Discovery of Novel Binders to Sterol Regulatory Element-Binding Protein-1 by High-Throughput Screening

IF 3.5 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2024-04-17 DOI:10.1021/acsmedchemlett.4c00067

Takashi Maruyama, Yu Takahashi*, Kahori Hiro, Kohji Murase, Hirotatsu Kojima, Takayoshi Okabe, Yoshio Yamauchi and Ryuichiro Sato*,

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Abstract

Sterol regulatory element-binding protein-1 (SREBP-1) is a transcription factor that regulates the expression of genes related to fatty acid biosynthesis. Its high expression and activation in obesity and associated metabolic diseases make it a potential therapeutic target. However, the role of SREBP-1 in the development and exacerbation of these diseases remains unclear, partly because of the impossibility of inhibiting its function because of the lack of specific inhibitors. Here, we aimed to identify small-molecule compounds that directly bind to SREBP-1 using the recombinant N-terminal region of SREBP-1a, which is required for its transcriptional activity. A high-throughput screening campaign was conducted using a thermal shift assay and surface plasmon resonance assay to evaluate the compound affinity and specificity, which resulted in the identification of two compounds. Future analysis of their structure–activity relationships may lead to the development of specific SREBP-1 inhibitors, thereby potentially validating SREBP-1 as a therapeutic target for obesity and resultant atherosclerotic diseases.

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通过高通量筛选发现与甾醇调节因子结合蛋白-1 的新型结合剂

甾醇调节元件结合蛋白-1（SREBP-1）是一种转录因子，可调节与脂肪酸生物合成有关的基因的表达。它在肥胖症和相关代谢疾病中的高表达和激活使其成为潜在的治疗靶点。然而，SREBP-1 在这些疾病的发生和恶化中的作用仍不清楚，部分原因是由于缺乏特异性抑制剂而无法抑制其功能。在此，我们旨在利用SREBP-1a的重组N端区域（其转录活性需要该区域），鉴定能直接与SREBP-1结合的小分子化合物。为了评估化合物的亲和性和特异性，研究人员使用热转移分析法和表面等离子体共振分析法进行了高通量筛选，最终确定了两种化合物。今后对它们的结构-活性关系进行分析，可能会开发出特异性的 SREBP-1 抑制剂，从而有可能将 SREBP-1 作为肥胖症及其引起的动脉粥样硬化疾病的治疗靶点。

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来源期刊

ACS Medicinal Chemistry Letters CHEMISTRY, MEDICINAL-

CiteScore

7.30

自引率

2.40%

发文量

328

审稿时长

1 months

期刊介绍： ACS Medicinal Chemistry Letters is interested in receiving manuscripts that discuss various aspects of medicinal chemistry. The journal will publish studies that pertain to a broad range of subject matter, including compound design and optimization, biological evaluation, drug delivery, imaging agents, and pharmacology of both small and large bioactive molecules. Specific areas include but are not limited to: Identification, synthesis, and optimization of lead biologically active molecules and drugs (small molecules and biologics) Biological characterization of new molecular entities in the context of drug discovery Computational, cheminformatics, and structural studies for the identification or SAR analysis of bioactive molecules, ligands and their targets, etc. Novel and improved methodologies, including radiation biochemistry, with broad application to medicinal chemistry Discovery technologies for biologically active molecules from both synthetic and natural (plant and other) sources Pharmacokinetic/pharmacodynamic studies that address mechanisms underlying drug disposition and response Pharmacogenetic and pharmacogenomic studies used to enhance drug design and the translation of medicinal chemistry into the clinic Mechanistic drug metabolism and regulation of metabolic enzyme gene expression Chemistry patents relevant to the medicinal chemistry field.