Journal
CHEMISTRY-A EUROPEAN JOURNAL
Volume 17, Issue 6, Pages 1946-1953Publisher
WILEY-V C H VERLAG GMBH
DOI: 10.1002/chem.201002065
Keywords
combinatorial chemistry; molecular recognition; RNA ligands; RNA structures; template synthesis
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Funding
- Spanish Ministerio de Educacion y Ciencia [CTQ 2007-68014-01/02]
- Generalitat de Catalunya [2005SGR-693]
- Xarxa de Referencia de Biotecnologia
- Universitat de Barcelona
- Ministerio de Educacion y Ciencia
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We describe the use of dynamic combinatorial chemistry (DCC) to identify ligands for the stem-loop structure located at the exon 10-5'-intron junction of Tau pre-mRNA, which is involved in the onset of several tauopathies including frontotemporal dementia with Parkinsonism linked to chromosome 17 (FTDP-17). A series of ligands that combine the small aminoglycoside neamine and heteroaromatic moieties (azaquinolone and two acridines) have been identified by using DCC. These compounds effectively bind the stem-loop RNA target (the concentration required for 50% RNA response (EC50): 2-58 mu M), as determined by fluorescence titration experiments. Importantly, most of them are able to stabilize both the wild-type and the +3 and +14 mutated sequences associated with the development of FTDP-17 without producing a significant change in the overall structure of the RNA (as analyzed by circular dichroism (CD) spectroscopy), which is a key factor for recognition by the splicing regulatory machinery. A good correlation has been found between the affinity of the ligands for the target and their ability to stabilize the RNA secondary structure.
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