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的糖尿病中的关键特征。最近是表明，增加的促硫素错误折叠发生在糖尿病发作之前，并且负责事件，包括内质网（ER）应激，导致糖尿病的β细胞功能障碍和死亡。那里目前没有介入的意味着抑制促硫素错误折叠。在我们的初步研究中，我们确定了一个小分子（称为pttd），该分子保护β细胞免受高ER应力诱导的高死亡死亡吞吐量屏幕。我们发现PTTD抑制了ER应力诱导的这三个激活在ER应力下，β细胞中展开的蛋白质反应（UPR）途径的分支（IRE1，PERK和ATF6）。然后，我们观察到PTTD消除了错误折叠蛋白的积累，同时增加成熟 β细胞中的胰岛素产生，PTTD抑制了细胞中纯化的胰岛素蛋白折叠/聚集的胰岛素蛋白质折叠/聚集免费的生化测定。重要的是，在体内动物研究中，PTTD显着改善了高血糖症在多个小鼠糖尿病模型中，β细胞衰竭。这些令人兴奋的结果表明了抑制 PTTD的促硫蛋白折叠折叠可保护β细胞并改善糖尿病。在此应用程序中，我们将使用PTTD 作为开发潜在类似物的起始分子作为第一类促硫素错误折叠抑制剂。实现这，我们将使用一种将迭代且平行的医学化学与体外和体内整合的方法具有特定目的的功效和DMPK研究。在AIM 1中，我们将改进和优化我们的铅化合物， PTTD，通过基于医学化学的结构活性关系研究。在AIM 2中，化合物与改善的效力将使用标准化的ADMET进行身体和药物的特征和体内PK分析。在AIM 3中，我们将评估两个良好的铅PTTD类似物的体内效率确定的糖尿病糖尿病模型错误折叠和进行性β细胞损失。这项工作的完成将不仅将PTTD及其类似物识别为Proinsulin错误折叠的第一类化学补充剂保护，但也将抑制抑制促硫素错误折叠为新的治疗方向糖尿病将作为基础并提供铅化合物，可以指导进一步发展 Proinsulin折叠疗法。