PCSK9-LDLR inhibitors from fragment-based design

描述：最近的II期临床研究表明，靶向比例转化酶枯草杆菌/可信9型(PCSK9)的抗体成功且安全地降低了接受他汀类药物治疗的高胆固醇血症患者的低密度脂蛋白胆固醇(LDL)含量。1，2然而，到目前为止，还没有报道小分子或多肽达到同样的效果。这项应用提供了一种成熟的基于片段的设计方法来创造新型的小分子PCSK9抑制剂，在表面等离子共振直接和竞争分析以及功能分析中实现靶向活性，即肝细胞的低密度脂蛋白摄取。这样一种解决这个问题的替代方法是令人信服的，因为大型制药公司的高通量筛查活动通常没有为PCSK9带来进展。使用我们最近描述的热点作图技术，3，6我们在低密度脂蛋白-胆固醇受体(LDLR)/PCSK9界面上发现了具有高相互作用能量的位点，并且似乎是可药物的。我们提议的研究的主要成果是改善物理性质，并围绕显示基于细胞的功能活动的初始点击开发SAR。初步的命中是因为测试了不到50种新化合物(一、两和三个片段构建)。小分子配体是专门为实现量子共振(部分共价结合)可以提供增强亲和力的假设而设计的，以克服凸的、暴露在溶剂中的PCSK9/LDLR界面的脱水成本。这些化合物在临床试验中取得成功，将在降低人类胆固醇和治疗冠心病方面显示出巨大的前景。

DESCRIPTION: Recent phase II clinical studies demonstrate that an antibody targeting proportion convertase subtilisin/kexin type 9 (PCSK9)-a target for the treatment of hypercholesterolemia and coronary heart disease-successfully and safely decreases amounts of low-density lipoprotein-cholesterol (LDL) in patients with hypercholesterolaemia undertaking statin treatment.1,2 However, to date, there are no reports of small molecules or peptides achieving the same effect. This application offers a mature fragment-based design methodology to create novel small molecule PCSK9 inhibitors that achieve a targeted activity in surface plasmon resonance direct and competition assays as well as in a functional assay, LDL uptake in hepatocyte cells. Such an alternative approach to this problem is compelling because high-throughput screening campaigns at large pharmaceutical companies have generally not yielded progressable hits for PCSK9. Using our recently described hot-spot mapping technique,3,6 we found sites at the low-density lipoprotein-cholesterol receptor (LDLR)/PCSK9 interface that are sites of high interaction energy and appear druggable. Our primary deliverable for the proposed research is to improve physical properties and develop SAR around our initial hits that show functional cell-based activity. The primary hits resulted from testing fewer than 50 novel compounds (one, two and three fragment builds). The small molecule ligands were specifically designed to implement a hypothesis that quantum resonance (partially covalent binding) can provide enhanced affinity to overcome the dehydration costs of the convex, solvent-exposed PCSK9/LDLR interface. Such compounds achieving success in clinical trials would show great promise as a therapeutic to lower cholesterol and treat coronary heart disease in humans.