title: Identification of ligands for the Tau exon 10 splicing regulatory element RNA by using dynamic combinatorial chemistry.
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.
authors.affiliation: Departament de Química Orgànica and IBUB, Universitat de Barcelona, Martí i Franquès 1-11, 08028 Barcelona, Spain.
authors.forename: Paula
authors.initials: P
authors.lastname: López-Senín
authors.forename: Irene
authors.initials: I
authors.lastname: Gómez-Pinto
authors.forename: Anna
authors.initials: A
authors.lastname: Grandas
authors.forename: Vicente
authors.initials: V
authors.lastname: Marchán
mesh_terms: D002886:Chromosomes, Human, Pair 17 / Q000235:genetics*; D002942:Circular Dichroism; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D003704:Dementia / Q000235:genetics; D005091:Exons; D005470:Fluorometry / Q000379:methods; D005601:Framycetin / Q000737:chemistry; D006801:Humans; D007438:Introns; D008024:Ligands; D020734:Parkinsonian Disorders / Q000235:genetics; D012313:RNA / Q000737:chemistry / Q000235:genetics*; D012322:RNA Precursors / Q000235:genetics / Q000378:metabolism; D012326:RNA Splicing; D024801:Tauopathies / Q000235:genetics*
chemical_list: D008024:Ligands; D012322:RNA Precursors; D005601:Framycetin; C488396:neamine; D012313:RNA