دورية أكاديمية
أعرض في EDS

Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity.

التفاصيل البيبلوغرافية
العنوان: Structure-Based Design of Potent Iminosugar Inhibitors of Endoplasmic Reticulum α-Glucosidase I with Anti-SARS-CoV-2 Activity.
المؤلفون: Karade SS; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States., Franco EJ; Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, Florida 32827, United States., Rojas AC; Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, Florida 32827, United States., Hanrahan KC; Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, Florida 32827, United States., Kolesnikov A; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States., Yu W; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States.; Center for Biomolecular Therapeutics (CBT), Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States., MacKerell AD Jr; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Computer-Aided Drug Design Center, Department of Pharmaceutical Sciences, School of Pharmacy, University of Maryland, Baltimore, Maryland 21201, United States.; Center for Biomolecular Therapeutics (CBT), Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States., Hill DC; Emergent BioSolutions, Gaithersburg, Maryland 20879, United States., Weber DJ; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Center for Biomolecular Therapeutics (CBT), Department of Biochemistry and Molecular Biology, School of Medicine, University of Maryland, Baltimore, Maryland 21201, United States., Brown AN; Institute for Therapeutic Innovation, Department of Medicine, College of Medicine, University of Florida, Orlando, Florida 32827, United States., Treston AM; Emergent BioSolutions, Gaithersburg, Maryland 20879, United States., Mariuzza RA; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States.
المصدر: Journal of medicinal chemistry [J Med Chem] 2023 Feb 23; Vol. 66 (4), pp. 2744-2760. Date of Electronic Publication: 2023 Feb 10.
نوع المنشور: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't; Research Support, U.S. Gov't, Non-P.H.S.
اللغة: English
بيانات الدورية: Publisher: American Chemical Society Country of Publication: United States NLM ID: 9716531 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1520-4804 (Electronic) Linking ISSN: 00222623 NLM ISO Abbreviation: J Med Chem Subsets: MEDLINE
أسماء مطبوعة: Publication: Washington Dc : American Chemical Society
Original Publication: [Easton, Pa.] : American Chemical Society, [c1963-
مواضيع طبية MeSH: 1-Deoxynojirimycin*/chemistry , 1-Deoxynojirimycin*/pharmacology , alpha-Glucosidases*/drug effects , Antiviral Agents*/chemistry , Antiviral Agents*/pharmacology , COVID-19* , Glycoside Hydrolase Inhibitors*/chemistry , Glycoside Hydrolase Inhibitors*/pharmacology, Animals ; Endoplasmic Reticulum/enzymology ; Glycoproteins ; SARS-CoV-2/metabolism ; Quantitative Structure-Activity Relationship
مستخلص: 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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معلومات مُعتمدة: P30 GM133894 United States GM NIGMS NIH HHS; R35 GM131710 United States GM NIGMS NIH HHS
المشرفين على المادة: 19130-96-2 (1-Deoxynojirimycin)
EC 3.2.1.20 (alpha-Glucosidases)
0 (Antiviral Agents)
EC 3.2.1.- (glucosidase I)
0 (Glycoproteins)
0 (Glycoside Hydrolase Inhibitors)
83465-22-9 (valiolamine)
تواريخ الأحداث: Date Created: 20230210 Date Completed: 20230320 Latest Revision: 20240224
رمز التحديث: 20240224
مُعرف محوري في PubMed: PMC10278443
DOI: 10.1021/acs.jmedchem.2c01750
PMID: 36762932
قاعدة البيانات: MEDLINE
الوصف
تدمد:1520-4804
DOI:10.1021/acs.jmedchem.2c01750