Probing A-form DNA: A fluorescent aminosugar probe and dual recognition by anthraquinone-neomycin conjugates

Watkins, Davita L.; Gong, Changjun; Kellish, Patrick; Arya, Dev P.

doi:10.1016/j.bmc.2016.11.003

Cited by 19 publications

(19 citation statements)

References 46 publications

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“…Previously, we developed a fluorescent probe displacement assay using fluorescein conjugated to neomycin (F-neo) to screen various novel small molecules for binding nucleic acids in a high throughput format. [37][38][39][40][41][42] We have used this fluorescence displacement assay to screen the PA-Kan conjugate library for binding to pre-miR21. The stoichiometry of F-neo binding to pre-miR21 was determined by addition of increasing concentrations of pre-miR21 with 100 nM F-neo.…”

Section: In Vitro Screening Resultsmentioning

confidence: 99%

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

et al. 2018

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Epithelial to mesenchymal transition (EMT) is a process in which epithelial cells lose cell polarity and cell-cell adhesion and gain migratory and invasive properties to become mesenchymal cells that are very vital for development, wound healing and stem cell behavior and contribute pathologically to fibrosis and cancer progression. miR21, a potent regulator of the tumor suppressor gene PTEN, can be silenced to reverse EMT, thereby providing an attractive target for abrogating the malignant behavior of breast cancer. Here, we report the design, synthesis and binding of a peptidic-aminoglycoside (PA) based chemical library against pre-miR21 that led to the identification of a group of small molecules that bind to pre-miR21 with high affinities and antagonize miR-21 maturation and function, thereby reversing EMT. The approach described here offers a promising miRNA targeting platform where such aminosugar conjugates can be similarly used to target other oncogenic miRNAs. Minor changes in the amino acid sequence allow us to tailor the binding effectiveness and downstream biological effects, thus making this approach a potentially tunable method of regulation of miRNA function.

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Section: In Vitro Screening Resultsmentioning

confidence: 99%

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

et al. 2018

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“…Compound purity was verified by RP-HPLC and HPLC purity profiles and has been reported previously. 31 …”

Section: Figurementioning

confidence: 99%

Antimicrobial Activity, AME Resistance, and A-Site Binding Studies of Anthraquinone–Neomycin Conjugates

et al. 2017

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The antibacterial effects of aminoglycosides are based on their association with the A-site of bacterial rRNA and interference with the translational process in the bacterial cell, causing cell death. The clinical use of aminoglycosides is complicated by resistance and side effects, some of which arise from their interactions with the human mitochondrial 12S rRNA and its deafness-associated mutations, C1494U and A1555G. We report a rapid assay that allows screening of aminoglycoside compounds to these classes of rRNAs. These screening tools are important to find antibiotics that selectively bind to the bacterial A-site rather than human, mitochondrial A-sites and its mutant homologues. Herein, we report our preliminary work on the optimization of this screen using 12 anthraquinone–neomycin (AMA–NEO) conjugates against molecular constructs representing five A-site homologues, Escherichia coli, human cytosolic, mitochondrial, C1494U, and A1555G, using a fluorescent displacement screening assay. These conjugates were also tested for inhibition of protein synthesis, antibacterial activity against 14 clinically relevant bacterial strains, and the effect on enzymes that inactivate aminoglycosides. The AMA–NEO conjugates demonstrated significantly improved resistance against aminoglycoside-modifying enzymes (AMEs), as compared with NEO. Several compounds exhibited significantly greater inhibition of prokaryotic protein synthesis as compared to NEO and were extremely poor inhibitors of eukaryotic translation. There was significant variation in antibacterial activity and MIC of selected compounds between bacterial strains, with Escherichia coli, Enteroccocus faecalis, Citrobacter freundii, Shigella flexneri, Serratia marcescens, Proteus mirabilis, Enterobacter cloacae, Staphylococcus epidermidis, and Listeria monocytogenes exhibiting moderate to high sensitivity (50–100% growth inhibition) whereas Acinetobacter baumannii, Pseudomonas aeruginosa, Klebsiellla pneumoniae, and MRSA strains expressed low sensitivity, as compared to the parent aminoglycoside NEO.

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“…We have reported the synthesis and RNA binding of a diverse series of aminoglycoside derivatives. 48,50,[52][53][54][55][56][57][58][59][60][61][62][63] A number of these studies identified promising RNA binders where aromatic units were covalently attached to the amino-glycoside. Here in this study, we report the comparative cellular studies of 13 aromatic-neomycin conjugates (Figure 1) identified via a miR-21 displacement assay using F-neo, a reporter molecule.…”

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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Probing A-form DNA: A fluorescent aminosugar probe and dual recognition by anthraquinone-neomycin conjugates

Cited by 19 publications

References 46 publications

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

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

Antimicrobial Activity, AME Resistance, and A-Site Binding Studies of Anthraquinone–Neomycin Conjugates

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

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