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Novel screening platform for O-GlcNAc transferase substrate-specific inhibitors to combat aging-related diseases

Novel screening platform for O-GlcNAc transferase substrate-specific inhibitors to combat aging-related diseases
用于对抗衰老相关疾病的 O-GlcNAc 转移酶底物特异性抑制剂的新型筛选平台
批准号:
10287662
负责人:
Arielis Estevez Davila
金额:
$7.13万
依托单位国家:
美国
项目类别:
财政年份:
2021
资助国家:
美国
项目状态:
已结题
起止时间:
2021-09-01 至 2023-05-31

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英文摘要
Project Summary The O-linked β-N-acetylglucosamine (O-GlcNAc) is an essential post-translational modification found in thousands of proteins involved in a broad range of important biological processes, including epigenetics, metabolism, and protein degradation. The O-GlcNAc modification is dynamically added and removed by a single pair of human enzymes, O-GlcNAc transferase (OGT) and O-GlcNAcase (OGA), respectively. Dysregulation of O-GlcNAcylation has been detected in many aging-related diseases including cancer, diabetes, Alzheimer’s and Huntington’s disease. To date, several effective active-site inhibitors have been reported for OGT and OGA, but they are likely to induce undesired side effects as these essential enzymes regulate O-GlcNAc dynamics on thousands of protein substrates. Currently, there is no report on substrate-specific inhibitors of OGT or OGA, largely due to the lack of suitable assays. Here, I propose to develop a novel high-throughput screening assay for identifying small molecules that can specifically bind to different regions of OGT and modulate O-GlcNAcylation of a particular protein of interest without perturbing the global O-GlcNAc level in cells. From the proposed screen and the following in vitro and cellular characterization and optimization processes, I expect to identify several compounds as the first generation of substrate-specific inhibitor candidates of OGT that can modulate O-GlcNAcylation on particular proteins related to aging diseases. This new assay platform can be potentially adapted for other protein substrates and facilitate the therapeutic development to combat aging disorders.
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Novel screening platform for O-GlcNAc transferase substrate-specific inhibitors to combat aging-related diseases
  • 批准号:
    10475192
  • 项目类别:
  • 资助金额:
    $7.19万
  • 财政年份:
    2021
  • 负责人:
    Arielis Estevez Davila
  • 依托单位:
海外基金