Guay Kevin P, Ibba Roberta, Kiappes J L, Vasiljević Snežana, Bonì Francesco, De Benedictis Maria, Zeni Ilaria, Le Cornu James D, Hensen Mario, Chandran Anu V, Kantsadi Anastassia L, Caputo Alessandro T, Blanco Capurro Juan I, Bayo Yusupha, Hill Johan C, Hudson Kieran, Lia Andrea, Brun Juliane, Withers Stephen G, Martí Marcelo, Biasini Emiliano, Santino Angelo, De Rosa Matteo, Milani Mario, Modenutti Carlos P, Hebert Daniel N, Zitzmann Nicole, Roversi Pietro
Department of Biochemistry and Molecular Biology, and Program in Molecular and Cellular Biology, University of Massachusetts, Amherst, MA, USA.
Oxford Glycobiology Institute, Department of Biochemistry and Kavli Institute for Nanoscience Discovery, South Parks Road, Oxford OX1 3QU, UK.
iScience. 2023 Sep 20;26(10):107919. doi: 10.1016/j.isci.2023.107919. eCollection 2023 Oct 20.
Misfolded glycoprotein recognition and endoplasmic reticulum (ER) retention are mediated by the ER glycoprotein folding quality control (ERQC) checkpoint enzyme, UDP-glucose glycoprotein glucosyltransferase (UGGT). UGGT modulation is a promising strategy for broad-spectrum antivirals, rescue-of-secretion therapy in rare disease caused by responsive mutations in glycoprotein genes, and many cancers, but to date no selective UGGT inhibitors are known. The small molecule 5-[(morpholin-4-yl)methyl]quinolin-8-ol (5M-8OH-Q) binds a UGGT "WY" conserved surface motif conserved across UGGTs but not present in other GT24 family glycosyltransferases. 5M-8OH-Q has a 47 μM binding affinity for UGGT as measured by ligand-enhanced fluorescence. , 5M-8OH-Q inhibits both human UGGT isoforms at concentrations higher than 750 μM. 5M-8OH-Q binding to UGGT appears to be mutually exclusive to M5-9 glycan binding in an competition experiment. A medicinal program based on 5M-8OH-Q will yield the next generation of UGGT inhibitors.
错误折叠的糖蛋白识别和内质网（ER）滞留由内质网糖蛋白折叠质量控制（ERQC）检查点酶UDP-葡萄糖糖蛋白葡糖基转移酶（UGGT）介导。UGGT调节是一种有前景的策略，可用于开发广谱抗病毒药物、治疗由糖蛋白基因中响应性突变引起的罕见疾病的分泌挽救疗法以及多种癌症，但迄今为止尚无已知的选择性UGGT抑制剂。小分子5-[(吗啉-4-基)甲基]喹啉-8-醇（5M-8OH-Q）结合UGGT的一个“WY”保守表面基序，该基序在所有UGGT中保守，但在其他GT24家族糖基转移酶中不存在。通过配体增强荧光测量，5M-8OH-Q对UGGT的结合亲和力为47μM。此外，5M-8OH-Q在浓度高于750μM时可抑制两种人类UGGT同工型。在竞争实验中，5M-8OH-Q与UGGT的结合似乎与M5-9聚糖结合相互排斥。基于5M-8OH-Q的药物研发计划将产生下一代UGGT抑制剂。
