Novel β‐Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization,Angewandte Chemie International Edition

当前位置： X-MOL 学术 › Angew. Chem. Int. Ed. › 论文详情

Our official English website, www.x-mol.net, welcomes your feedback! (Note: you will need to create a separate account there.)

Novel β‐Glucocerebrosidase Activators That Bind to a New Pocket at a Dimer Interface and Induce Dimerization
Angewandte Chemie International Edition ( IF 16.1 ) Pub Date : 2020-11-25 , DOI: 10.1002/anie.202013890
Joerg Benz ₁ , Arne C Rufer ₁ , Sylwia Huber ₁ , Andreas Ehler ₁ , Melanie Hug ₁ , Andreas Topp ₁ , Wolfgang Guba ₂ , Eva Carolina Hofmann ₃ , Ravi Jagasia ₄ , Rosa María Rodríguez Sarmiento ₅

Affiliation

Genetic, preclinical and clinical data link Parkinson's disease and Gaucher's disease and provide a rational entry point to disease modification therapy via enhancement of β‐Glucocerebrosidase (GCase) activity. We discovered a new class of pyrrolo[2,3‐b]pyrazine activators effecting both Vmax and Km. They bind to human GCase and increase substrate metabolism in the lysosome in a cellular assay. We obtained the first crystal structure for an activator and identified a novel non‐inhibitory binding mode at the interface of a dimer, rationalizing the observed structure–activity relationship (SAR). The compound binds GCase inducing formation of a dimeric state at both endoplasmic reticulum (ER) and lysosomal pHs, as confirmed by analytical ultracentrifugation. Importantly, the pyrrolo[2,3‐b]pyrazines have central nervous system (CNS) drug‐like properties. Our findings are important for future drug discovery efforts in the field of GCase activation and provide a deeper mechanistic understanding of the requirements for enzymatic activation, pointing to the relevance of dimerization.

中文翻译：

新型β-葡萄糖脑苷脂酶激活剂，可在二聚体界面处结合至新的口袋并诱导二聚化

遗传，临床前和临床数据将帕金森氏病和高雪氏病联系起来，并通过增强β-葡萄糖脑苷脂酶（GCase）活性为疾病改良治疗提供了合理的切入点。我们发现了一类新型的吡咯并[2,3-b]吡嗪活化剂，可同时影响Vmax和Km。它们在细胞测定法中与人GCase结合并增加溶酶体中的底物代谢。我们获得了活化剂的第一个晶体结构，并在二聚体的界面处发现了一种新型的非抑制性结合模式，从而合理化了所观察到的结构-活性关系（SAR）。该化合物与GCase结合，诱导在内质网（ER）和溶酶体pH值上形成二聚体状态，这已通过分析超速离心法得到证实。重要的是，pyrrolo [2，3-b]吡嗪具有中枢神经系统（CNS）药物样特性。我们的发现对于未来GCase激活领域的药物发现工作非常重要，并提供了对酶促激活要求的更深入的机械理解，并指出了二聚化的重要性。

更新日期：2020-11-25

点击分享查看原文

点击收藏

阅读更多本刊最新论文本刊介绍/投稿指南11