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:
  • 金额:
    $ 38.42万
  • 依托单位:
  • 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

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

项目成果

期刊论文数量(0)
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Weidong Wang其他文献

Weidong Wang的其他文献

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{{ truncateString('Weidong Wang', 18)}}的其他基金

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:
    10529960
  • 财政年份:
    2022
  • 资助金额:
    $ 38.42万
  • 项目类别:
Preclinical Validation of PPARg Acetylation Inhibitors for Diabetes Prevention and Treatment
PPARg 乙酰化抑制剂预防和治疗糖尿病的临床前验证
  • 批准号:
    10580851
  • 财政年份:
    2021
  • 资助金额:
    $ 38.42万
  • 项目类别:
Cytoprotection and the mechanism of action of a natural product Khellin against ER stress
天然产物 Khellin 对抗 ER 应激的细胞保护和作用机制
  • 批准号:
    9974514
  • 财政年份:
    2018
  • 资助金额:
    $ 38.42万
  • 项目类别:
Cytoprotection and the mechanism of action of a natural product Khellin against ER stress
天然产物 Khellin 对抗 ER 应激的细胞保护和作用机制
  • 批准号:
    10285537
  • 财政年份:
    2018
  • 资助金额:
    $ 38.42万
  • 项目类别:
Preclinical Development of Khellin Analogs for Anti-Diabetic Therapy
用于抗糖尿病治疗的 Khellin 类似物的临床前开发
  • 批准号:
    9336063
  • 财政年份:
    2016
  • 资助金额:
    $ 38.42万
  • 项目类别:
Preclinical Development of Khellin Analogs for Anti-Diabetic Therapy
用于抗糖尿病治疗的 Khellin 类似物的临床前开发
  • 批准号:
    9353780
  • 财政年份:
    2016
  • 资助金额:
    $ 38.42万
  • 项目类别:
Structural And Functional Studies Of Human Swi/snf Chromatin-remodeling
人类 Swi/snf 染色质重塑的结构和功能研究
  • 批准号:
    10467892
  • 财政年份:
  • 资助金额:
    $ 38.42万
  • 项目类别:
Investigating the roles of Topoisomerase 3b-TDRD3 complex in neurodegeneration and Alzheimer's disease
研究拓扑异构酶 3b-TDRD3 复合物在神经退行性疾病和阿尔茨海默病中的作用
  • 批准号:
    10469229
  • 财政年份:
  • 资助金额:
    $ 38.42万
  • 项目类别:
Identification and Characterization of human Rsc Chromatin-Remodeling Complex
人类 Rsc 染色质重塑复合物的鉴定和表征
  • 批准号:
    6431445
  • 财政年份:
  • 资助金额:
    $ 38.42万
  • 项目类别:
Identification Of A Complex Involved In Bloom Syndrome
布卢姆综合征相关复合物的鉴定
  • 批准号:
    6668115
  • 财政年份:
  • 资助金额:
    $ 38.42万
  • 项目类别:

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