Identification of ligands for the Tau exon 10 splicing regulatory element RNA by using dynamic combinatorial chemistry
Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim..
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 (EC(50)): 2-58 μM), 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.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2011 |
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| Erschienen: |
2011 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:17 |
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| Enthalten in: |
Chemistry (Weinheim an der Bergstrasse, Germany) - 17(2011), 6 vom: 07. Feb., Seite 1946-53 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
López-Senín, Paula [VerfasserIn] |
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| Links: |
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| Themen: |
4BOC774388 |
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| Anmerkungen: |
Date Completed 22.03.2011 Date Revised 21.11.2013 published: Print-Electronic Citation Status MEDLINE |
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| doi: |
10.1002/chem.201002065 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM205428401 |
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| 245 | 1 | 0 | |a Identification of ligands for the Tau exon 10 splicing regulatory element RNA by using dynamic combinatorial chemistry |
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| 500 | |a Date Revised 21.11.2013 | ||
| 500 | |a published: Print-Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a Copyright © 2011 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim. | ||
| 520 | |a 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 (EC(50)): 2-58 μM), 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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| 700 | 1 | |a Gómez-Pinto, Irene |e verfasserin |4 aut | |
| 700 | 1 | |a Grandas, Anna |e verfasserin |4 aut | |
| 700 | 1 | |a Marchán, Vicente |e verfasserin |4 aut | |
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