20S Proteasome Inhibition: Designing Noncovalent Linear Peptide Mimics of the Natural Product TMC-95A

Authors

  • Prof. Dr. Michael Groll,

    1. Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany), Fax: (+49) 89-289-13363
    Search for more papers by this author
  • Nerea Gallastegui,

    1. Center for Integrated Protein Science at the Department Chemie, Lehrstuhl für Biochemie, Technische Universität München, Lichtenbergstr. 4, 85747 Garching (Germany), Fax: (+49) 89-289-13363
    Search for more papers by this author
  • Xavier Maréchal,

    1. Enzymologie Moléculaire et Fonctionnelle, UR4-UPMC, Case 256, 6eme Étage A, 7 Quai St-Bernard 75252 Paris Cedex 05 (France), Fax: (+33) 144-27-5022
    Search for more papers by this author
  • Dr. Virginie Le Ravalec,

    1. Chimie et Photonique Moléculaires, Université de Rennes 1, CNRS UMR 6510, Bâtiment 10, Case 1012, Campus de Beaulieu, 35042 Rennes Cedex (France), Fax: (+33) 223-23-6955
    Search for more papers by this author
  • Dr. Nicolas Basse,

    1. Enzymologie Moléculaire et Fonctionnelle, UR4-UPMC, Case 256, 6eme Étage A, 7 Quai St-Bernard 75252 Paris Cedex 05 (France), Fax: (+33) 144-27-5022
    Search for more papers by this author
  • Dr. Nicolas Richy,

    1. Chimie et Photonique Moléculaires, Université de Rennes 1, CNRS UMR 6510, Bâtiment 10, Case 1012, Campus de Beaulieu, 35042 Rennes Cedex (France), Fax: (+33) 223-23-6955
    Search for more papers by this author
  • Dr. Emilie Genin,

    1. Chimie et Photonique Moléculaires, Université de Rennes 1, CNRS UMR 6510, Bâtiment 10, Case 1012, Campus de Beaulieu, 35042 Rennes Cedex (France), Fax: (+33) 223-23-6955
    Search for more papers by this author
  • Prof. Dr. Robert Huber,

    1. Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, 82152 Martinsried (Germany)
    Search for more papers by this author
  • Prof. Dr. Luis Moroder,

    1. Max-Planck-Institut für Biochemie, Am Klopferspitz 18a, 82152 Martinsried (Germany)
    Search for more papers by this author
  • Prof. Dr. Joëlle Vidal,

    1. Chimie et Photonique Moléculaires, Université de Rennes 1, CNRS UMR 6510, Bâtiment 10, Case 1012, Campus de Beaulieu, 35042 Rennes Cedex (France), Fax: (+33) 223-23-6955
    Search for more papers by this author
  • Prof. Dr. Michèle Reboud-Ravaux

    1. Enzymologie Moléculaire et Fonctionnelle, UR4-UPMC, Case 256, 6eme Étage A, 7 Quai St-Bernard 75252 Paris Cedex 05 (France), Fax: (+33) 144-27-5022
    Search for more papers by this author

Abstract

original image

Stop the shredder: The 20S proteasome maintains homeostasis and regulates important intracellular processes by subjecting most intracellular proteins to endoproteolytic cleavage. This complex hydrolysis machinery has received considerable attention for the treatment of many diseases, including cancer. We report a new set of noncovalent peptide mimics based on TMC-95A and our rational approach to inhibitor optimization using both crystallographic and kinetic studies.

Ancillary