Grassystatins D-F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer.

Abstract

Three new modified peptides named grassystatins D-F (1-3) were discovered from a marine cyanobacterium from Guam. Their structures were elucidated using NMR spectroscopy and mass spectrometry. The hallmark structural feature in the peptides is a statine unit, which contributes to their aspartic protease inhibitory activity preferentially targeting cathepsins D and E. Grassystatin F (3) was the most potent analogue, with IC50 values of 50 and 0.5 nM against cathepsins D and E, respectively. The acidic tumor microenvironment is known to increase the activation of some of the lysosomal proteases associated with tumor metastasis such as cathepsins. Because cathepsin D is a biomarker in aggressive forms of breast cancer and linked to poor prognosis, the effects of cathepsin D inhibition by 1 and 3 on the downstream cellular substrates cystatin C and PAI-1 were investigated. Furthermore, the functional relevance of targeting cathepsin D substrates was evaluated by examining the effect of 1 and 3 on the migration of MDA-MD-231 cells. Grassystatin F (3) inhibited the cleavage of cystatin C and PAI-1, the activities of their downstream targets cysteine cathepsins and tPA, and the migration of the highly aggressive triple negative breast cancer cells, phenocopying the effect of siRNA-mediated knockdown of cathepsin D.

• Authors: Fatma H Al-Awadhi, Brian K Law, Valerie J Paul, Hendrik Luesch
• Journal: Journal of natural products (J Nat Prod) Vol. 80 Issue 11 Pg. 2969-2986 (11 22 2017) ISSN: 1520-6025 [Electronic] United States
• PMID: 29087712 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Amino Acids
• Peptides
• Plasminogen Activator Inhibitor 1
• Protease Inhibitors
• SERPINE1 protein, human
• grassystatin D
• grassystatin E
• grassystatin F
• Aspartic Acid Proteases
• Endopeptidases
• Cathepsin L
• Cathepsin E
• Cathepsin D
• statine

Topics

• Amino Acids
• Aspartic Acid Proteases (drug effects)
• Cathepsin D (antagonists & inhibitors)
• Cathepsin E (antagonists & inhibitors)
• Cathepsin L (metabolism)
• Cyanobacteria (chemistry)
• Dose-Response Relationship, Drug
• Endopeptidases (metabolism)
• Female
• Guam
• Humans
• Inhibitory Concentration 50
• Lysosomes (metabolism)
• Molecular Structure
• Nuclear Magnetic Resonance, Biomolecular
• Peptides (chemistry, isolation & purification, pharmacology)
• Plasminogen Activator Inhibitor 1 (metabolism)
• Protease Inhibitors (pharmacology)