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Selective immunoproteasome inhibitors with non-peptide scaffolds identified from structure-based virtual screening
Institution:1. Molecular Modeling and Biopharmaceutical Center, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States;2. Department of Pharmaceutical Sciences, College of Pharmacy, University of Kentucky, 789 South Limestone Street, Lexington, KY 40536, United States;1. Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta, GA 30322, USA;2. Department of Microbiology and Immunology, Emory University School of Medicine, 1510 Clifton Road, Atlanta, GA 30322, USA;3. Yerkes National Primate Research Center, Emory University, 201 Dowman Drive, Atlanta, GA 30322, USA;1. Shanghai Key Laboratory of New Drug Design, State Key Laboratory of Bioreactor Engineering, School of Pharmacy, East China University of Science and Technology, Shanghai 200237, China;2. Department of Phytochemistry, School of Pharmacy, Second Military Medical University, Shanghai 200433, China;1. Enzymologie Moléculaire et Fonctionnelle, UR4, Université Pierre et Marie Curie – Sorbonne Universités (UPMC), case courrier 256, 7, quai St Bernard, 75252 Paris Cedex 05, France;2. Molécules Thérapeutiques in silico (MTi), Université Paris-Diderot, Inserm UMR-S, 973 Lamarck Building, 35 rue Hélène Brion, 75205 Paris Cedex 13, France;3. INSERM U781, Université Paris Descartes – Sorbonne Paris Cité, Institut Imagine, Necker Hospital, 149 rue de Sèvres, France;4. Department of Genetics, Necker Hospital, 149 rue de Sèvres, 75743 Paris Cedex 15, France;1. Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, Stanford University, 300 Pasteur Drive, HH333, Stanford, CA 94305-5317, USA;2. Biomaterials and Advanced Drug Delivery Laboratory, Stanford University, Stanford, CA, USA
Abstract:As a major component of the crucial nonlysosomal protein degradation pathway in the cells, the proteasome has been implicated in many diseases such as Alzheimer’s disease, Huntington’s disease, inflammatory bowel diseases, autoimmune diseases, multiple myeloma (MM) and other cancers. There are two main proteasome subtypes: the constitutive proteasome which is expressed in all eukaryotic cells and the immunoproteasome which is expressed in immune cells and can be induced in other cell types. Majority of currently available proteasome inhibitors are peptide backbone-based, having short half-lives in the body. It is highly desirable to identify novel, immunoproteasome-selective inhibitors with non-peptide scaffolds for development of novel therapeutics. Through combined virtual screening and experimental studies targeting the immunoproteasome, we have identified a set of novel immunoproteasome inhibitors with diverse non-peptide scaffolds. Some of the identified inhibitors have significant selectivity for the immunoproteasome over the constitutive proteasome. Unlike most of the currently available proteasome inhibitors, these new inhibitors lacking electrophilic pharmacophores are not expected to form a covalent bond with proteasome after the binding. These non-peptide scaffolds may provide a new platform for future rational drug design and discovery targeting the immunoproteasome.
Keywords:Immunoproteasome  Selective inhibitor  Non-peptide scaffold  Inhibitor identification
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