Bifunctional small molecule-oligonucleotide hybrid as microRNA inhibitor

Bhattarai, Umesh; Hsieh, Wei-Che; Hao, Yan; Guo, Zhi-Fo; Shaikh, Ashif Y.; Soltani, Aria; Song, Yabin; Ly, Danith H.; Liang, Fu‐Sen

doi:10.1016/j.bmc.2020.115394

Cited by 9 publications

(9 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Our bioinformatics analysis revealed that ∼20% of human pre-miRNAs are predicted to contain junction regions, and therefore may by targetable using this antisense oligo approach. Previous studies using ASOs that targeted the apical loop of pre-miR-21 had no impact on Dicer/TRBP cleavage (29). Interestingly, unlike pre-miR-31 and pre-miR-144, pre-miR-21 does not contain a junction structure.…”

Section: Discussionmentioning

confidence: 92%

“…ASOs that bind to the apical loop region and block the dicing sites of pre-miR-16, pre-miR-15a, and pre-miR-125b, are effective inhibitors of Dicer/TRBP processing (28). However, ASOs that do not span the dicing site, binding only to the apical loop region, appear to have no effect of the Dicer/TRBP processing of pre-miR-21 (29). We therefore sought to examine the common features of pre-miRNAs that make them suitable targets for ASO steric blocking and cleavage inhibition.…”

Section: Introductionmentioning

confidence: 99%

See 1 more Smart Citation

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

Ma,

Howden,

Keane

2024

Preprint

View full text Add to dashboard Cite

Antisense oligonucleotides (ASOs) are widely used as therapeutics for neurodegenerative diseases, cancers, and virus infections. One class of ASOs functions to enhance protein expression by sequestering the mature microRNA (miRNA) in a double-stranded structure within the RNA-induced silencing complex (RISC). An alternative approach for the targeted control of gene expression is to use ASOs that bind to the pre-elements of miRNAs (pre-miRNAs) and modulate their enzymatic processing. Here, we demonstrate that ASOs can be used to disrupt a specific structural feature, “junction,” within pre-miR-31 that is important in directing efficient processing by the Dicer/TRBP complex. Furthermore, we extend and validate this strategy to pre-miR-144, which has a similar junction-dependent structure-function relationship. We found that a significant number of human pre-miRNAs are predicted to contain junctions, and validated our ASO approach on several members of this group. Importantly, we also verified the application of junction-targeting ASOs for the specific inhibition of pre-miRNA processingin cell. Our study reemphasizes the important roles of RNA structure in regulating Dicer/TRBP processing of pre-miRNAs and provides the framework to develop structure-informed ASOs that serve to inhibit miRNA production.

show abstract

Section: Discussionmentioning

confidence: 92%

Section: Introductionmentioning

confidence: 99%

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

Ma,

Howden,

Keane

2024

Preprint

View full text Add to dashboard Cite

show abstract

“…Bifunctional Dicer inhibitors allow specific inhibition of processing of a selected target RNA, avoiding affecting all canonically generated miRNAs by Dicer inhibition. The bifunctional inhibitors consist of an RNA-binding molecule and a weak Dicer inhibitor. − The reported Dicer inhibitors were derived from pharmacophores of other endoribonuclease III inhibitors initially developed against influenza endonuclease and harbor the typical metal-chelating three oxygen pharmacophore . Aminoglycosides neomycin and kanamycin were employed as the RNA-binding molecules to target the oncogenic miRNA miR-21. , The specificity of such bifunctional Dicer inhibitors was increased using antisense oligonucleotides, which alone did not inhibit the processing of pre-miR-21 by Dicer .…”

Section: Bifunctional Molecules Targeting Rnasesmentioning

confidence: 99%

“…The bifunctional inhibitors consist of an RNA-binding molecule and a weak Dicer inhibitor. − The reported Dicer inhibitors were derived from pharmacophores of other endoribonuclease III inhibitors initially developed against influenza endonuclease and harbor the typical metal-chelating three oxygen pharmacophore . Aminoglycosides neomycin and kanamycin were employed as the RNA-binding molecules to target the oncogenic miRNA miR-21. , The specificity of such bifunctional Dicer inhibitors was increased using antisense oligonucleotides, which alone did not inhibit the processing of pre-miR-21 by Dicer . A following study showed the possibility of incorporating a light-cleavable linker in the bifunctional molecule to deactivate the inhibitory activity by light …”

Section: Bifunctional Molecules Targeting Rnasesmentioning

confidence: 99%

Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

Borgelt

2023

ACS Chem. Biol.

View full text Add to dashboard Cite

Ribonucleases (RNases) cleave and process RNAs, thereby regulating the biogenesis, metabolism, and degradation of coding and noncoding RNAs. Thus, small molecules targeting RNases have the potential to perturb RNA biology, and RNases have been studied as therapeutic targets of antibiotics, antivirals, and agents for autoimmune diseases and cancers. Additionally, the recent advances in chemically induced proximity approaches have led to the discovery of bifunctional molecules that target RNases to achieve RNA degradation or inhibit RNA processing. Here, we summarize the efforts that have been made to discover small-molecule inhibitors and activators targeting bacterial, viral, and human RNases. We also highlight the emerging examples of RNase-targeting bifunctional molecules and discuss the trends in developing such molecules for both biological and therapeutic applications.

show abstract

“…Furthermore, exon skipping could also be used to coordinate the downregulation of a protein, thus allowing for the directed targeting of pathological isoforms. Due to their potential and thus popularity amongst researchers, a range of oligonucleotide-based therapies have been developed and extensively reviewed, including spliceosome-mediated RNA trans-splicing (SMaRT) technologies [ 75 ], antisense oligonucleotides (ASOs) [ 76 ] and bifunctional oligonucleotides [ 77 ] to name a few. Oligonucleotides therefore have great potential as therapeutics for a range of diseases through directly targeting specific splice sites.…”

Section: Alternative Splicing Based Therapeutic Strategiesmentioning

confidence: 99%

Alternative Splicing: A Key Mediator of Diabetic Vasculopathy

Cornelius¹,

Fulton²,

Margariti³

2021

Genes

View full text Add to dashboard Cite

Cardiovascular disease is the leading cause of death amongst diabetic individuals. Atherosclerosis is the prominent driver of diabetic vascular complications, which is triggered by the detrimental effects of hyperglycemia and oxidative stress on the vasculature. Research has extensively shown diabetes to result in the malfunction of the endothelium, the main component of blood vessels, causing severe vascular complications. The pathogenic mechanism in which diabetes induces vascular dysfunction, however, remains largely unclear. Alternative splicing of protein coding pre-mRNAs is an essential regulatory mechanism of gene expression and is accepted to be intertwined with cellular physiology. Recently, a role for alternative splicing has arisen within vascular health, with aberrant mis-splicing having a critical role in disease development, including in atherosclerosis. This review focuses on the current knowledge of alternative splicing and the roles of alternatively spliced isoforms within the vasculature, with a particular focus on disease states. Furthermore, we explore the recent elucidation of the alternatively spliced QKI gene within vascular cell physiology and the onset of diabetic vasculopathy. Potential therapeutic strategies to restore aberrant splicing are also discussed.

show abstract

Bifunctional small molecule-oligonucleotide hybrid as microRNA inhibitor

Cited by 9 publications

References 39 publications

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

Use of steric blocking antisense oligonucleotides for the targeted inhibition of junction containing precursor microRNAs

Targeting Ribonucleases with Small Molecules and Bifunctional Molecules

Alternative Splicing: A Key Mediator of Diabetic Vasculopathy

Contact Info

Product

Resources

About