A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.
A small molecule mitigates hearing loss in a mouse model of Usher syndrome III.
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DOI：
10.1038/nchembio.2069
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发表时间：
2016-06
影响因子：
14.8
通讯作者：
Imanishi Y
中科院分区：
文献类型：
--
作者：
Alagramam KN;Gopal SR;Geng R;Chen DH;Nemet I;Lee R;Tian G;Miyagi M;Malagu KF;Lock CJ;Esmieu WR;Owens AP;Lindsay NA;Ouwehand K;Albertus F;Fischer DF;Bürli RW;MacLeod AM;Harte WE;Palczewski K;Imanishi Y
Usher综合征III型（USH 3）的特征在于进行性耳聋、可变平衡障碍和失明，其是由编码clarin-1蛋白（CLRN 1）的基因中的去稳定化突变引起的。在这里，我们报告了一种新的策略，以减轻听力损失与一个共同的USH 3突变CLRN 1 N48 K，涉及基于细胞的高通量筛选的小分子能够稳定CLRN 1 N48 K，二次筛选，以消除一般蛋白酶体抑制剂，最后一个迭代过程，以优化结构活性关系。这导致了BF 844的鉴定。为了测试BF 844的功效，开发了模拟USH 3的进行性听力损失的小鼠模型。在该模型中，BF 844有效地减弱了进行性听力损失并预防了耳聋。由于人类CLRN 1 N48 K突变导致听力和视力丧失，BF 844原则上可以预防USH 3中的两种感觉缺陷。此外，这里描述的策略可以帮助确定其他蛋白质不稳定单基因疾病的药物。
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 protein (CLRN1). Here we report a novel strategy to mitigate hearing loss associated with a common USH3 mutation CLRN1N48K that involved a cell-based high-throughput screening of small molecules capable of stabilizing CLRN1N48K, a secondary screening to eliminate general proteasome inhibitors, and finally an iterative process to optimize structure activity relationships. This resulted in the identification of BF844. To test the efficacy of BF844, a mouse model was developed that mimicked the progressive hearing loss of USH3. BF844 effectively attenuated progressive hearing loss and prevented deafness in this model. Because the human CLRN1N48K mutation causes both hearing and vision loss, BF844 could in principle prevent both sensory deficiencies in USH3. Moreover, the strategy described here could help identify drugs for other protein-destabilizing monogenic disorders.