Omuralide and vibralactone: differences in the proteasome- β-lactone-γ-lactam binding scaffold alter target preferences

Angew Chem Int Ed Engl. 2014 Jan 7;53(2):571-4. doi: 10.1002/anie.201308567. Epub 2013 Nov 28.

Abstract

Despite their structural similarity, the natural products omuralide and vibralactone have different biological targets. While omuralide blocks the chymotryptic activity of the proteasome with an IC50 value of 47 nM, vibralactone does not have any effect at this protease up to a concentration of 1 mM. Activity-based protein profiling in HeLa cells revealed that the major targets of vibralactone are APT1 and APT2.

Keywords: click chemistry; drug development; natural products; proteasome; protein crystallography.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Binding Sites
  • Cell Survival / drug effects
  • Dose-Response Relationship, Drug
  • HeLa Cells
  • Humans
  • Lactams / chemistry*
  • Lactams / pharmacology
  • Lactones / chemistry*
  • Lactones / pharmacology
  • Proteasome Inhibitors / chemistry*
  • Proteasome Inhibitors / pharmacology
  • Protein Binding
  • Protein Subunits
  • Structure-Activity Relationship
  • Thiolester Hydrolases / antagonists & inhibitors*

Substances

  • Lactams
  • Lactones
  • Proteasome Inhibitors
  • Protein Subunits
  • omuralide
  • vibralactone
  • LYPLA1 protein, human
  • LYPLA2 protein, human
  • Thiolester Hydrolases