title: Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation.
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.
authors.affiliation: Department of Medicinal Chemistry, University of Florida, Gainesville, Florida 32610, USA.
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kwan
authors.forename: Erika A
authors.initials: EA
authors.lastname: Eksioglu
authors.forename: Chen
authors.initials: C
authors.lastname: Liu
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Paul
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D000596:Amino Acids / Q000737:chemistry*; D000818:Animals; D017951:Antigen Presentation / Q000187:drug effects*; D020059:Cathepsin E / Q000037:antagonists & inhibitors* / Q000737:chemistry / Q000378:metabolism; D045744:Cell Line, Tumor; D000458:Cyanobacteria / Q000737:chemistry*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D006801:Humans; D020128:Inhibitory Concentration 50; D009682:Magnetic Resonance Spectroscopy; D008958:Models, Molecular; D008968:Molecular Conformation; D009792:Oceans and Seas; D009842:Oligopeptides / Q000737:chemistry* / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology*; D011480:Protease Inhibitors / Q000737:chemistry / Q000302:isolation & purification / Q000378:metabolism / Q000494:pharmacology; D021241:Spectrometry, Mass, Electrospray Ionization; D013379:Substrate Specificity
chemical_list: D000596:Amino Acids; D009842:Oligopeptides; D011480:Protease Inhibitors; D020059:Cathepsin E; C013165:statine