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N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity.
Karade, Sharanbasappa S; Hill, Michelle L; Kiappes, J L; Manne, Rajkumar; Aakula, Balakishan; Zitzmann, Nicole; Warfield, Kelly L; Treston, Anthony M; Mariuzza, Roy A.
  • Karade SS; University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.
  • Hill ML; Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States.
  • Kiappes JL; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, U.K.
  • Manne R; Department of Chemistry, University College, London WC1H 0AJ, U.K.
  • Aakula B; Sai Life Sciences Ltd., Hyderabad, 500032 Telangana, India.
  • Zitzmann N; Sai Life Sciences Ltd., Hyderabad, 500032 Telangana, India.
  • Warfield KL; Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, U.K.
  • Treston AM; Emergent BioSolutions, Gaithersburg, Maryland 20879, United States.
  • Mariuzza RA; Emergent BioSolutions, Gaithersburg, Maryland 20879, United States.
J Med Chem ; 64(24): 18010-18024, 2021 12 23.
Article in English | MEDLINE | ID: covidwho-1616926
ABSTRACT
Most enveloped viruses rely on the host cell endoplasmic reticulum (ER) quality control (QC) machinery for proper folding of glycoproteins. The key ER α-glucosidases (α-Glu) I and II of the ERQC machinery are attractive targets for developing broad-spectrum antivirals. Iminosugars based on deoxynojirimycin have been extensively studied as ER α-glucosidase inhibitors; however, other glycomimetic compounds are less established. Accordingly, we synthesized a series of N-substituted derivatives of valiolamine, the iminosugar scaffold of type 2 diabetes drug voglibose. To understand the basis for up to 100,000-fold improved inhibitory potency, we determined high-resolution crystal structures of mouse ER α-GluII in complex with valiolamine and 10 derivatives. The structures revealed extensive interactions with all four α-GluII subsites. We further showed that N-substituted valiolamines were active against dengue virus and SARS-CoV-2 in vitro. This study introduces valiolamine-based inhibitors of the ERQC machinery as candidates for developing potential broad-spectrum therapeutics against the existing and emerging viruses.
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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Imino Sugars / Alpha-Glucosidases / Glycoside Hydrolase Inhibitors / Inositol Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c01377

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Full text: Available Collection: International databases Database: MEDLINE Main subject: Antiviral Agents / Imino Sugars / Alpha-Glucosidases / Glycoside Hydrolase Inhibitors / Inositol Limits: Animals / Humans Language: English Journal: J Med Chem Journal subject: Chemistry Year: 2021 Document Type: Article Affiliation country: Acs.jmedchem.1c01377