N-Substituted Valiolamine Derivatives as Potent Inhibitors of Endoplasmic Reticulum α-Glucosidases I and II with Antiviral Activity

  • J Med Chem. 2021 Dec 23;64(24):18010-18024. doi: 10.1021/acs.jmedchem.1c01377.
Sharanbasappa S Karade  1  2 ,  Michelle L Hill  3 ,  J L Kiappes  4 ,  Rajkumar Manne  5 ,  Balakishan Aakula  5 ,  Nicole Zitzmann  3 ,  Kelly L Warfield  6 ,  Anthony M Treston  6 ,  Roy A Mariuzza  1  2
Affiliations
  • 1. University of Maryland Institute for Bioscience and Biotechnology Research, Rockville, Maryland 20850, United States.
  • 2. Department of Cell Biology and Molecular Genetics, University of Maryland, College Park, Maryland 20742, United States.
  • 3. Oxford Glycobiology Institute, Department of Biochemistry, University of Oxford, Oxford OX1 3QU, U.K.
  • 4. Department of Chemistry, University College, London WC1H 0AJ, U.K.
  • 5. Sai Life Sciences Ltd., Hyderabad, 500032 Telangana, India.
  • 6. Emergent BioSolutions, Gaithersburg, Maryland 20879, United States.
PMID: 34870992 DOI: 10.1021/acs.jmedchem.1c01377
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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