2026-04-17T18:37:32Zhttps://recercat.cat/oai/request

oai:recercat.cat:2445/444072025-12-04T21:42:52Zcom_2072_1057col_2072_478917col_2072_478933

Identification of Ligands for the Tau Exon 10 Splicing Regulatory Element RNA Using Dynamic Combinatorial Chemistry López-Senín, Paula Gómez-Pinto, Irene Grandas Sagarra, Anna Marchán Sancho, Vicente Química combinatòria Bioquímica RNA Reconeixement molecular Combinatorial chemistry Biochemistry RNA Molecular recognition 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. 2013-06-25T08:38:59Z 2020-11-01T06:10:17Z 2011 2013-06-21T06:39:16Z info:eu-repo/semantics/article info:eu-repo/semantics/submittedVersion 0947-6539 https://hdl.handle.net/2445/44407 586607 eng Versió preprint del document publicat a: http://dx.doi.org/10.1002/chem.201002065 Chemistry-A European Journal, 2011, vol. 17, num. 6, p. 1946-1953 http://dx.doi.org/10.1002/chem.201002065 (c) Wiley-VCH, 2011 info:eu-repo/semantics/openAccess 14 p. application/pdf Wiley-VCH Articles publicats en revistes (Química Inorgànica i Orgànica)