Structure-based design of derivatives of tyropeptin A as the potent and selective inhibitors of mammalian 20S proteasome

Bioorg Med Chem Lett. 2005 Apr 1;15(7):1867-71. doi: 10.1016/j.bmcl.2005.02.013.

Abstract

Tyropeptin A, a new potent proteasome inhibitor, was produced by Kitasatospora sp. MK993-dF2. To enhance the inhibitory potency of tyropeptin A, we constructed the structural model of tyropeptin A bound to the site responsible for the chymotrypsin-like activity of mammalian 20S proteasome. Based on these modeling experiments, we designed and synthesized several derivatives of tyropeptin A. Among them, the most potent compound, TP-104, exhibited a 20-fold enhancement in its inhibitory potency compared to tyropeptin A. Additionally, TP-110 specifically inhibited the chymotrypsin-like activity, but did not inhibit the PGPH and the trypsin-like activities.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Chymotrypsin / antagonists & inhibitors
  • Dipeptides / chemical synthesis*
  • Dipeptides / pharmacology
  • Drug Design
  • Endopeptidases / metabolism
  • Enzyme Inhibitors / chemical synthesis*
  • Enzyme Inhibitors / pharmacology
  • Models, Molecular
  • Multienzyme Complexes / antagonists & inhibitors*
  • Proteasome Inhibitors*
  • Structure-Activity Relationship

Substances

  • Dipeptides
  • Enzyme Inhibitors
  • Multienzyme Complexes
  • Proteasome Inhibitors
  • tyropeptin A
  • Endopeptidases
  • Chymotrypsin
  • peptidylglutamylpeptide hydrolase