PCSK9-LDLR inhibitors from fragment-based design

描述：最近的II期临床研究表明，一种靶向比例转化酶枯草素/克辛9型（PCSK9）的抗体-治疗高胆固醇血症和冠心病的靶点-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）含量然而，到目前为止，还没有小分子或多肽达到同样效果的报道。该应用程序提供了一种成熟的基于片段的设计方法，用于创建新型小分子PCSK9抑制剂，该抑制剂在表面等离子体共振直接和竞争分析以及肝细胞中LDL摄取的功能分析中实现靶向活性。这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选活动通常没有产生可进展的PCSK9。利用我们最近描述的热点定位技术，我们在低密度脂蛋白-胆固醇受体(LDLR)/PCSK9界面上发现了高相互作用能的位点，并且似乎是可药物化的。我们提出的研究的主要成果是改善物理性质，并在我们的初始目标周围开发SAR，显示功能性细胞活性。最初的成功来自于对不到50种新化合物的测试（1、2和3个片段构建）。这些小分子配体是专门设计来实现一个假设，即量子共振（部分共价结合）可以提供增强的亲和力，以克服凸的、溶剂暴露的PCSK9/LDLR界面的脱水成本。这些化合物在临床试验中取得成功，将显示出降低胆固醇和治疗人类冠心病的巨大希望。

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.