权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

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

基本信息

批准号：
10529960
负责人：
Weidong Wang
金额：
$ 39.55万
依托单位：
UNIVERSITY OF OKLAHOMA HLTH SCIENCES CTR
依托单位国家：
美国
项目类别：
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/10529960
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 Pharmacology 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 Sum Testing Therapeutic Toxic effect Treatment Efficacy Weight Gain Work absorption analog base db/db mouse diabetic endoplasmic reticulum stress high throughput screening improved in vivo in vivo evaluation inhibitor insulin sensitivity misfolded protein novel novel therapeutics prevent protein misfolding response small molecule small molecule inhibitor systemic toxicity time use

项目摘要

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.

抽象的胰腺β细胞的功能障碍和死亡是所有类型糖尿病的关键特征。这是最近研究表明，胰岛素原错误折叠的增加早在糖尿病发病之前就发生了，并且是造成糖尿病的原因事件，包括内质网（ER）应激，导致β细胞功能障碍和糖尿病死亡。那里目前尚无抑制胰岛素原错误折叠的干预手段。在我们的初步研究中，我们鉴定出一种小分子（称为 PTTD），可以保护 β 细胞免受 ER 应激诱导的死亡。吞吐量屏幕。我们发现 PTTD 抑制了 ER 应激诱导的所有三个激活 ER 应激下 β 细胞中未折叠蛋白反应 (UPR) 途径的分支（IRE1、PERK 和 ATF6）。然后我们观察到 PTTD 消除了错误折叠的胰岛素原的积累，同时增加了成熟的胰岛素原的积累。 β 细胞中胰岛素的产生以及 PTTD 抑制细胞中纯化的胰岛素蛋白错误折叠/聚集免费生化检测。重要的是，在体内动物研究中，PTTD 显着改善高血糖在多个β细胞衰竭的小鼠糖尿病模型中。这些令人兴奋的结果表明，抑制 PTTD 导致的胰岛素原错误折叠可保护 β 细胞并改善糖尿病。在此应用程序中，我们将使用 PTTD 作为开发有效类似物作为首创胰岛素原错误折叠抑制剂的起始分子。达到为此，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功效和 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结构-活性关系研究。在目标 2 中，与改进的效力将使用标准化 ADMET 进行物理化学和药理学表征和体内 PK 测定。在目标 3 中，我们将评估先导 PTTD 类似物在两种情况下的体内功效：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确定 PTTD 及其类似物是 β 细胞胰岛素原错误折叠的一流化学抑制剂保护，同时也确立了抑制胰岛素原错误折叠作为新的治疗方向糖尿病，它将作为基础并提供可指导进一步开发的先导化合物胰岛素原折叠疗法。