文献类型：期刊文献

英文题名：N-Acylamino Saccharin as an Emerging Cysteine-Directed Covalent Warhead and Its Application in the Identification of Novel FBPase Inhibitors toward Glucose Reduction

作者：Wen, Wuqiang[1];Cao, Hongxuan[1];Xu, Yixiang[2];Ren, Yanliang[1,2];Rao, Li[1];Shao, Xubo[1];Chen, Han[1];Wu, Lixia[1];Liu, Jiaqi[1];Su, Chen[3];Peng, Chao[3];Huang, Yunyuan[1,2];Wan, Jian[1]

机构：[1]Cent China Normal Univ, Coll Chem, Key Lab Pesticide & Chem Biol CCNU, Minist Educ, Wuhan 430079, Peoples R China;[2]East China Univ Sci & Technol, Sch Pharm, Shanghai Key Lab New Drug Design, Shanghai 200237, Peoples R China;[3]Zhangjiang Lab, Natl Facil Prot Sci Shanghai, Shanghai 201210, Peoples R China

年份：2022

卷号：65

期号：13

起止页码：9126

外文期刊名：JOURNAL OF MEDICINAL CHEMISTRY

收录：;WOS:【SCI-EXPANDED(收录号:WOS:000826218000001)】；

基金：This work was supported by the Natural Science Foundation of China (Nos. 22177036, 21877046, and 21572077), the Program for PCSIRT (No. IRT0953), the Guizi Scholarship of CCNU (No. 31101222098), the self-determined research funds of CCNU from the colleges' basic research and operation of MOE (Nos. CCNU19TS011 and CCNU16A02041), and the support from the Program of Introducing Talents of Discipline to Universities of China (111 Program, B17019) is also appreciated.

语种：英文

摘要：ABSTRACT: With a resurgence of covalent drugs, there is an urgent need for the identification of new moieties capable of cysteine bond formation. Herein, we report on the N-acylamino saccharin moieties capable of novel covalent reactions with cysteine. Their utility as alternative electrophilic warheads was demonstrated through the covalent modification of fructose-1,6bisphosphatase (FBPase), a promising target associated with cancer and type 2 diabetes. The cocrystal structure of title compound W8 bound with FBPase unexpectedly revealed that the N-acylamino saccharin moiety worked as an electrophile warhead that covalently modified the noncatalytic C128 site in FBPase while releasing saccharin, suggesting a previously undiscovered covalent reaction mechanism of saccharin derivatives with cysteine. Treatment of title compound W8 displayed potent inhibition of glucose production in vitro and in vivo. This newly discovered reactive warhead supplements the current repertoire of cysteine covalent modifiers while avoiding some of the limitations generally associated with established moieties.