Synthesis and SAR study of novel peptide aldehydes as inhibitors of 20S proteasome

Molecules. 2011 Sep 5;16(9):7551-64. doi: 10.3390/molecules16097551.

Abstract

Based on the analysis of the crystal structure of MG101 (1) and 20S proteasomes, a new series of peptide aldehyde derivatives were designed and synthesized. Their ability to inhibit 20S proteasome was assayed. Among them, Cbz-Glu(OtBu)-Phe-Leucinal (3c), Cbz-Glu(OtBu)-Leu-Leucinal (3d), and Boc-Ser(OBzl)-Leu-Leucinal (3o) exhibited the most activity, which represented an order of magnitude enhancement compared with MG132 (2). The covalent docking protocol was used to explore the binding mode. The structure-activity relationship of the peptide aldehyde inhibitors is discussed.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Aldehydes / chemical synthesis*
  • Aldehydes / chemistry
  • Amino Acid Motifs
  • Binding Sites
  • Computer Simulation
  • Enzyme Assays
  • Models, Molecular
  • Oligopeptides / chemical synthesis*
  • Oligopeptides / chemistry
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / chemistry
  • Proteasome Endopeptidase Complex / chemistry
  • Proteasome Inhibitors*
  • Protein Binding
  • Structure-Activity Relationship
  • Surface Properties

Substances

  • Aldehydes
  • Oligopeptides
  • Protease Inhibitors
  • Proteasome Inhibitors
  • Proteasome Endopeptidase Complex