2. Academic Validation
  3. Structure-based design of human immuno- and constitutive proteasomes inhibitors

Structure-based design of human immuno- and constitutive proteasomes inhibitors

  • Eur J Med Chem. 2018 Feb 10:145:570-587. doi: 10.1016/j.ejmech.2018.01.013.
Nicolas Richy 1,  Daad Sarraf 1,  Xavier Maréchal 2,  Naëla Janmamode 1,  Rémy Le Guével 3,  Emilie Genin 1,  Michèle Reboud-Ravaux 4,  Joëlle Vidal 5
Affiliations

Affiliations

  • 1 Université Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes, Cedex, France.
  • 2 Sorbonne Universités, UPMC Univ Paris 06-CNRS, IBPS, UMR 8256, Inserm ERL1164, B2A, 7 Quai Saint Bernard, F75005 Paris, France.
  • 3 Université Rennes 1, Technology Platform ImPACcell, SFR UMS CNRS 3480, INSERM 018, Bâtiment 8, Campus de Villejean, 35043 Rennes, Cedex, France.
  • 4 Sorbonne Universités, UPMC Univ Paris 06-CNRS, IBPS, UMR 8256, Inserm ERL1164, B2A, 7 Quai Saint Bernard, F75005 Paris, France. Electronic address: michele.reboud@upmc.fr.
  • 5 Université Rennes 1, Institut des Sciences Chimiques de Rennes, CNRS UMR 6226, Bâtiment 10A, Campus de Beaulieu, 35042 Rennes, Cedex, France. Electronic address: joelle.vidal@univ-rennes1.fr.
PMID: 29339252 DOI: 10.1016/j.ejmech.2018.01.013
Abstract

Starting from the X-ray structure of our previous tripeptidic linear mimics of TMC-95A in complex with yeast 20S Proteasome, we introduced new structural features to induce a differential inhibition between human constitutive and immunoproteasome 20S particles. Libraries of 24 tripeptidic and 6 dipeptidic derivatives were synthesized. The optimized preparation of 3-hydroxyoxindolyl alanine residues from tryptophan and their incorporation in Peptides were described. Several potent inhibitors of human constitutive Proteasome and immunoproteasome acting at the nanomolar level (IC50 = 7.1 nM against the chymotrypsin-like activity for the best inhibitor) were obtained. A cytotoxic effect at the submicromolar level was observed against 6 human Cancer cell lines.

Keywords

3-HydroxyOxindolylalanine derivatives; Constitutive proteasome; Immunoproteasome; Proteasome inhibitors; Tryptophan oxidation.

Figures