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Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides

Jiang, J and Kurnikov, I and Belikova, NA and Xiao, J and Zhao, Q and Amoscato, AA and Braslau, R and Studer, A and Fink, MP and Greenberger, JS and Wipf, P and Kagan, VE (2007) Structural requirements for optimized delivery, inhibition of oxidative stress, and antiapoptotic activity of targeted nitroxides. Journal of Pharmacology and Experimental Therapeutics, 320 (3). 1050 - 1060. ISSN 0022-3565

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Suppression of mitochondrial production of reactive oxygen species is a promising strategy against intrinsic apoptosis typical of degenerative diseases. Stable nitroxide radicals such as 4-hydroxy-2,2,6,6-tetramethyl piperidine-1-oxyl (TEMPOL) and its analogs combine several important features, including recycleability, electron acceptance from respiratory complexes, superoxide dismutase mimicry, and radical scavenging. Although successful in antioxidant protection, their effective concentrations are too high for successful in vivo applications. Recently (J Am Chem Soc 127:12460, 2005), we reported that 4-amino 2,2,6,6-tetramethyl-1-piperidinyloxy, covalently conjugated to a five-residue segment of gramicidin S (GS), was integrated into mitochondria and blocked actinomycin D (ActD)-induced superoxide generation and apoptosis. Using a model of ActD-induced apoptosis in mouse embryonic cells, we screened a library of nitroxides to explore structure-activity relationships between their antioxidant/antiapoptotic properties and chemical composition and three-dimensional (3D) structure. High hydrophobicity and effective mitochondrial integration are necessary but not sufficient for high antiapoptotic/antioxidant activity of a nitroxide conjugate. By designing conformationally preorganized peptidyl nitroxide conjugates and characterizing their 3D structure experimentally (circular dichroism and NMR) and theoretically (molecular dynamics), we established that the presence of the β-turn/β-sheet secondary structure is essential for the desired activity. Monte Carlo simulations in model lipid membranes confirmed that the conservation of the D-Phe-Pro reverse turn in hemi-GS analogs ensures the specific positioning of the nitroxide moiety at the mitochondrial membrane interface and maximizes their protective effects. These new insights into the structure-activity relationships of nitroxide-peptide and -peptide isostere conjugates are instrumental for development of new mechanism-based therapeutically effective agents. Copyright © 2007 by The American Society for Pharmacology and Experimental Therapeutics.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Jiang, Jjjf73@pitt.eduJJF73
Kurnikov, I
Belikova, NA
Xiao, J
Zhao, Q
Amoscato, AAaaa5@pitt.eduAAA5
Braslau, R
Studer, A
Fink, MP
Greenberger, JSjoelg@pitt.eduJOELG
Wipf, Ppwipf@pitt.eduPWIPF
Kagan, VEkagan@pitt.eduKAGAN
Date: 1 March 2007
Date Type: Publication
Journal or Publication Title: Journal of Pharmacology and Experimental Therapeutics
Volume: 320
Number: 3
Page Range: 1050 - 1060
DOI or Unique Handle: 10.1124/jpet.106.114769
Schools and Programs: Dietrich School of Arts and Sciences > Chemistry
Refereed: Yes
ISSN: 0022-3565
MeSH Headings: Animals; Antioxidants--chemistry; Antioxidants--pharmacology; Apoptosis--drug effects; Cell Membrane--drug effects; Cell Membrane--metabolism; Cells, Cultured; Circular Dichroism; Cyclic N-Oxides--chemistry; Cyclic N-Oxides--pharmacology; Dactinomycin--pharmacology; Gramicidin--analogs & derivatives; Gramicidin--chemistry; Magnetic Resonance Spectroscopy; Mice; Mitochondria--drug effects; Mitochondria--metabolism; Models, Molecular; Oxidative Stress--drug effects; Protein Structure, Secondary; Structure-Activity Relationship
PubMed ID: 17179468
Date Deposited: 09 Oct 2013 16:06
Last Modified: 02 Feb 2019 16:58


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