亚氨基糖
内质网
化学
酶
糖蛋白
钙连接素
生物化学
活动站点
体外
钙网蛋白
作者
S.S. Karade,Evelyn J Franco,Ana C Rojas,Kaley C Hanrahan,А. С. Колесников,Wenbo Yu,Alexander D. MacKerell,Daniel C Hill,David J. Weber,Ashley N. Brown,Anthony M. Treston,Roy A. Mariuzza
标识
DOI:10.1021/acs.jmedchem.2c01750
摘要
Enveloped viruses depend on the host endoplasmic reticulum (ER) quality control (QC) machinery for proper glycoprotein folding. The endoplasmic reticulum quality control (ERQC) enzyme α-glucosidase I (α-GluI) is an attractive target for developing broad-spectrum antivirals. We synthesized 28 inhibitors designed to interact with all four subsites of the α-GluI active site. These inhibitors are derivatives of the iminosugars 1-deoxynojirimycin (1-DNJ) and valiolamine. Crystal structures of ER α-GluI bound to 25 1-DNJ and three valiolamine derivatives revealed the basis for inhibitory potency. We established the structure-activity relationship (SAR) and used the Site Identification by Ligand Competitive Saturation (SILCS) method to develop a model for predicting α-GluI inhibition. We screened the compounds against SARS-CoV-2 in vitro to identify those with greater antiviral activity than the benchmark α-glucosidase inhibitor UV-4. These host-targeting compounds are candidates for investigation in animal models of SARS-CoV-2 and for testing against other viruses that rely on ERQC for correct glycoprotein folding.
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