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

Jason C. Kwan, Erika A. Eksioglu, Chen Liu, Valerie J. Paul, Hendrik Luesch

Research output: Contribution to journalArticlepeer-review

69 Scopus citations


In our efforts to exploremarine 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, grassy-statins B (2) and C(3), using NMR, MS, and chiral HPLC techniques. Compound 1 selectively inhibited cathepsins D and Ewith IC 50s of 26.5 nM and 886 pM, respectively. Compound 2 showed similar potency and selectivity against cathepsins D and E (IC50s 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.

Original languageEnglish (US)
Pages (from-to)5732-5747
Number of pages16
JournalJournal of Medicinal Chemistry
Issue number18
StatePublished - Sep 24 2009
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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