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Proc Natl Acad Sci U S A. 2004 Apr 27;101(17):6599-604. Epub 2004 Apr 14.

Fas-disabling small exocyclic peptide mimetics limit apoptosis by an unexpected mechanism.

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  • 1Department 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.


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.

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