Mitochondrial targeting of radioprotectants using peptidyl conjugates

Ionizing radiation activates a mitochondrial nitric oxide synthase, leading to inhibition of the respiratory chain, generation of excess superoxide, peroxynitrite production and nitrosative damage. We have measured the radioprotective effects of a nitric oxide synthase antagonist (AMT) versus a free radical scavenger (4-amino-TEMPO) using electrochemical detection of nitric oxide and peroxynitrite. To enhance their efficacy, we have conjugated these compounds to peptides and peptide isosteres derived from the antibiotic gramicidin S - that target the mitochondria. The targeting ability of these peptidyl conjugates was measured using quantitative mass spectrometry.