Hunter-killer peptides (HKPs) are synthetic peptides designed for the purpose of targeting specific tissues for programmed cell death. These peptides contain a """"""""homing domain"""""""" that defines cell surface specificity through receptor interactions, and an """"""""apoptotic domain"""""""" that initiates programmed cell death. Homing domains have been designed for delivery of HKPs to angiogenic tissue, arthritic tissue and prostate cells. The positively charged apoptotic domain directs the peptide to the mitochondria where it disrupts the membrane, initiating programmed cell death. HKP specificity requires that the peptides have weak affinity for eukaryotic membranes, which contain zwitterionic lipids and strong affinity for mitochondrial membranes, which contain anionic phospholipids. Design of safe, effective HKPs requires biophysical characterization of their structure and activities. The experiments proposed herein will use NMR, fluorescence and circular dichroism spectroscopy to examine the membrane affinity, membrane-bound structure, orientation and leakage activities of three HKPs in membrane models. A left-handed helical conformation is predicted for the apoptotic domain, but the structure of the homing domains is unknown. The effect of differing homing domains on membrane affinity and leakage is also of great interest. These experiments will lay a structural foundation and will characterize peptide interactions with model membranes for further design of HKPs and their potential use as therapeutics.
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