title: Structural analysis of caspase-1 inhibitors derived from Tethering.
abstract: Caspase-1 is a key endopeptidase responsible for the post-translational processing of the IL-1beta and IL-18 cytokines and small-molecule inhibitors that modulate the activity of this enzyme are predicted to be important therapeutic treatments for many inflammatory diseases. A fragment-assembly approach, accompanied by structural analysis, was employed to generate caspase-1 inhibitors. With the aid of Tethering with extenders (small molecules that bind to the active-site cysteine and contain a free thiol), two novel fragments that bound to the active site and made a disulfide bond with the extender were identified by mass spectrometry. Direct linking of each fragment to the extender generated submicromolar reversible inhibitors that significantly reduced secretion of IL-1beta but not IL-6 from human peripheral blood mononuclear cells. Thus, Tethering with extenders facilitated rapid identification and synthesis of caspase-1 inhibitors with cell-based activity and subsequent structural analyses provided insights into the enzyme's ability to accommodate different inhibitor-binding modes in the active site.
authors.affiliation: Department of Biology, Sunesis Pharmaceuticals Inc., USA.
authors.forename: Tom
authors.initials: T
authors.lastname: O'Brien
authors.forename: Bruce T
authors.initials: BT
authors.lastname: Fahr
authors.forename: Michelle M
authors.initials: MM
authors.lastname: Sopko
authors.forename: Joni W
authors.initials: JW
authors.lastname: Lam
authors.forename: Nathan D
authors.initials: ND
authors.lastname: Waal
authors.forename: Brian C
authors.initials: BC
authors.lastname: Raimundo
authors.forename: Hans E
authors.initials: HE
authors.lastname: Purkey
authors.forename: Phuongly
authors.initials: P
authors.lastname: Pham
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Romanowski
mesh_terms: D001665:Binding Sites / Q000187:drug effects; D020170:Caspase 1 / Q000737:chemistry; D061945:Caspase Inhibitors; D020650:Combinatorial Chemistry Techniques / Q000379:methods*; D018360:Crystallography, X-Ray; D015853:Cysteine Proteinase Inhibitors / Q000737:chemistry* / Q000378:metabolism / Q000494:pharmacology; D015195:Drug Design; D006801:Humans; D007375:Interleukin-1 / Q000037:antagonists & inhibitors / Q000097:blood; D015850:Interleukin-6 / Q000097:blood; D007963:Leukocytes, Mononuclear / Q000187:drug effects / Q000201:enzymology / Q000378:metabolism; D008958:Models, Molecular; D011485:Protein Binding / Q000187:drug effects; D012995:Solubility; D000093242:Interleukin-6 Inhibitors
chemical_list: D020170:Caspase 1; D061945:Caspase Inhibitors; D015853:Cysteine Proteinase Inhibitors; D007375:Interleukin-1; D015850:Interleukin-6; D000093242:Interleukin-6 Inhibitors