RNA und die Welt der kleinen Moleküle

Tor, Yitzhak

doi:10.1002/(sici)1521-3757(19990601)111:11<1681::aid-ange1681>3.0.co;2-6

Angewandte Chemie

1999

DOI: 10.1002/(sici)1521-3757(19990601)111:11<1681::aid-ange1681>3.0.co;2-6

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RNA und die Welt der kleinen Moleküle

Yitzhak Tor

Abstract: Eine Schlüsselrolle bei lebenswichtigen zellulären Prozessen spielen RNA‐Moleküle, die deshalb interessante Ziele für das Wirkstoff‐Design sind. Die Vielfältigkeit der Funktionen von RNA kann auf die komplexen dreidimensionalen Strukturen zurückgeführt werden, die diese einnehmen kann. Die komplizierten Faltungsmuster enthalten potentielle Bindungstaschen für Ionen, niedermolekulare Liganden und Proteine. Neuere Untersuchungen haben ergeben, daß kleine Moleküle wie Tobramycin 1 die Genexpression in lebenden Ze… Show more

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Cited by 17 publications

References 66 publications

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A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

Luedtke

Tor

2000

Angewandte Chemie

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Replication of the human immunodeficiency virus (HIV-1) requires an ordered pattern of viral gene expression. [1] This process is dependent upon the association of Rev, an essential viral regulatory protein, with its respective RNA binding site, the Rev-response-element (RRE). [2] The RRE is necessary for the active export of unspliced genomic viral RNA from the nucleus and serves as part of the envelope ± protein coding sequence. [2] This dual function makes the Rev ± RRE binding event an attractive target for therapeutic intervention because the evolution of resistant variants may be prevented or impeded. Small molecules that specifically bind the RRE and preclude or competitively displace the Rev protein are therefore promising antiviral candidates. [3±5] Aminoglycoside antibiotics have been shown to competitively block the binding of the Rev protein to the RRE, thus providing an important precedent for the use of low molecular weight ligands to target viral RNA sites. [3,6] These natural antibiotics, however, bind the RRE with relatively low affinity and specificity. [7] Since aminoglycosides and most other RNA ligands appear to recognize certain RNA folds, rather than specific RNA sequences, the design and discovery of RNA ligands is a challenging and empirical process. [7b] Commonly employed RNA-binding assays are limited in their ability to probe both the affinity and specificity of potential binders. [7a, 8, 9] New approaches that allow the rapid determination of both the RNA affinity and specificity of small molecules will assist in the discovery of new lead compounds and advance the understanding of RNA recognition. To this end, we report the assembly of an immobilized RNA ± protein complex and demonstrate its application to the discovery and characterization of new RNA binders.The high-affinity Rev binding site within the RRE is the purine-rich bulge shown in Figure 1. [10] The arginine-rich segment, Rev 34±50 , binds the RRE with a dissociation constant similar to that of the full-length Rev protein. [11] We have developed an assay based on the competition between potential RNA binders and a fluorescent Rev peptide (ªRev-Flº) for binding to an immobilized RRE fragment. The assay identifies small molecules that specifically interfere with Rev ± RRE binding (Figure 1). Ligands that bind to the [1] Magnetic Molecular Materials

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A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

Luedtke

Tor

2000

Angewandte Chemie

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A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

Luedtke

Tor

2000

Angew. Chem. Int. Ed.

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Strategien für die Entwicklung gegen RNA und RNA-Protein-Komplexe gerichteter pharmakologischer Wirkstoffe

Hermann

2000

Angewandte Chemie

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RNA und die Welt der kleinen Moleküle

Cited by 17 publications

References 66 publications

A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

A Novel Solid-Phase Assembly for Identifying Potent and Selective RNA Ligands

Strategien für die Entwicklung gegen RNA und RNA-Protein-Komplexe gerichteter pharmakologischer Wirkstoffe

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