TY - JOUR
T1 - Grassystatins A-C from marine cyanobacteria, potent cathepsin E inhibitors that reduce antigen presentation
AU - Kwan, Jason C.
AU - Eksioglu, Erika A.
AU - Liu, Chen
AU - Paul, Valerie J.
AU - Luesch, Hendrik
N1 - Copyright:
Copyright 2011 Elsevier B.V., All rights reserved.
PY - 2009/9/24
Y1 - 2009/9/24
N2 - 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.
AB - 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.
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U2 - 10.1021/jm9009394
DO - 10.1021/jm9009394
M3 - Article
C2 - 19715320
AN - SCOPUS:70349203850
VL - 52
SP - 5732
EP - 5747
JO - Journal of Medicinal Chemistry
JF - Journal of Medicinal Chemistry
SN - 0022-2623
IS - 18
ER -