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PDBsum entry 4gvu
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Hydrolase/hydrolase inhibitor
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PDB id
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4gvu
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References listed in PDB file
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Key reference
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Title
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Potent elastase inhibitors from cyanobacteria: structural basis and mechanisms mediating cytoprotective and anti-Inflammatory effects in bronchial epithelial cells.
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Authors
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L.A.Salvador,
K.Taori,
J.S.Biggs,
J.Jakoncic,
D.A.Ostrov,
V.J.Paul,
H.Luesch.
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Ref.
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J Med Chem, 2013,
56,
1276-1290.
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PubMed id
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Abstract
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We discovered new structural diversity to a prevalent, yet medicinally
underappreciated, cyanobacterial protease inhibitor scaffold and undertook
comprehensive protease profiling to reveal potent and selective elastase
inhibition. Structure-activity relationship (SAR) studies and X-ray cocrystal
structure analysis allowed a detailed assessment of critical and tunable
structural elements. To realize the therapeutic potential of these
cyclodepsipeptides, we probed the cellular effects of a novel and representative
family member, symplostatin 5 (1), which attenuated the downstream cellular
effects of elastase in an epithelial lung airway model system, alleviating
clinical hallmarks of chronic pulmonary diseases such as cell death, cell
detachment, and inflammation. This compound attenuated the effects of elastase
on receptor activation, proteolytic processing of the adhesion protein ICAM-1,
NF-κB activation, and transcriptomic changes, including the expression of
pro-inflammatory cytokines IL1A, IL1B, and IL8. Compound 1 exhibited activity
comparable to the clinically approved elastase inhibitor sivelestat in
short-term assays and demonstrated superior sustained activity in longer-term
assays.
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