Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation

J Med Chem. 2009 Sep 24;52(18):5732-47. doi: 10.1021/jm9009394.

Abstract

In our efforts to explore marine cyanobacteria as a source of novel bioactive compounds, we discovered a statine unit-containing linear decadepsipeptide, grassystatin A (1), which we screened against a diverse set of 59 proteases. We describe the structure determination of 1 and two natural analogues, grassystatins B (2) and C (3), using NMR, MS, and chiral HPLC techniques. Compound 1 selectively inhibited cathepsins D and E with IC(50)s of 26.5 nM and 886 pM, respectively. Compound 2 showed similar potency and selectivity against cathepsins D and E (IC(50)s of 7.27 nM and 354 pM, respectively), whereas the truncated peptide analogue grassystatin C (3), which consists of two fewer residues than 1 and 2, was less potent against both but still selective for cathepsin E. The selectivity of compounds 1-3 for cathepsin E over D (20-38-fold) suggests that these natural products may be useful tools to probe cathepsin E function. We investigated the structural basis of this selectivity using molecular docking. We also show that 1 can reduce antigen presentation by dendritic cells, a process thought to rely on cathepsin E.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.

MeSH terms

  • Amino Acids / chemistry*
  • Animals
  • Antigen Presentation / drug effects*
  • Cathepsin E / antagonists & inhibitors*
  • Cathepsin E / chemistry
  • Cathepsin E / metabolism
  • Cell Line, Tumor
  • Cyanobacteria / chemistry*
  • Dendritic Cells / drug effects
  • Dendritic Cells / immunology
  • Humans
  • Inhibitory Concentration 50
  • Magnetic Resonance Spectroscopy
  • Models, Molecular
  • Molecular Conformation
  • Oceans and Seas
  • Oligopeptides / chemistry*
  • Oligopeptides / isolation & purification
  • Oligopeptides / metabolism
  • Oligopeptides / pharmacology*
  • Protease Inhibitors / chemistry
  • Protease Inhibitors / isolation & purification
  • Protease Inhibitors / metabolism
  • Protease Inhibitors / pharmacology
  • Spectrometry, Mass, Electrospray Ionization
  • Substrate Specificity

Substances

  • Amino Acids
  • Oligopeptides
  • Protease Inhibitors
  • Cathepsin E
  • statine