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Nat Chem Biol. 2016 Jun;12(6):444-51. doi: 10.1038/nchembio.2069. Epub 2016 Apr 25.

A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.

Author information

1
Otolaryngology Head and Neck Surgery, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, Ohio, USA.
2
Genetics and Genome Sciences, Case Western Reserve University, Cleveland, Ohio, USA.
3
Neurosciences, Case Western Reserve University, Cleveland, Ohio, USA.
4
Pharmacology and Cleveland Center for Membrane and Structural Biology, Case Western Reserve University, Cleveland, Ohio, USA.
5
Center for Proteomics and Bioinformatics, Case Western Reserve University, Cleveland, Ohio, USA.
6
BioFocus, a Charles River company, Chesterford Research Park, Saffron Walden, UK.
7
Charles River Nederland BV, Leiden, the Netherlands.
8
Office of Translation and Innovation, Case Western Reserve University, Cleveland, Ohio, USA.

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.

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PMID:
27110679
PMCID:
PMC4871731
DOI:
10.1038/nchembio.2069
[Indexed for MEDLINE]
Free PMC Article

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