Structure-based optimisation of 2-aminobenzylstatine derivatives: potent and selective inhibitors of the chymotrypsin-like activity of the human 20S proteasome

Bioorg Med Chem Lett. 2002 May 20;12(10):1331-4. doi: 10.1016/s0960-894x(02)00178-6.

Abstract

We have identified 2-aminobenzylstatine derivatives that inhibit non-covalently the chymotrypsin-like activity of the human 20S proteasome. A structure-based optimisation approach has allowed us to improve the potency of this structural class of proteasome inhibitors from micromolar to nanomolar level. The new derivatives showed good selectivity against the trypsin-like and post-glutamyl-peptide hydrolytic activities of this enzyme.

MeSH terms

  • Benzyl Compounds / chemical synthesis*
  • Benzyl Compounds / pharmacology
  • Chymotrypsin / antagonists & inhibitors*
  • Cysteine Endopeptidases
  • Drug Design
  • Humans
  • Kinetics
  • Models, Molecular
  • Molecular Conformation
  • Multienzyme Complexes / antagonists & inhibitors*
  • Protease Inhibitors / chemical synthesis*
  • Protease Inhibitors / pharmacology
  • Proteasome Endopeptidase Complex
  • Structure-Activity Relationship

Substances

  • Benzyl Compounds
  • Multienzyme Complexes
  • Protease Inhibitors
  • Chymotrypsin
  • Cysteine Endopeptidases
  • Proteasome Endopeptidase Complex