Grassypeptolides as Natural Inhibitors of Dipeptidyl Peptidase 8 and T-Cell Activation

• Published in: Chembiochem : a European journal of chemical biology Vol. 15; no. 6; pp. 799 - 804
• Main Authors: Kwan, Jason C., Liu, Yanxia, Ratnayake, Ranjala, Hatano, Ryo, Kuribara, Akiko, Morimoto, Chiko, Ohnuma, Kei, Paul, Valerie J., Ye, Tao, Luesch, Hendrik
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 14.04.2014; WILEY‐VCH Verlag; Wiley Subscription Services, Inc
• Subjects: Binding Sites; Catalytic Domain; Cell Survival - drug effects; Depsipeptides - chemistry; Depsipeptides - metabolism; Depsipeptides - pharmacology; Dipeptidases - antagonists & inhibitors; Dipeptidases - metabolism; dipeptidyl peptidases; grassypeptolides; Humans; immunochemistry; Interleukin-2 - metabolism; Jurkat Cells; Lymphocyte Activation - drug effects; Molecular Docking Simulation; natural products; protease inhibition; Protease Inhibitors - chemistry; Protease Inhibitors - metabolism; Protease Inhibitors - pharmacology; T cell receptors; T-Lymphocytes - immunology; T-Lymphocytes - metabolism; protease inhibition; natural products; dipeptidyl peptidases; immunochemistry; grassypeptolides
• ISSN: 1439-4227; 1439-7633
• DOI: 10.1002/cbic.201300762

Natural products made by marine cyanobacteria are often highly modified peptides and depsipeptides that have the potential to act as inhibitors for proteases. In the interests of finding new protease inhibition activity and selectivity, grassypeptolide A (1) was screened against a panel of proteases and found to inhibit DPP8 selectively over DPP4. Grassypeptolides were also found to inhibit IL‐2 production and proliferation in activated T‐cells, consistent with a putative role of DPP8 in the immune system. These effects were also observed in Jurkat cells, and DPP activity in Jurkat cell cytosol was shown to be inhibited by grassypeptolides. In silico docking suggests two possible binding modes of grassypeptolides—at the active site of DPP8 and at one of the entrances to the internal cavity. Collectively these results suggest that grassypeptolides might be useful tool compounds in the study of DPP8 function. Always greener: Protease activity profiling indicated that the natural product grassypeptolide A inhibits DPP8. Docking suggested that the compound can bind to DPP8 at two sites, and it was found that grassypeptolide A also inhibits T‐cell activation and DPP activity in the cytosol of Jurkat cells.