Title:
|
Identification of Ligands for the Tau Exon 10 Splicing Regulatory Element RNA Using Dynamic Combinatorial Chemistry
|
Author:
|
López-Senín, Paula; Gómez-Pinto, Irene; Grandas Sagarra, Anna; Marchán Sancho, Vicente
|
Other authors:
|
Universitat de Barcelona |
Abstract:
|
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. |
Subject(s):
|
-Química combinatòria -Bioquímica -RNA -Reconeixement molecular -Combinatorial chemistry -Biochemistry -RNA -Molecular recognition |
Rights:
|
(c) Wiley-VCH, 2011
info:eu-repo/semantics/embargoedAccess |
Document type:
|
Article Article - Submitted version |
Published by:
|
Wiley-VCH
|
Share:
|
|