title: Fas-disabling small exocyclic peptide mimetics limit apoptosis by an unexpected mechanism.
abstract: Fas ligand- (FasL) mediated apoptosis is an important element of tissue-specific organ damage. We have developed biologically active small exocyclic peptide mimetics that disable apoptotic functions of Fas. The most effective mimetic binds to both its receptor and FasL with comparable affinity. In vitro, the most effective antagonist blocked FasL-induced cytotoxicity completely and specifically. In vivo, the antagonistic mimetic also prevented Concanavilin A (Con A) induced hepatitis, a CD4(+) T cell-mediated animal model of liver injury. Although current approaches prevent Fas receptor signaling by excluding FasL binding to Fas, the small molecule mimetics reported here disable Fas by promoting a defective Fas-FasL receptor complex. This event desensitizes FasL-mediated apoptosis by inhibiting extracellular signal regulated kinase activity and up-regulating NF-kappaB.
authors.affiliation: Department of Pathology and Laboratory Medicine, Abramson Family Cancer Research Institute, University of Pennsylvania School of Medicine, 252 John Morgan Building, 36th and Hamilton Walk, Philadelphia, PA 19104-6082, USA.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Hasegawa
authors.forename: Xin
authors.initials: X
authors.lastname: Cheng
authors.forename: Kiichi
authors.initials: K
authors.lastname: Kajino
authors.forename: Alan
authors.initials: A
authors.lastname: Berezov
authors.forename: Kaoru
authors.initials: K
authors.lastname: Murata
authors.forename: Toshinori
authors.initials: T
authors.lastname: Nakayama
authors.forename: Hideo
authors.initials: H
authors.lastname: Yagita
authors.forename: Ramachandran
authors.initials: R
authors.lastname: Murali
authors.forename: Mark I
authors.initials: MI
authors.lastname: Greene
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D015153:Blotting, Western; D003208:Concanavalin A / Q000494:pharmacology; D053222:Fas Ligand Protein; D005434:Flow Cytometry; D008099:Liver / Q000187:drug effects; D008562:Membrane Glycoproteins / Q000037:antagonists & inhibitors* / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D008958:Models, Molecular; D018716:Molecular Mimicry; D016328:NF-kappa B / Q000378:metabolism; D010455:Peptides / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology*; D011485:Protein Binding
chemical_list: D053222:Fas Ligand Protein; C505658:Fasl protein, mouse; D008562:Membrane Glycoproteins; D016328:NF-kappa B; D010455:Peptides; D003208:Concanavalin A; D020928:Mitogen-Activated Protein Kinases