Grassystatins D–F, Potent Aspartic Protease Inhibitors from Marine Cyanobacteria as Potential Antimetastatic Agents Targeting Invasive Breast Cancer
| Autor: | Valerie J. Paul, Brian K. Law, Hendrik Luesch, Fatma H. Al-Awadhi |
|---|---|
| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
Aspartic Acid Proteases Cathepsin L Pharmaceutical Science Cathepsin D Cathepsin E Cyanobacteria Article Analytical Chemistry Inhibitory Concentration 50 03 medical and health sciences chemistry.chemical_compound Endopeptidases Plasminogen Activator Inhibitor 1 Drug Discovery Statine Humans Protease Inhibitors Amino Acids Nuclear Magnetic Resonance Biomolecular Pharmacology Cathepsin Tumor microenvironment Dose-Response Relationship Drug Molecular Structure biology Organic Chemistry Molecular biology 030104 developmental biology Complementary and alternative medicine Biochemistry Cystatin C chemistry Guam biology.protein Molecular Medicine Female Lysosomes Peptides |
| Zdroj: | Journal of Natural Products. 80:2969-2986 |
| ISSN: | 1520-6025 0163-3864 |
| DOI: | 10.1021/acs.jnatprod.7b00551 |
| Popis: | 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 (MS). 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, as well as the migration of the highly aggressive triple negative breast cancer cells, phenocopying the effect of siRNA mediated knockdown of cathepsin D. |
| Databáze: | OpenAIRE |
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