Mitochondrial targeting of radioprotectants using peptidyl conjugates

Abstract

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.