A small molecule UPR modulator for diabetes identified by high throughput screening

作     者：Valeria Marrocco Tuan Tran Siying Zhu Seung Hyuk Choi Ana M.Gamo Sijia Li Qiangwei Fu Marta Diez Cunado Jason Roland Mitch Hull Van Nguyen-Tran Sean Joseph Arnab K.Chatterjee Nikki Rogers Matthew S.Tremblay Weijun Shen Valeria Marrocco;Tuan Tran;Siying Zhu;Seung Hyuk Choi;Ana M.Gamo;Sijia Li;Qiangwei Fu;Marta Diez Cunado;Jason Roland;Mitch Hull;Van Nguyen-Tran;Sean Joseph;Arnab K.Chatterjee;Nikki Rogers;Matthew S.Tremblay;Weijun Shen

作者机构：Calibr at Scripps ResearchThe Scripps Research InstituteLa JollaCA 92037USA 

出 版 物：《Acta Pharmaceutica Sinica B》 (药学学报（英文版）)

年 卷 期：2021年第11卷第12期

页      面：3983-3993页

核心收录：

学科分类：1007[医学-药学(可授医学、理学学位)] 1006[医学-中西医结合] 100706[医学-药理学] 100602[医学-中西医结合临床] 10[医学] 

基　　金：supported by the Juvenile Diabetes Research Foundation (JDRF) [3-PAR-2016-241-I-X  US] 

主　　题：βcells Unfolded protein response Small molecules Protein folding Endoplasmic reticulum Chaperones Cell signaling Diabetes ER stress Liver Pancreas Metabolic diseases 

摘      要：Unfolded protein response(UPR) is a stress response that is specific to the endoplasmic reticulum(ER).UPR is activated upon accumulation of unfolded(or misfolded) proteins in the ER s lumen to restore protein folding capacity by increasing the synthesis of *** addition,UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ***,we describe a cell-based ultra-high throughput screening(uHTS) campaign that identifies a small molecule that can modulate UPR and ER stress in cellular and in vivo disease *** asialoglycoprotein receptor 1(ASGR) fused with Cypridina luciferase(CLuc) as reporter assay for folding capacity,we have screened a million small molecule library and identified APC655 as a potent activator of protein folding,that appears to act by promoting chaperone ***,APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or ***655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient(ob/ob) mouse *** results demonstrate a successful uHTS campaign that identified a modulator of UPR,which can provide a novel candidate for potential therapeutic development for a host of metabolic diseases.