A small molecule UPR modulator for diabetes identified by high throughput screening |
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| Authors: | 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 |
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| Affiliation: | Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA |
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| Abstract: | 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 chaperones. In addition, UPR also enhances degradation of unfolded proteins and reduces global protein synthesis to alleviate additional accumulation of unfolded proteins in the ER. Herein, 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 models. Using 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 expression. Furthermore, APC655 improved pancreatic β cell viability and insulin secretion under ER stress conditions induced by thapsigargin or cytokines. APC655 was also effective in preserving β cell function and decreasing lipid accumulation in the liver of the leptin-deficient (ob/ob) mouse model. These 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. |
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| Keywords: | Unfolded protein response Small molecules Protein folding Endoplasmic reticulum Chaperones Cell signaling Diabetes ER stress Liver Pancreas Metabolic diseases ASGR},{#name:keyword,$:{id:kwrd0075},$$:[{#name:text,_:asialoglycoprotein receptor 1 ATF4},{#name:keyword,$:{id:kwrd0085},$$:[{#name:text,_:activating transcription factor 4 ATF6},{#name:keyword,$:{id:kwrd0095},$$:[{#name:text,$$:[{#name:__text__,_:activating transcription factor 6},{#name:italic,_:α},{#name:__text__,_:/},{#name:italic,_:β BID},{#name:keyword,$:{id:kwrd0105},$$:[{#name:text,_:twice a day CLuc},{#name:keyword,$:{id:kwrd0115},$$:[{#name:text,$$:[{#name:italic,_:Cypridina},{#name:__text__,_: luciferase EGFP-VSVG},{#name:keyword,$:{id:kwrd0125},$$:[{#name:text,_:enhanced green fluorescence protein-vesicular stomatitis virus ts045 G protein ER},{#name:keyword,$:{id:kwrd0135},$$:[{#name:text,_:endoplasmic reticulum ERP72},{#name:keyword,$:{id:kwrd0145},$$:[{#name:text,_:endoplasmic reticulum proteins 72 GAPDH},{#name:keyword,$:{id:kwrd0155},$$:[{#name:text,_:glyceraldehyde 3-phosphate dehydrogenase GLuc},{#name:keyword,$:{id:kwrd0165},$$:[{#name:text,_:Gaussia luciferase GRP78},{#name:keyword,$:{id:kwrd0175},$$:[{#name:text,_:78-kDa glucose-regulated protein GRPRP94},{#name:keyword,$:{id:kwrd0185},$$:[{#name:text,_:glucose-regulated protein 94 GSIS},{#name:keyword,$:{id:kwrd0195},$$:[{#name:text,_:glucose stimulated insulin secretion inhibitor of nuclear factor kappa-B kinase subunit beta interferon gamma i.p.},{#name:keyword,$:{id:kwrd0235},$$:[{#name:text,_:intraperitoneal IRE1},{#name:keyword,$:{id:kwrd0245},$$:[{#name:text,$$:[{#name:__text__,_:inositol requiring enzyme 1},{#name:italic,_:α},{#name:__text__,_:/},{#name:italic,_:β NASH},{#name:keyword,$:{id:kwrd0255},$$:[{#name:text,_:nonalcoholic steatohepatitis nuclear factor kappa-light-chain-enhancer of activated B cells Nod},{#name:keyword,$:{id:kwrd0275},$$:[{#name:text,_:non-obese diabetic OGTT},{#name:keyword,$:{id:kwrd0285},$$:[{#name:text,_:oral glucose tolerance test PERK},{#name:keyword,$:{id:kwrd0295},$$:[{#name:text,_:PKR-like ER kinase SP1/2},{#name:keyword,$:{id:kwrd0305},$$:[{#name:text,_:serine protease1/2 T1/2D},{#name:keyword,$:{id:kwrd0315},$$:[{#name:text,_:type1/2 diabetes TG},{#name:keyword,$:{id:kwrd0325},$$:[{#name:text,_:thapsigargin Tm},{#name:keyword,$:{id:kwrd0335},$$:[{#name:text,_:tunicamycin tumor necrosis factor alpha uHTS},{#name:keyword,$:{id:kwrd0355},$$:[{#name:text,_:ultra-high throughput screening UPR},{#name:keyword,$:{id:kwrd0365},$$:[{#name:text,_:unfolded protein response XBP1},{#name:keyword,$:{id:kwrd0375},$$:[{#name:text,_:X-box-binding protein 1 |
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