Strategies for the Design of Rna-Binding Small Molecules

Aboul‐ela, Fareed

doi:10.4155/fmc.09.149

Cited by 73 publications

(60 citation statements)

References 234 publications

(284 reference statements)

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“…24,25 The benzimidazole scaffold is a privileged pharmacophore of many therapeutic agents. 26 Benzimidazole derivatives have also been shown to elicit a variety of pharmacological effects by interacting with RNA structural elements.…”

Section: Introductionmentioning

confidence: 99%

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

et al. 2015

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(2015) Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation, RNA Biology, 12:5, 555-568, DOI: 10.1080/15476286.2015 The internal ribosome entry site (IRES) element located at the 5´untranslated genomic region of various RNA viruses mediates cap-independent initiation of translation. Picornavirus IRES activity is highly dependent on both its structural organization and its interaction with host factors. Small molecules able to interfere with RNA function are valuable candidates for antiviral agents. Here we show that a small molecule based on benzimidazole (IRAB) inhibited foot-andmouth disease virus (FMDV) IRES-dependent protein synthesis in cells transfected with infectious RNA leading to a decrease of the virus titer, which was higher than that induced by a structurally related benzimidazole derivative. Interestingly, IRAB preferentially inhibited IRES-dependent translation in cell free systems in a dose-dependent manner. RNA structural analysis by SHAPE demonstrated an increased local flexibility of the IRES structure upon incubation with IRAB, which affected 3 stem-loops (SL) of domain 3. Fluorescence binding assays conducted with individual aminopurinelabeled oligoribonucleotides indicated that the SL3A binds IRAB (EC 50 18 mM). Taken together, the results derived from SHAPE reactivity and fluorescence binding assays suggested that the target site of IRAB within the FMDV IRES might be a folded RNA structure that involves the entire apical region of domain 3. Our data suggest that the conformational changes induced by this compound on a specific region of the IRES structure which is essential for its activity is, at least in part, responsible for the reduced IRES efficiency observed in cell free lysates and, particularly, in RNA-transfected cells.

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Section: Introductionmentioning

confidence: 99%

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

et al. 2015

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“…Considerable effort has been directed at finding compounds that target HIV-1 TAR RNA (Bannwarth and Gatignol 2005). Thus, RNA can be now considered an important class of potential therapeutic targets (for reviews, see Thomas and Hergenrother 2008;Aboul-ela 2010).…”

Section: Introductionmentioning

confidence: 99%

LigandRNA: computational predictor of RNA–ligand interactions

Philips

Milanowska

Łach

et al. 2013

RNA

104

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RNA molecules have recently become attractive as potential drug targets due to the increased awareness of their importance in key biological processes. The increase of the number of experimentally determined RNA 3D structures enabled structure-based searches for small molecules that can specifically bind to defined sites in RNA molecules, thereby blocking or otherwise modulating their function. However, as of yet, computational methods for structure-based docking of small molecule ligands to RNA molecules are not as well established as analogous methods for protein-ligand docking. This motivated us to create LigandRNA, a scoring function for the prediction of RNA-small molecule interactions. Our method employs a grid-based algorithm and a knowledge-based potential derived from ligand-binding sites in the experimentally solved RNA-ligand complexes. As an input, LigandRNA takes an RNA receptor file and a file with ligand poses. As an output, it returns a ranking of the poses according to their score. The predictive power of LigandRNA favorably compares to five other publicly available methods. We found that the combination of LigandRNA and Dock6 into a "meta-predictor" leads to further improvement in the identification of near-native ligand poses. The LigandRNA program is available free of charge as a web server at http:// ligandrna.genesilico.pl.

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“…[32][33][34][35] In addition, like proteins, RNA adopts complex three-dimensional structures that can be exploited to design specific small molecules to modulate its functions. [36][37][38] In recent years, microRNAs (miRNAs) have also emerged as new therapeutic targets for cancer therapy since the abnormal expression of these non-coding small RNAs is associated with the pathogenesis of human cancer. 39,40 Like other RNAs, miRNA precursors adopt secondary structures that can be targeted with small molecules, to interfere with miRNA maturation and, for instance, to manipulate miRNA levels.…”

Section: Introductionmentioning

confidence: 99%

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

et al. 2013

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&These two authors contributed equally to this work. ABSTRACTA straightforward methodology for the synthesis of conjugates between a cytotoxic organometallic ruthenium(II) complex and amino-and guanidinoglycosides, as potential RNA-targeted anticancer compounds, is described. Under microwave irradiation, the imidazole ligand incorporated on the aminoglycoside moiety (neamine or neomycin) was found to replace one triphenylphosphine ligand from the ruthenium precursor [(η 6 -p-cym)RuCl(PPh 3 ) 2 ] + , allowing the assembly of the target conjugates. The guanidinylated analogue was easily prepared from the neomycin-ruthenium conjugate by reaction with N,N'-di-Boc-N"-triflylguanidine, a powerful guanidinylating reagent that was compatible with the integrity of the metal complex. All conjugates were purified by semi-preparative HPLC and characterized by ESI and MALDI-TOF MS and NMR spectroscopy. The cytotoxicity of the compounds was tested in and DU-145 (prostate) human cancer cells, as well as in the normal HEK293 (Human Embryonic Kidney) cell line, revealing a dependence on the nature of the glycoside moiety and the type of cell (cancer or healthy). Indeed, neomycin-ruthenium conjugate (2) displayed moderate anti-proliferative activity in both cancer cell lines (IC 50 ≈ 80 µM), whereas that of the neamine conjugate (4) was inactive (IC 50 ≈ 200 µM).However, the guanidinylated analogue of the neomycin-ruthenium conjugate (3) required much lower concentrations than the parent conjugate for equal effect (IC 50 = 7.17 µM in DU-145 and IC 50 = 11.33 µM in MCF-7). Although the same ranking in anti-proliferative activity was found in the non-tumorigenic cell line (3 >> 2 > 4), IC 50 values indicate that aminoglycoside-containing conjugates are about 2-fold more cytotoxic in normal cells (e.g. IC 50 = 49.4 µM for 2) than in cancer cells, whereas an opposite tendency was found with the guanidinylated conjugate, since its cytotoxicity in the normal cell line (IC 50 = 12.75 µM for 3) was similar or even lower than that found in MCF-7 and DU-145 cancer cell lines, respectively. Cell uptake studies performed by ICP-MS with conjugates 2 and 3 revealed that guanidinylation of the neomycin moiety had a positive effect on accumulation (about 3-fold higher in DU-145 and 4-fold higher in HEK293), which correlates well with the higher anti-proliferative activity of 3.Interestingly, despite the slightly higher accumulation in the normal cell than in the cancer cell line (about 1.4-fold), guanidinoneomycin-ruthenium conjugate (3) was more cytotoxic to cancer cells (about 1.8-fold), whereas the opposite tendency applied for neomycin-ruthenium conjugate (2). Such differences in cytotoxic activity and cellular 3 accumulation between cancer and normal cells open the way to the creation of more selective, less toxic anticancer metallodrugs by conjugating cytotoxic metal-based complexes such as ruthenium(II) arene derivatives to guanidinoglycosides.

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Strategies for the Design of Rna-Binding Small Molecules

Cited by 73 publications

References 234 publications

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

Local RNA flexibility perturbation of the IRES element induced by a novel ligand inhibits viral RNA translation

LigandRNA: computational predictor of RNA–ligand interactions

Conjugation of a Ru(II) Arene Complex to Neomycin or to Guanidinoneomycin Leads to Compounds with Differential Cytotoxicities and Accumulation between Cancer and Normal Cells

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