Cellular uptake of circulating cholesterol occurs via the low density lipoprotein receptor (LDLR). The E3 ubiquitin ligase IDOL is a mediator of LDLR degradation, with IDOL homodimerization thought to be required for its activity. To probe the possibility of modulating LDLR levels with an inhibitor of IDOL homodimerization, we screened a SICLOPPS library of 3.2 million cyclic peptides for compounds that disrupt this protein–protein interaction. We identified cyclo-CFFLYT as the lead inhibitor, and improved its activity through the incorporation of non-natural amino acids. The activity of the optimized cyclic peptide was assessed in hepatic cells, with a dose-dependent increase in LDLR levels observed in the presence of our IDOL homodimerization inhibitor.

中文翻译：

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用环肽抑制低密度脂蛋白受体降解，从而破坏IDOL E3泛素连接酶的同二聚化†

循环胆固醇的细胞摄取通过低密度脂蛋白受体（LDLR）发生。E3泛素连接酶IDOL是LDLR降解的介体，IDOL均二聚作用被认为是其活性所必需的。为了探究用IDOL同二聚化抑制剂调节LDLR水平的可能性，我们筛选了320万个环肽的SICLOPPS文库中破坏该蛋白与蛋白相互作用的化合物。我们确定环-CFFLYT为先导抑制剂，并通过掺入非天然氨基酸提高了其活性。在肝细胞中评估了优化的环肽的活性，在我们的IDOL均二聚化抑制剂存在下观察到了LDLR水平的剂量依赖性增加。