title: Grassypeptolides as natural inhibitors of dipeptidyl peptidase 8 and T-cell activation.
abstract: 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.
authors.affiliation: Department of Medicinal Chemistry, College of Pharmacy, University of Florida, 1345 Center Drive, Gainesville FL 32610 (USA); Current address: Pharmaceutical Sciences Division, School of Pharmacy, University of Wisconsin-Madison, 777 Highland Ave, Madison WI 53705 (USA).
authors.forename: Jason C
authors.initials: JC
authors.lastname: Kwan
authors.forename: Yanxia
authors.initials: Y
authors.lastname: Liu
authors.forename: Ranjala
authors.initials: R
authors.lastname: Ratnayake
authors.forename: Ryo
authors.initials: R
authors.lastname: Hatano
authors.forename: Akiko
authors.initials: A
authors.lastname: Kuribara
authors.forename: Chiko
authors.initials: C
authors.lastname: Morimoto
authors.forename: Kei
authors.initials: K
authors.lastname: Ohnuma
authors.forename: Valerie J
authors.initials: VJ
authors.lastname: Paul
authors.forename: Tao
authors.initials: T
authors.lastname: Ye
authors.forename: Hendrik
authors.initials: H
authors.lastname: Luesch
mesh_terms: D001665:Binding Sites; D020134:Catalytic Domain; D002470:Cell Survival / Q000187:drug effects; D047630:Depsipeptides / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D004150:Dipeptidases / Q000037:antagonists & inhibitors* / Q000378:metabolism; D006801:Humans; D007376:Interleukin-2 / Q000378:metabolism; D019169:Jurkat Cells; D008213:Lymphocyte Activation / Q000187:drug effects; D062105:Molecular Docking Simulation; D011480:Protease Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D013601:T-Lymphocytes / Q000276:immunology / Q000378:metabolism
chemical_list: D047630:Depsipeptides; D007376:Interleukin-2; D011480:Protease Inhibitors; C528460:grassypeptolide; D004150:Dipeptidases; C487997:DPP8 protein, human
keywords: dipeptidyl peptidases; grassypeptolides; immunochemistry; natural products; protease inhibition