Leitch Eilidh K, Elumalai Nagarajan, Fridén-Saxin Maria, Dahl Göran, Wan Paul, Clarkson Paul, Valeur Eric, Pairaudeau Garry, Boyd Helen, Tavassoli Ali
Chemistry , University of Southampton , Southampton , SO17 1RE , UK . Email:
Medicinal Chemistry , Cardiovascular and Metabolic Diseases , IMED Biotech Unit , AstraZeneca , Pepparedsleden 1 , Mölndal , 43150 , Sweden.
Chem Sci. 2018 Jun 26;9(27):5957-5966. doi: 10.1039/c8sc01186a. eCollection 2018 Jul 21.
Cellular uptake of circulating cholesterol occurs 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 -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.
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降解的介质，IDOL同源二聚化被认为是其活性所必需的。为了探索用IDOL同源二聚化抑制剂调节LDLR水平的可能性，我们在一个包含320万个环肽的SICLOPPS文库中筛选能够破坏这种蛋白质-蛋白质相互作用的化合物。我们确定-CFFLYT为先导抑制剂，并通过掺入非天然氨基酸提高其活性。在肝细胞中评估了优化后的环肽的活性，在我们的IDOL同源二聚化抑制剂存在的情况下，观察到LDLR水平呈剂量依赖性增加。
