discovery of Small Molecule Ligands Targeting microRNAs

Cited by 14 publications

References 156 publications

High-Throughput Amenable MALDI-MS Detection of RNA and DNA with On-Surface Analyte Enrichment Using Fluorous Partitioning

High-Throughput Amenable MALDI-MS Detection of RNA and DNA with On-Surface Analyte Enrichment Using Fluorous Partitioning

cat-ELCCA: catalyzing drug discovery through click chemistry

Small molecules with big roles in microRNA chemical biology and microRNA-targeted therapeutics

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