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Dahua Wang^1,2, Hongling Wang^1,2, Lu Fan^1,2

¹Gottfried-Wilhelm-Leibniz University of Hannover, BMWZ (Zentrum für Biomolekulare Wirkstoffe), Schneiderberg 38, 30167 Hannover, Germany.

ACS pharmacology & translational science

|July 20, 2023

概括

研究人员确定了可以恢复连接素26 (Cx26) 功能的化合物,为Cx26突变引起的听力障碍提供了潜在的治疗方法. 一个新的选系统确定了化合物3和8,其中化合物3显示出有希望的结合亲和力.

科学领域:

遗传学和分子生物学
生物物理学的生物物理.
药理学药理学是指药理学的学科.

背景情况:

结合素26 (Cx26) 的突变是遗传性听力损失的主要原因.
恢复突变的Cx26通道的功能是治疗听力障碍的治疗目标.
现有的听力损失治疗方法有限,需要新的治疗策略.

研究的目的:

开发一种选系统,以识别可恢复连接素26 (Cx26) 功能的化合物.
发现能够挽救突变Cx26通道功能的小分子.
评估已识别的化合物的疗效和结合特性.

主要方法:

开发一个小型化的基于微阵列的选系统,用于Cx26功能测试.
使用表达野生类型 (WT) 和突变Cx26的HeLa细胞进行生命力和流量测试.
采用热泳来评估化合物与重组Cx26蛋白质的结合.

主要成果:

已确定化合物3 (VRT-534) 和8能够恢复突变的Cx26通道功能.
化合物3对WT和突变Cx26 (K188N) 进行了剂量反应的结合.
WT Cx26表达细胞对HSP90抑制剂radicicol表现出敏感性,有助于查.

结论:

新型化合物,特别是VRT-534,显示出治疗Cx26相关听力障碍的潜力.
重新利用现有的药物和利用功能生物测试可以加速发现听力障碍治疗方法.
开发的选平台提供了一种强大的方法来识别Cx26调节器.

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