A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.
Nat Chem Biol
; 12(6): 444-51, 2016 06.
Article
en En
| MEDLINE
| ID: mdl-27110679
ABSTRACT
Usher syndrome type III (USH3), characterized by progressive deafness, variable balance disorder and blindness, is caused by destabilizing mutations in the gene encoding the clarin-1 (CLRN1) protein. Here we report a new strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1(N48K) that involves cell-based high-throughput screening of small molecules capable of stabilizing CLRN1(N48K), followed by a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure-activity relationships. This resulted in the identification of BioFocus 844 (BF844). To test the efficacy of BF844, we developed a mouse model that mimicked the progressive hearing loss associated with USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the CLRN1(N48K) mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in patients with USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.
Texto completo:
1
Colección:
01-internacional
Banco de datos:
MEDLINE
Asunto principal:
Pirazoles
/
Piridazinas
/
Modelos Animales de Enfermedad
/
Síndromes de Usher
/
Bibliotecas de Moléculas Pequeñas
/
Proteínas de la Membrana
Tipo de estudio:
Prognostic_studies
Límite:
Animals
/
Humans
Idioma:
En
Revista:
Nat Chem Biol
Asunto de la revista:
BIOLOGIA
/
QUIMICA
Año:
2016
Tipo del documento:
Article
País de afiliación:
Estados Unidos