Trafficking deficiency caused by missense mutations is a well known phenomenon that occurs for mutant, misfolded proteins. Typically, the misfolded protein is retained by the protein quality-control system and degraded by the endoplasmic reticulum-associated protein degradation pathway and thus does not reach its destination, although residual function of the protein may be preserved. Chemical and pharmacological chaperones can improve the targeting of trafficking-deficient proteins and thus may be promising candidates for therapeutic applications. Here, we report the application of a cellular bioassay based on the bioluminescent calcium reporter aequorin to quantify surface expression of mutant CNGA3 channels associated with the autosomal recessively inherited retinal disease achromatopsia. A screening of 77 compounds enabled the identification of effective chemical and pharmacological chaperones that result in a 1.5- to 4.8-fold increase of surface expression of mutant CNGA3. Using selected compounds, we confirmed that the rescue of the defective trafficking is not limited to a single mutation in CNGA3. Active compounds and our structure-activity correlated data for the dihydropyridine compound class may provide valuable information for developing a treatment of the trafficking defect in achromatopsia.

中文翻译：

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鉴定用于纠正贩运缺陷突变环状核苷酸门控 A3 通道的化学和药理学伴侣

由错义突变引起的运输缺陷是一种众所周知的现象，发生在突变的错误折叠蛋白质上。通常，错误折叠的蛋白质被蛋白质质量控​​制系统保留并被内质网相关蛋白质降解途径降解，因此不会到达其目的地，尽管蛋白质的残余功能可能会被保留。化学和药理分子伴侣可以改善运输缺陷蛋白的靶向性，因此可能是治疗应用的有希望的候选者。在这里，我们报告了基于生物发光钙报告分子水母发光蛋白的细胞生物测定的应用，以量化与常染色体隐性遗传的视网膜疾病色盲相关的突变 CNGA3 通道的表面表达。对 77 种化合物的筛选能够鉴定出有效的化学和药理学分子伴侣，这些分子伴侣导致突变体 CNGA3 的表面表达增加 1.5 至 4.8 倍。使用选定的化合物，我们确认对有缺陷的运输的拯救不仅限于 CNGA3 中的单个突变。活性化合物和我们的二氢吡啶类化合物的结构-活性相关数据可能为开发治疗色盲中的运输缺陷提供有价值的信息。