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科学家发现一种可口服的糖尿病治疗小分子药物
2020-07-30 09:55

近日,美国阿拉巴马大学Anath Shalev课题组鉴定出一种可口服的糖尿病治疗小分子药物。这一研究成果于2020年7月28日在线发表在《细胞—代谢》上。

研究人员对300,000种化合物进行了高通量筛选,并进行了广泛的药物化学优化,并报告了SRI-37330的发现,这是一种口服生物可利用的无毒小分子,可从链脲佐菌素和肥胖症诱导(db/db )的小鼠中有效挽救糖尿病。
 
有趣的是,在大鼠细胞以及小鼠和人类的胰岛中,SRI-37330抑制了硫氧还蛋白相互作用蛋白的表达和信号传导,研究人员先前发现该蛋白在糖尿病中升高,并且对胰岛功能有不利影响。
 
此外,SRI-37330治疗可抑制胰高血糖素的分泌和功能,减少肝脏葡萄糖的产生,并逆转肝脏脂肪变性。因此,这些研究描述了一种新设计的化合物,与目前可用的疗法相比,可以提供一种独特而有效的糖尿病治疗方法。
 
据悉,糖尿病的特征在于高血糖症、功能性胰岛β细胞量的丢失、葡萄糖降低胰岛素的缺乏以及糖异生胰高血糖素的持续分泌。目前仍然没有针对这些基本过程的疗法。
 
附:英文原文

Title: Identification of an Anti-diabetic, Orally Available Small Molecule that Regulates TXNIP Expression and Glucagon Action

Author: Lance A. Thielen, Junqin Chen, Gu Jing, Omar Moukha-Chafiq, Guanlan Xu, SeongHo Jo, Truman B. Grayson, Brian Lu, Peng Li, Corinne E. Augelli-Szafran, Mark J. Suto, Matt Kanke, Praveen Sethupathy, Jason K. Kim, Anath Shalev

Issue&Volume: 2020-07-28

Abstract: Diabetes is characterized by hyperglycemia, loss of functional islet beta cell mass,deficiency of glucose-lowering insulin, and persistent alpha cell secretion of gluconeogenicglucagon. Still, no therapies that target these underlying processes are available.We therefore performed high-throughput screening of 300,000 compounds and extensivemedicinal chemistry optimization and here report the discovery of SRI-37330, an orallybioavailable, non-toxic small molecule, which effectively rescued mice from streptozotocin-and obesity-induced (db/db) diabetes. Interestingly, in rat cells and in mouse and human islets, SRI-37330 inhibitedexpression and signaling of thioredoxin-interacting protein, which we have previouslyfound to be elevated in diabetes and to have detrimental effects on islet function.In addition, SRI-37330 treatment inhibited glucagon secretion and function, reducedhepatic glucose production, and reversed hepatic steatosis. Thus, these studies describea newly designed chemical compound that, compared to currently available therapies,may provide a distinct and effective approach to treating diabetes.

DOI: 10.1016/j.cmet.2020.07.002

Source: https://www.cell.com/cell-metabolism/fulltext/S1550-4131(20)30360-0

Cell Metabolism:《细胞—代谢》,创刊于2005年。隶属于细胞出版社,最新IF:22.415
官方网址:https://www.cell.com/cell-metabolism/home
投稿链接:https://www.editorialmanager.com/cell-metabolism/default.aspx


本期文章:《细胞—代谢》:Online/在线发表

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