Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a secreted protein that downregulates low-density lipoprotein (LDL) receptor (LDL-R) levels on the surface of hepatocytes, resulting in decreased clearance of LDL-cholesterol (LDL-C). Phenotypic screening of a small-molecule compound collection was used to identify an inhibitor of PCSK9 secretion, (R)-N-(isoquinolin-1-yl)-3-(4-methoxyphenyl)-N-(piperidin-3-yl)propanamide (R-IMPP), which was shown to stimulate uptake of LDL-C in hepatoma cells by increasing LDL-R levels, without altering levels of secreted transferrin. Systematic investigation of the mode of action revealed that R-IMPP did not decrease PCSK9 transcription or increase PCSK9 degradation, but instead caused transcript-dependent inhibition of PCSK9 translation. In support of this surprising mechanism of action, we found that R-IMPP was able to selectively bind to human, but notE. coli, ribosomes. This study opens a new avenue for the development of drugs that modulate the activity of target proteins by mechanisms involving inhibition of eukaryotic translation.

中文翻译：

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PCSK9的小分子抗secretagogue靶向80S核糖体以抑制PCSK9蛋白质翻译。

前蛋白转化酶枯草杆菌蛋白酶/ kexin 9型（PCSK9）是一种分泌蛋白，可下调肝细胞表面的低密度脂蛋白（LDL）受体（LDL-R）水平，从而降低LDL-胆固醇（LDL-C）的清除率。使用小分子化合物的表型筛选来鉴定PCSK9分泌的抑制剂（R）-N-（异喹啉-1-基）-3-（4-甲氧基苯基）-N-（哌啶-3-基）丙酰胺（R-IMPP），已显示可通过增加LDL-R水平刺激肝癌细胞中LDL-C的摄取，而不会改变分泌的转铁蛋白水平。对作用方式的系统研究表明，R-IMPP不会降低PCSK9转录或增加PCSK9降解，而是引起转录物依赖性的PCSK9翻译抑制。为了支持这种令人惊讶的作用机制，我们发现R-IMPP能够选择性地与人结合，但不能与人结合。大肠杆菌，核糖体。这项研究为通过抑制真核翻译的机制调节靶蛋白活性的药物开发开辟了一条新途径。