5 research outputs found
Lyngbyastatins 8–10, Elastase Inhibitors with Cyclic Depsipeptide Scaffolds Isolated from the Marine Cyanobacterium Lyngbya semiplena
Investigation of an extract from the marine cyanobacterium Lyngbya semiplena, collected in Tumon Bay, Guam, led to the identification of three new cyclodepsipeptides, lyngbyastatins 8–10 (1–3). The structures of 1–3 were determined by NMR, MS, ESIMS fragmentation and chemical degradation. Compounds 1–3 are closely related to lyngbyastatins 4–7. Like the latter compounds, we found 1–3 to inhibit porcine pancreatic elastase, with IC50 values of 123 nM, 210 nM and 120 nM, respectively
Cytomegalovirus Capsid Protease: Biological Substrates Are Cleaved More Efficiently by Full-Length Enzyme (pUL80a) than by the Catalytic Domain (Assemblin)
Potent Elastase Inhibitors from Cyanobacteria: Structural Basis and Mechanisms Mediating Cytoprotective and Anti-Inflammatory Effects in Bronchial Epithelial Cells
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 (<b>1</b>), 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 <i>IL1A</i>, <i>IL1B</i>, and <i>IL8</i>. Compound <b>1</b> exhibited activity comparable to the clinically approved
elastase inhibitor sivelestat in short-term assays and demonstrated
superior sustained activity in longer-term assays