Hunter killer peptides (HKPs) are synthetic pro-apoptotic peptides that have been designed for the purpose of targeting specific tissue for programmed cell death. These peptides are chimera containing a tissue-specific homing sequence, a linker and a pro-apoptotic amino acid sequence. Homing sequences bind to cell surface receptors, which aid in intracellular delivery. Pro-apoptotic sequences are positively charged and direct the peptide toward the mitochondria, where the membrane is disrupted and cell death is initiated. Thus far, peptides have been designed to target angiogenic tumor cells, arthritic tissue, white adipose tissue and prostate. Safe and effective HKPs will have high affinity for mitochondrial membranes and weak affinity for the plasma membrane. Design of new peptides requires biophysical characterization of their structure and activity, as well as, interactions with cell surface receptors. The experiments proposed herein will use NMR, spectrophotometric kinetic assays, fluorescence and circular dichroism spectroscopy to examine the membrane-associated structure, orientation and membrane perturbing activities of several HKPs. In addition, experiments will probe receptor interactions for one class of peptides that target tumor vasculature. Design of future HKPs will be more facile if swapping homing domains has only minor effects on the peptide activity. Hunter killer peptides have potential as therapeutics to treat cancer, obesity, arthritis and prostate hypertrophy. The first peptide, HKP1, was designed to target tumor vasculature, and has been shown to be effective against breast cancer cells and kaposi sarcoma. A second HKP that kills white fat tissue reduces fatty deposits and has a positive impact on glucose metabolism, reducing symptoms of diabetes. ? ? ?
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