Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer

Petros Andrew M.; Korepanova Alla; Jakob Clarissa G.; Qiu Wei; Panchal Sanjay C.; Wang Jie; Dietrich Justin D.; Brewer Jason T.; Pohlki Frauke; Kling Andreas; Wilcox Kyle; Lakics Viktor; Bahnassawy Lamiaa; Reinhardt Peter; Partha Sarathy Karunan; Bodelle Pierre M.; Lake Marc; Charych Erik I.; Stoll Vincent S.; Sun Chaohong; Mohler Eric G.

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Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer

机译：基于片段的载脂蛋白E4（APOE4）稳定剂的发现

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Apolipoprotein E is a 299-residue lipid carrier protein produced in both the liver and the brain. The protein has three major isoforms denoted apoE2, apoE3, and apoE4 which differ at positions 112 and 158 and which occur at different frequencies in the human population. Genome-wide association studies indicate that the possession of two apoE4 alleles is a strong genetic risk factor for late-onset Alzheimer's disease (LOAD). In an attempt to identify a small molecule stabilizer of apoE4 function that may have utility as a therapy for Alzheimer's disease, we carried out an NMR-based fragment screen on the N-terminal domain of apoE4 and identified a benzyl amidine based fragment binder. In addition to NMR, binding was characterized using various other biophysical techniques, and a crystal structure of the bound core was obtained. Core elaboration ultimately yielded a compound that showed activity in an IL-6 and IL-8 cytokine release assay.

机译：载脂蛋白E是在肝脏和脑中产生的299-残基脂质载体蛋白。蛋白质具有三个主要同种型，其表示在112和158处的位置112和158处不同的ApoE2，ApoE3和ApoE4，并且在人群中的不同频率发生。基因组 - 范围的协会研究表明，两个APOE4等位基因的拥有是晚期疾病（载荷）的强大遗传危险因素。为了试图鉴定APOE4功能的小分子稳定剂，其可能具有效用作为阿尔茨海默病的疗法，我们在ApoE4的N-末端结构域上进行了基于NMR的片段筛网，并鉴定了基于苄酰胺的片段粘合剂。除了NMR之外，使用各种其他生物物理技术表征结合，并获得结合芯的晶体结构。核心阐述最终产生了一种在IL-6和IL-8细胞因子释放测定中显示活性的化合物。

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《Journal of Medicinal Chemistry》 |2019年第8期|共11页
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Petros Andrew M.; Korepanova Alla; Jakob Clarissa G.; Qiu Wei; Panchal Sanjay C.; Wang Jie; Dietrich Justin D.; Brewer Jason T.; Pohlki Frauke; Kling Andreas; Wilcox Kyle; Lakics Viktor; Bahnassawy Lamiaa; Reinhardt Peter; Partha Sarathy Karunan; Bodelle Pierre M.; Lake Marc; Charych Erik I.; Stoll Vincent S.; Sun Chaohong; Mohler Eric G.;
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1. Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer [J] . Petros Andrew M., Korepanova Alla, Jakob Clarissa G., Journal of Medicinal Chemistry . 2019,第8期

机译：基于片段的载脂蛋白E4（APOE4）稳定剂的发现
2. Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer's disease (ASUi001-A) and non-demented control (ASUi002-A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant - ScienceDirect [J] . Nicholas Brookhouser, Ping Zhang, Richard Caselli, Stem cell research . 2017,第2期

机译：载脂蛋白e4（APOE4）风险变异纯合的人自阿尔茨海默氏病（ASUi001-A）和非痴呆对照（ASUi002-A）患者纯合的人诱导多能干细胞（hiPSC）系的生成和表征-ScienceDirect
3. Site-Directed Fragment-Based Screening for the Discovery of Protein-Protein Interaction Stabilizers [J] . Sijbesma Eline, Hallenbeck Kenneth K., Leysen Seppe, Journal of the American Chemical Society . 2019,第8期

机译：基于定点片段的筛选，用于发现蛋白质-蛋白质相互作用稳定剂
4. Total Apolipoprotein E and Apolipoprotein E4 isoform assay (n=672) by targeted mass spectrometry: a pilot assay for methionine-containing proteotypic peptide [C] . Romain Simon, Marion Girod, Catherine Fonbonne, American Society for Mass Spectrometry Conference on Mass Spectrometry and Allied Topics . 2012

机译：通过靶向质谱法（N = 672）总载脂蛋白E和载脂蛋白E4同种型测定：含甲硫氨酸的蛋白质肽的试验试验
5. Endogenous Apolipoprotein E4 Modulates an Alzheimer's Disease Phenotype in Human Stem-Cell Derived Neurons [D] . Wadhwani, Anil R. 2019

机译：内源性载脂蛋白E4调节人类干细胞衍生神经元中的阿尔茨海默病表型
6. Fatty Acid Binding Protein 3 (FABP3) and Apolipoprotein E4 (ApoE4) as Lipid Metabolism-Related Biomarkers of Alzheimer’s Disease [O] . Maciej Dulewicz, Agnieszka Kulczyńska-Przybik, Agnieszka Słowik, 2021

机译：脂肪酸结合蛋白3（FABP3）和载脂蛋白E4（APOE4）作为阿尔茨海默病相关的脂质代谢相关生物标志物
7. Generation and characterization of human induced pluripotent stem cell (hiPSC) lines from an Alzheimer's disease (ASUi001-A) and non-demented control (ASUi002-A) patient homozygous for the Apolipoprotein e4 (APOE4) risk variant [O] . Nicholas Brookhouser, Ping Zhang, Richard Caselli, 2017

机译：载脂蛋白e4（apOE4）风险变异

Fragment-Based Discovery of an Apolipoprotein E4 (apoE4) Stabilizer

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