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(19)F NMR‐Based Fragment Screening for 14 Different Biologically Active RNAs and 10 DNA and Protein Counter‐Screens

We report here the nuclear magnetic resonance (19)F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specif...

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Detalles Bibliográficos
Autores principales: Binas, Oliver, de Jesus, Vanessa, Landgraf, Tom, Völklein, Albrecht Eduard, Martins, Jason, Hymon, Daniel, Kaur Bains, Jasleen, Berg, Hannes, Biedenbänder, Thomas, Fürtig, Boris, Lakshmi Gande, Santosh, Niesteruk, Anna, Oxenfarth, Andreas, Shahin Qureshi, Nusrat, Schamber, Tatjana, Schnieders, Robbin, Tröster, Alix, Wacker, Anna, Wirmer‐Bartoschek, Julia, Wirtz Martin, Maria Alexandra, Stirnal, Elke, Azzaoui, Kamal, Richter, Christian, Sreeramulu, Sridhar, José Blommers, Marcel Jules, Schwalbe, Harald
Formato: Online Artículo Texto
Lenguaje:English
Publicado: John Wiley and Sons Inc. 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7436455/
https://www.ncbi.nlm.nih.gov/pubmed/32794266
http://dx.doi.org/10.1002/cbic.202000476
Descripción
Sumario:We report here the nuclear magnetic resonance (19)F screening of 14 RNA targets with different secondary and tertiary structure to systematically assess the druggability of RNAs. Our RNA targets include representative bacterial riboswitches that naturally bind with nanomolar affinity and high specificity to cellular metabolites of low molecular weight. Based on counter‐screens against five DNAs and five proteins, we can show that RNA can be specifically targeted. To demonstrate the quality of the initial fragment library that has been designed for easy follow‐up chemistry, we further show how to increase binding affinity from an initial fragment hit by chemistry that links the identified fragment to the intercalator acridine. Thus, we achieve low‐micromolar binding affinity without losing binding specificity between two different terminator structures.