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

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

Author: Valeria MARROCCO ¹ ; Tuan TRAN ¹ ; Siying ZHU ¹ ; Seung Hyuk CHOI ¹ ; Ana M GAMO ¹ ; Sijia LI ¹ ; Qiangwei FU ¹ ; Marta Diez CUNADO ¹ ; Jason ROLAND ¹ ; Mitch HULL ¹ ; Van NGUYEN-TRAN ¹ ; Sean JOSEPH ¹ ; Arnab K CHATTERJEE ¹ ; Nikki ROGERS ¹ ; Matthew S TREMBLAY ¹ ; Weijun SHEN ¹
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1. Calibr at Scripps Research, The Scripps Research Institute, La Jolla, CA 92037, USA.
Publication Type:Journal Article
Keywords: ASGR, asialoglycoprotein receptor 1; ATF4, activating transcription factor 4; ATF6, activating transcription factor 6α/β; BID, twice a day; CLuc, Cypridina luciferase; Cell signaling; Chaperones; Diabetes; EGFP-VSVG, enhanced green fluorescence protein-vesicular stomatitis virus ts045 G protein; ER stress; ER, endoplasmic reticulum; ERP72, endoplasmic reticulum proteins 72; Endoplasmic reticulum; GAPDH, glyceraldehyde 3-phosphate dehydrogenase; GLuc, Gaussia luciferase; GRP78, 78-kDa glucose-regulated protein; GRPRP94, glucose-regulated protein 94; GSIS, glucose stimulated insulin secretion; IKKβ, inhibitor of nuclear factor kappa-B kinase subunit beta; IL1β, interleukin 1β; INFγ, interferon gamma; IRE1, inositol requiring enzyme 1α/β; Liver; Metabolic diseases; NASH, nonalcoholic steatohepatitis; NF-κB, nuclear factor kappa-light-chain-enhancer of activated B cells; Nod, non-obese diabetic; OGTT, oral glucose tolerance test; PERK, PKR-like ER kinase; Pancreas; Protein folding; SP1/2, serine protease1/2; Small molecules; T1/2D, type1/2 diabetes; TG, thapsigargin; TNFα, tumor necrosis factor alpha; Tm, tunicamycin; UPR, unfolded protein response; Unfolded protein response; XBP1, X-box-binding protein 1; i.p., intraperitoneal; uHTS, ultra-high throughput screening; β cells
From: Acta Pharmaceutica Sinica B 2021;11(12):3983-3993
CountryChina
Language:English
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