Targeting miRNA by tunable small molecule binders: peptidic aminosugar mediated interference in miR-21 biogenesis reverts epithelial to mesenchymal transition

Ghosh, Arpita; Degyatoreva, Natalya; Kukielski, Casey; Story, Sandra; Bhaduri, Sayantan; Maiti, Krishnagopal; Nahar, Smita; A, Ray; Arya, Dev P.; Maiti, Souvik

doi:10.1039/c8md00092a

Cited by 18 publications

(18 citation statements)

References 41 publications

(50 reference statements)

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“…It is worth noting that combination of small molecule modifiers of miRNAs with oligonucleotides could also enhance miRNA-targeted therapeutics [99,100]. Moreover, small molecules could also be hybridized with peptide to inhibit the maturation of pre-miRNA, thereby reversing miRNA function in disease development [101]. Currently reported studies mainly focused on the identification of small molecules that target cancer-related miRNAs and using them for cancer treatment.…”

Section: Discussionmentioning

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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Section: Discussionmentioning

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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“…The use of small molecule chemicals has gained much attention recently to initiate and alter the cellular changes between mesenchymal and epithelial phenotypes, and to regulate cell fate as well as to facilitate target gene reprogramming [53,54]. We reported a MET protocol antagonizing GSK3 (glycogen synthase kinase 3) and TGFβ (transforming growth factor β) pathways (using a combination of valproic acid, A-83-01, CHIR99021, RepSox, tranylcypromine and all-trans retinoic acid) to generate corneal epithelial progenitors (MET-Epi) from human adipose MSCs [55].…”

Section: Mscs In Corneal Regenerationmentioning

confidence: 99%

Current Trends and Future Perspective of Mesenchymal Stem Cells and Exosomes in Corneal Diseases

Mansoor

Ong

Riau

et al. 2019

IJMS

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The corneal functions (transparency, refractivity and mechanical strength) deteriorate in many corneal diseases but can be restored after corneal transplantation (penetrating and lamellar keratoplasties). However, the global shortage of transplantable donor corneas remains significant and patients are subject to life-long risk of immune response and graft rejection. Various studies have shown the differentiation of multipotent mesenchymal stem cells (MSCs) into various corneal cell types. With the unique properties of immunomodulation, anti-angiogenesis and anti-inflammation, they offer the advantages in corneal reconstruction. These effects are widely mediated by MSC differentiation and paracrine signaling via exosomes. Besides the cell-free nature of exosomes in circumventing the problems of cell-fate control and tumorigenesis, the vesicle content can be genetically modified for optimal therapeutic affinity. The pharmacology and toxicology, xeno-free processing with sustained delivery, scale-up production in compliant to Good Manufacturing Practice regulations, and cost-effectiveness are the current foci of research. Routes of administration via injection, topical and/or engineered bioscaffolds are also explored for its applicability in treating corneal diseases.

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“…49 Their easy delivery and uptake with lower diffusion and dissociation rates within cells gave them an upper hand over antisense miRs. Added advantages, such as longer stability and minimal toxicity [50][51][52] made them more suitable. Small molecules bind to the bulged loop structure of the pre-miR sequence and competes with Dicer for binding, thereby hindering it to process the miR into mature form.…”

Section: Introductionmentioning

confidence: 99%

Fine-tuning miR-21 expression and inhibition of EMT in breast cancer cells using aromatic-neomycin derivatives

Ghosh

Ranjan

Jiang

et al. 2022

Molecular Therapy - Nucleic Acids

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MicroRNAs (miRs) are a class of endogenously expressed noncoding RNAs that negatively regulate gene expression within cells and participate in maintaining cellular homeostasis. By targeting 3 0 UTRs of target genes, individual miRs can control a wide array of gene expressions. Previous research has shed light upon the fact that aberrantly expressed miRs within cells can pertain to diseased conditions, such as cancer. Malignancies caused due to miRs are because of the high expression of onco-miRs or feeble expression of tumor-suppressing miRs. Studies have also shown miRs to engage in epithelial to mesenchymal transition (EMT), which allows cancer cells to become more invasive and metastasize. miR-21 is an onco-miR highly expressed in breast cancer cells and targets protein PTEN, which abrogates EMT. Therefore, we discuss an approach where in-house-developed peptidic amino sugar molecules have been used to target pre-miR-21 to inhibit miR-21 biogenesis, and hence antagonize its tumor-causing effect and inhibit EMT. Our study shows that small-molecule-based fine-tuning of miR expression can cause genotypic as well as phenotypic changes and also reinstates the potential and importance of nucleic acid therapeutics.

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Targeting miRNA by tunable small molecule binders: peptidic aminosugar mediated interference in miR-21 biogenesis reverts epithelial to mesenchymal transition

Cited by 18 publications

References 41 publications

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

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

Current Trends and Future Perspective of Mesenchymal Stem Cells and Exosomes in Corneal Diseases

Fine-tuning miR-21 expression and inhibition of EMT in breast cancer cells using aromatic-neomycin derivatives

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