依培力松类似物，作为CDKAL1的原核同源物，MiaB缺陷的救援者，抑制大鼠血糖升高。

IF 4 3区医学 Q2 CHEMISTRY, MEDICINAL ACS Medicinal Chemistry Letters Pub Date : 2025-01-17 eCollection Date: 2025-02-13 DOI:10.1021/acsmedchemlett.4c00560

Manabu Tejima, Tomoko Hashimoto, Osamu Ohno, Tomoyuki Hoshina, Kotaro Takasaki, Shintaro Taniguchi, Kanako Nakamura, Fan-Yan Wei, Kazuhito Tomizawa, Kenji Matsuno

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引用次数: 0

摘要

Cdk5调控相关蛋白1-样1 （CDKAL1）是2型糖尿病（T2DM）最可靠的危险基因之一。由于CDKAL1通过KATP通道的反应性和对Lys密码子的忠实解码来控制葡萄糖诱导的胰岛素分泌，从而防止胰腺β细胞的误翻译，因此CDKAL1缺陷的拯救剂有望成为一种新的抗糖尿病药物。我们发现，培力松类似物有效地挽救了MiaB缺陷大肠杆菌双荧光素酶报告基因系统（MiaB是真核CDKAL1的原核同源物）中的误翻译。其中，化合物1f和1t在Wister大鼠皮下口服糖耐量试验中显示出明显的降糖作用，同时显著增强MIN6胰岛素瘤细胞系的胰岛素分泌，但无细胞毒性。这些结果表明CDKAL1可能是一种新的抗t2dm药物的可行分子靶点。

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Eperisone Analogs, Rescuers of MiaB Defects As a Prokaryotic Homologue of CDKAL1, Suppress Blood Glucose Elevation in Rats.

Cdk5 regulatory associated protein 1-like 1 (CDKAL1) is one of the most reliable risk genes for type 2 diabetes mellitus (T2DM). Because CDKAL1 controls glucose-induced insulin secretion by K_ATP channel responsiveness and faithful decoding of Lys codons to prevent mistranslation in pancreatic β-cells, a rescuer of CDKAL1 defects is expected as a new antidiabetes drug. We found that eperisone analogs effectively rescued mistranslation in a MiaB-deficient Escherichia coli dual-luciferase reporter gene system (MiaB is a prokaryotic homologue of eukaryotic CDKAL1). Among them, compounds 1f and 1t demonstrated significant antihyperglycemic efficacy in an oral glucose tolerance test by subcutaneous administration in Wister rats, along with a significant enhancement of insulin secretion in the MIN6 insulinoma cell line without cytotoxicity. These results indicate that CDKAL1 could be a viable molecular target for a new anti-T2DM medication.

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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.