文献类型：期刊文献

英文题名：Development of disulfide-derived fructose-1,6-bisphosphatase (FBPase) covalent inhibitors for the treatment of type 2 diabetes

作者：Xu, Yi-xiang[1];Huang, Yun-yuan[1,2];Song, Rong-rong[2];Ren, Yan-liang[2];Chen, Xin[1];Zhang, Chao[1];Mao, Fei[1];Li, Xiao-kang[1];Zhu, Jin[1];Ni, Shuai-shuai[3];Wan, Jian[2];Li, Jian[1]

机构：[1]East China Univ Sci & Technol, Sch Pharm, State Key Lab Bioreactor Engn, Shanghai Key Lab New Drug Design, 130 Mei Long Rd, Shanghai 200237, Peoples R China;[2]Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol CCNU, Minist Educ, Wuhan 430079, Peoples R China;[3]Shanghai Univ Tradit Chinese Med, Canc Inst, Longhua Hosp, 725 South Wan Ping Rd, Shanghai 200032, Peoples R China

年份：2020

卷号：203

外文期刊名：EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000568867400004)】；

基金：Financial support for this research provided by the National Natural Science Foundation of China (Grant 81872747), the Innovative Research Team of High-level Local Universities in Shanghai, the 111 Project (Grant B07023), and the National Special Fund for State Key Laboratory of Bioreactor Engineering (Grant 2060204) are gratefully acknowledged. The authors thank Research Center of Analysis and Test of East China University of Science and Technology for the help on the characterization.

语种：英文

外文关键词：Diabetes; FBPase; Disulfiram; Covalent inhibitors; Drug repurposing

摘要：Fructose-1,6-bisphosphatase (FBPase), as a key rate-limiting enzyme in the gluconeogenesis (GNG) pathway, represents a practical therapeutic strategy for type 2 diabetes (T2D). Our previous work first identified cysteine residue 128 (C128) was an important allosteric site in the structure of FBPase, while pharmacologically targeting C128 attenuated the catalytic ability of FBPase. Herein, ten approved cysteine covalent drugs were selected for exploring FBPase inhibitory activities, and the alcohol deterrent disulfiram displayed superior inhibitory efficacy among those drugs. Based on the structure of lead compound disulfiram, 58 disulfide-derived compounds were designed and synthesized for investigating FBPase inhibitory activities. Optimal compound 3a exhibited significant FBPase inhibition and glucose-lowering efficacy in vitro and in vivo. Furthermore, 3a covalently modified the C128 site, and then regulated the N125-S124-S123 allosteric pathway of FBPase in mechanism. In summary, 3a has the potential to be a novel FBPase inhibitor for T2D therapy. (C) 2020 Elsevier Masson SAS. All rights reserved.