Developing proinsulin misfolding inhibitors for beta cell protection and diabetes treatment

开发用于 β 细胞保护和糖尿病治疗的胰岛素原错误折叠抑制剂

• 批准号: 10665748
• 负责人: Weidong Wang
• 金额: $ 38.42万
• 依托单位: UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-07-15 至 2027-05-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10665748
• 关键词: ATF6 gene; Animal Model; Animals; Area; Beta Cell; Binding Proteins; Biochemical; Biological Assay; Biological Availability; Cell Survival; Cell physiology; Cells; Cellular Assay; Cessation of life; Chemical Structure; Chemicals; Cytoprotection; Data; Development; Diabetes Mellitus; Diabetic mouse; Drug Kinetics; Drug or chemical Tissue Distribution; Eating; Endoplasmic Reticulum; Ensure; Event; Excretory function; Failure; Foundations; Functional disorder; Half-Life; Hyperglycemia; In Vitro; Insulin; Intervention; Lead; Metabolic; Metabolism; Modeling; Mus; Names; Organ; Pathologic; Pathway interactions; Patients; Peripheral; Permeability; Pharmaceutical Chemistry; Pharmaceutical Preparations; Plasma; Play; Process; Production; Proinsulin; Property; Proteins; Public Health; Research; Role; Safety; Solubility; Standardization; Streptozocin; Stress; Structure; Structure of beta Cell of islet; Structure-Activity Relationship; Testing; Therapeutic; Toxic effect; Treatment Efficacy; Weight Gain; Work; absorption; analog; db/db mouse; diabetic; endoplasmic reticulum stress; high throughput screening; improved; in vivo; in vivo evaluation; inhibitor; insulin sensitivity; misfolded protein; novel; novel therapeutics; pharmacologic; prevent; protein misfolding; response; small molecule; small molecule inhibitor; systemic toxicity; time use

Abstract The dysfunction and death of pancreatic β cells are key features in all types of diabetes. It was recently shown that increased proinsulin misfolding occurs well before the onset of diabetes and is responsible for events, including endoplasmic reticulum (ER) stress, leading to β-cell dysfunction and death in diabetes. There is currently no interventional means that suppresses proinsulin misfolding. In our preliminary studies, we identified a small molecule (named as PTTD) that protects β-cells from ER stress-induced death in a high- throughput screen. We discovered that PTTD suppressed the ER stress-induced activation of all three branches (IRE1, PERK, and ATF6) of unfolded protein response (UPR) pathways in β-cells under ER stress. We then observed that PTTD eliminated the accumulation of misfolded proinsulin while increasing mature insulin production in β-cells and that PTTD suppressed purified insulin protein misfolding/aggregation in cell- free biochemical assays. Importantly, in in vivo animal studies, PTTD significantly ameliorated hyperglycemia in multiple mouse diabetes models of β-cell failure. These exciting results demonstrate that suppression of proinsulin misfolding by PTTD protects β-cells and ameliorates diabetes. In this application, we will use PTTD as the starting molecule to develop potent analogs as first-in-class proinsulin misfolding inhibitors. To achieve this, we will use an approach that integrates iterative and parallel medicinal chemistry with in vitro and in vivo efficacy and DMPK studies with specific aims. In Aim 1, we will improve and optimize our lead compound, PTTD, through medicinal chemistry-based structure-activity relationship studies. In Aim 2, compounds with improved potency will be characterized physicochemically and pharmacologically using standardized ADMET and in vivo PK assays. In Aim 3, we will evaluate the in vivo efficacy of lead PTTD analogs in two well- established diabetes models of proinsulin misfolding and progressive β cell loss. Completion of this work will not only identify PTTD and its analogs as first-in-class chemical suppressors of proinsulin misfolding for β-cell protection, but also establish the suppression of proinsulin misfolding as a new therapeutic direction for diabetes, which will serve as a foundation and provide a lead compound that may guide further development of proinsulin folding therapeutics.

摘要 胰腺β细胞的功能障碍和死亡是所有类型糖尿病的关键特征。那是最近的事 研究表明，胰岛素原错误折叠增加在糖尿病发作之前很久就会发生，并与 事件，包括内质网(ER)应激，导致糖尿病患者β细胞功能障碍和死亡。那里 目前还没有抑制胰岛素原错误折叠的干预手段。在我们的初步研究中，我们 发现了一种小分子(名为PTTD)，它可以保护β细胞免受内质网应激诱导的高密度脂蛋白诱导的死亡。 吞吐量屏幕。我们发现，PTTD抑制了内质网应激诱导的这三种细胞的激活 内质网应激下β细胞中未折叠蛋白反应通路的分支(IRE1、PERK和ATF6)。 然后我们观察到，PTTD在增加成熟的同时消除了错误折叠的胰岛素原的积累。 β细胞胰岛素产生和PTTD抑制纯化的胰岛素蛋白在细胞内错误折叠/聚集 免费的生化检测。重要的是，在活体动物研究中，PTTD显著改善了高血糖 在多种糖尿病小鼠模型中，β细胞衰竭。这些令人兴奋的结果表明，抑制 PTTD错误折叠胰岛素原可保护β细胞并改善糖尿病。在本应用程序中，我们将使用PTTD 作为开发一流的胰岛素原错误折叠抑制剂的有效类似物的起始分子。要实现 为此，我们将使用一种将迭代和并行药物化学与体外和体内相结合的方法 有特定目的的疗效和DMPK研究。在目标1中，我们将改进和优化我们的先导化合物， PTTD，通过基于药物化学的构效关系研究。在目标2中，含有以下成分的化合物 改进的效力将使用标准化的ADMET进行物理化学和药理学表征 体内PK检测。在目标3中，我们将评估铅PTTD类似物在两个井中的体内疗效。 建立了胰岛素原错误折叠和进行性β细胞丢失的糖尿病模型。这项工作的完成将 不仅鉴定PTTD及其类似物为β-细胞胰岛素原错误折叠的一级化学抑制物 保护，也确立了抑制胰岛素原错误折叠为治疗糖尿病的新方向 糖尿病，这将作为基础，并提供可能指导进一步发展的先导化合物 胰岛素原折叠疗法。