Abstract
Protease inhibitors have been isolated from many variable sources; however, the need to identify and characterize new molecules has increased with the discovery of new therapeutic targets and the lack of specificity of already identified compounds with inhibitory activity. The goal of this work was to search for inhibitory activity against four proteolytic enzymes already recognized as therapeutic targets: human neutrophil elastase, dipeptidyl peptidase IV, subtilisin from Bacillus licheniformis and cathepsin K in selected marine invertebrates from the Caribbean Sea. A systematic screening was carried out with selected aqueous extracts belonging to 20 species from seven different phyla: Annelida, Bryozoa, Chordata, Cnidaria, Equinodermata, Mollusca and Porifera, all collected at the coast of Havana (Cuba). All extracts showing initial inhibitory activity were characterized in terms of IC50 values and specific inhibitory activity (SIA). Model enzymes were used in the case of human neutrophil elastase (porcine pancreatic elastase) and cathepsin K (papain) for the screening and all positive results were confirmed by testing toward the therapeutic targets. Ten extracts were identified showing inhibitory activity against human neutrophil elastase, for which the most promising values were obtained for Nerita peloronta. Only one extract, Bunodosoma granulifera, showed inhibitory activity against dipeptidyl peptidase IV with rather poor values of IC50 and SIA. Seven extracts showed inhibitory activity against B. licheniformis subtilisin with very good IC50 and SIA values for Lissodendorix isodyctialis, Cenchritis muricatus, and N. peloronta. Finally, eight extracts were positive for cathepsin K with almost similar parameters values among them. All these results confirmed the richness and potential of the marine invertebrate’s fauna and indicated new promising sources for the identification of natural compounds with potential application in therapeutics.
Highlights
Proteases represent about 2% of the genes in humans as well as in infectious organisms [1] [2]
The highest specific inhibitory activity (SIA) values were obtained for Stichodactyla helianthus, Lissodendorix isodyctialis, Holothuria mexicana and Nerita peloronta (Table 2(a))
All positive extracts were able to inhibit the enzymatic activity of human neutrophil elastase (HNE) and N. peloronta was confirmed the most promising extract in terms of SIA (Table 2(b))
Summary
Proteases represent about 2% of the genes in humans as well as in infectious organisms [1] [2]. Many examples show the functional role of proteases in the appearance or development of diseases [2] [4], e.g. the serine proteases human neutrophil elastase (HNE), subtilisins, dipeptidylpeptidase-IV (DPPIV) and papain-like proteases, such as cathepsin K. The former, which is involved in pulmonary emphysema, rheumatoid arthritis and cystic fibrosis, is released from human polymorphonuclear leukocytes in response to inflammatory stimuli and it is responsible for the degradation of connective tissue proteins [5] [6]. All these enzymes constitute potential therapeutic targets for the treatment of the diseases where they are involved
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