Fas-disabling small exocyclic peptide mimetics limit apoptosis by an unexpected mechanism.
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.
Hasegawa
Akihiro
A
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.
Cheng
Xin
X
Kajino
Kiichi
K
Berezov
Alan
A
Murata
Kaoru
K
Nakayama
Toshinori
T
Yagita
Hideo
H
Murali
Ramachandran
R
Greene
Mark I
MI
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
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