RNA and the Small Molecule World

Tor, Yitzhak

doi:10.1002/(sici)1521-3773(19990601)38:11<1579::aid-anie1579>3.0.co;2-h

Cited by 75 publications

(14 citation statements)

References 19 publications

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“…Small molecules that specifically bind unique RNA sites and prevent the formation of key RNA ± protein complexes can modulate cell functions and are likely to be of therapeutic potential. [72] RNA is, however, a very dynamic and challenging target. Much remains to be revealed as RNA slowly gains acceptance as a valid therapeutic objective.…”

Section: Discussionmentioning

confidence: 99%

Targeting RNA with Small Molecules

2003

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Section: Discussionmentioning

confidence: 99%

Targeting RNA with Small Molecules

2003

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“…4,5 Such knowledge is necessary to advance the understanding of RNA-small molecule recognition and for the continued development of small organic molecules as modulators of cellular processes at the RNA level. 6,7 The hammerhead ribozyme (HH) is one of the best characterized RNA enzymes. 8À10 A wealth of information regarding its conserved base requirements, kinetics, mechanisms and structure is available.…”

Section: Introductionmentioning

confidence: 99%

2-Aminopurine as a real-time probe of enzymatic cleavage and inhibition of hammerhead ribozymes

Kirk

2001

Bioorganic &Amp; Medicinal Chemistry

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Abstract-The design, synthesis and study of internally fluorescent hammerhead (HH) ribozymes, where changes in fluorescence parameters directly reflect the progress of the ribozyme's cleavage chemistry, are described. The approach relies on a HH substrate modified at position 1.1, proximal to the cleavage site, with 2-aminopurine (2AP), an intensely fluorescent adenosine isoster. The incorporation of 2AP, an unnatural nucleoside, does not interfere with the ribozyme folding and catalysis. Since 2AP is highly sensitive to environmental changes, its fluorescence is dramatically altered upon ribozyme-mediated cleavage of the substrate. This generates a measurable signal that directly reflects the progress of the ribozyme's reaction in real time. Identical pseudo first order rate constants are obtained for HH constructs using both continuous fluorescence monitoring and radioactive labeling. This rapid and real-time monitoring facilitates the study of ribozyme activity under different conditions (e.g., ionic strength, pH, etc.), and provides a useful assay to rapidly screen potential inhibitors. Three hitherto unknown HH inhibitors are presented and compared to neomycin B and chlortetracycline, two previously studied HH inhibitors. All three new small molecules, neo-acridine, guanidinoneomycin B, and [Á-(Eilatin)Ru(bpy) 2 ] 2+ , prove to be better inhibitors than neomycin B or chlortetracycline. Investigating HH inhibition under different ionic strengths reveals that the binding of neo-acridine, [Á-(Eilatin)Ru(bpy) 2 ] 2+ , and chlortetracycline to the HH involves hydrophobic interactions as their RNA affinities are largely unaffected by increasing salt concentrations. In contrast, neomycin B loses more than 50-fold of its inhibitory ability as the NaCl concentration is increased from 50 to 500 mM. #

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“…The composite set of properties is general and should be straightforward to adapt not only to screening anti-HIV chemical and biological molecules with abilities to disrupt and alter specific RRE-Rev interactions but also to the targeting of other important pathogens in viral and bacterial diseases. [39] Experimental Section Materials and measurements: The RRE RNA and oligonucleotide DNA were custom made by TaKaRa Biotechnology Co. Ltd. (Dalian), and their concentrations were determined by measuring the absorbance at 260 nm in 200 mL quartz cuvettes. The RNA was renatured by incubation in a buffer solution (pH 7.4) containing 20 mm HEPES, 5 mm KCl, 1 mm CaCl 2 , 1 mm MgCl 2 , and 14 0 mm NaCl for 2 min at 90 8C, followed by slow cooling to room temperature.…”

Section: Methodsmentioning

confidence: 99%