Development of Peptidomimetics Targeting IAPs |
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Authors: | Sushil K. Sharma Christopher Straub Leigh Zawel |
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Affiliation: | (1) Department of Oncology, Novartis Institute for Biomedical Research, Cambridge, MA, USA;(2) Department of Oncology, Novartis Institute for Biomedical Research, 250 Mass Ave, Cambridge, MA 02139, USA |
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Abstract: | Inhibitor of apoptosis proteins (IAPs) such as XIAP subvert apoptosis by binding and inhibiting caspases. Because occupation of the XIAP BIR3 peptide binding pocket by Smac abolishes the XIAP–caspase 9 interaction, it is a proapoptotic event of great therapeutic interest. An assay for pocket binding was developed based on the displacement of Smac 7-mer from BIR3. Through the physical and biochemical analysis of a variety of peptides, we have determined the minimum sequence required for inhibition of the Smac–BIR3 interaction and detailed the dimensions and topology of the BIR3 peptide binding pocket. This work describes the structure–activity relationship (SAR) for peptide inhibitors of Smac-IAP binding. |
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Keywords: | BIR cancer caspases inhibitors of apoptosis protein (IAP) peptidomimetics protein– protein interaction Smac/DIABLO |
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