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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：
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
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/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

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.

摘要