Selective targeting of synthetic antioxidants to mitochondria: towards a mitochondrial medicine for neurodegenerative diseases?

Dessolin, Jean; Schuler, Marie; Quinart, Alice; Giorgi, Francesca De; Ghosez, Léon; Ichas, François

doi:10.1016/s0014-2999(02)01839-3

Cited by 79 publications

(53 citation statements)

References 12 publications

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“…Cyclic polyamine (aza crown ethers)-based SOD mimics were characterized in details in vitro and in vivo (295). Mn salen derivatives were investigated as well (88). Along with metal-based SOD mimics, some nonmetallic and, thus far less-efficient compounds, such as nitroxides (140) and fullerenes (181,349), also have been explored.…”

Section: B Antioxidantsmentioning

confidence: 99%

“…Bioavailability is dependent on the size, charge, shape, (conformational flexibility and overall geometry), and lipophilicity and greatly affects the in vivo efficacy; data already indicate that whereas some drugs may be good in one model, they may fail or be less efficient in another one, as a consequence of differences in the extent of accumulation in subcellular compartments targeted (88,131,255). Detailed pharmacokinetic and toxicology data are still scarce.…”

Section: B Antioxidantsmentioning

confidence: 99%

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Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

471

689

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Oxidative stress has become widely viewed as an underlying condition in a number of diseases, such as ischemia-reperfusion disorders, central nervous system disorders, cardiovascular conditions, cancer, and diabetes. Thus, natural and synthetic antioxidants have been actively sought. Superoxide dismutase is a first line of defense against oxidative stress under physiological and pathological conditions. Therefore, the development of therapeutics aimed at mimicking superoxide dismutase was a natural maneuver. Metalloporphyrins, as well as Mn cyclic polyamines, Mn salen derivatives and nitroxides were all originally developed as SOD mimics. The same thermodynamic and electrostatic properties that make them potent SOD mimics may allow them to reduce other reactive species such as peroxynitrite, peroxynitrite-derived CO 3 _ À , peroxyl radical, and less efficiently H 2 O 2 . By doing so SOD mimics can decrease both primary and secondary oxidative events, the latter arising from the inhibition of cellular transcriptional activity. To better judge the therapeutic potential and the advantage of one over the other type of compound, comparative studies of different classes of drugs in the same cellular and=or animal models are needed. We here provide a comprehensive overview of the chemical properties and some in vivo effects observed with various classes of compounds with a special emphasis on porphyrin-based compounds. Antioxid. Redox Signal. 13, 877-918.

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Section: B Antioxidantsmentioning

confidence: 99%

Section: B Antioxidantsmentioning

confidence: 99%

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Batinić‐Haberle

Rebouças

Spasojević

2010

Antioxidants & Redox Signaling

471

689

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“…Nitroxide radicals targeted to mitochondria may be effective in preventing apoptotic cell death. Indeed, the latest developments in the field indicate that targeting of nitroxides to mitochondria enhances their antiapoptotic activity (Dessolin et al, 2002;Dhanasekaran et al, 2005;Wipf et al, 2005). Dessolin et al (2002) have reported that accumulation of TEMPOL in mitochondria was substantially increased by conjugating it with a Salen-Mn(III) complex of o-vanillin (EUK-134), and the targeted nitroxide delayed apoptosis after an exogenous oxidative insult.…”

mentioning

confidence: 99%

“…Indeed, the latest developments in the field indicate that targeting of nitroxides to mitochondria enhances their antiapoptotic activity (Dessolin et al, 2002;Dhanasekaran et al, 2005;Wipf et al, 2005). Dessolin et al (2002) have reported that accumulation of TEMPOL in mitochondria was substantially increased by conjugating it with a Salen-Mn(III) complex of o-vanillin (EUK-134), and the targeted nitroxide delayed apoptosis after an exogenous oxidative insult. Dhanasekaran et al (2005) have also demonstrated that mitochondria-targeted mitocarboxy peroxyl (coupled with the triphenylphosphine adduct of 11-bromo-undecanol) inhibited peroxide-induced oxidative damage and apoptosis.…”

mentioning

confidence: 99%

Structural Requirements for Optimized Delivery, Inhibition of Oxidative Stress, and Antiapoptotic Activity of Targeted Nitroxides

Jiang

Kurnikov²,

Belikova³

et al. 2006

J Pharmacol Exp Ther

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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 ActDinduced 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 ␤-turn/␤-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 nitroxidepeptide and -peptide isostere conjugates are instrumental for development of new mechanism-based therapeutically effective agents.Poorly controlled and excessive generation of reactive oxygen species (ROS), coupled with their ability to cause oxidative damage to phospholipids, proteins, and DNA, has been associated with the pathogenesis of a number of major human cardiovascular (Ambrosio and Tritto, 1999) and neurodegenerative diseases (Andersen, 2004) as well as cancer (Szatrowski and Nathan, 1991). Not surprisingly, significant efforts have been directed toward the use of radical scavengers and antioxidants in preventive and therapeutic strategies, albeit with limited success. The search for new protective remedies has been focused on molecules combining antioxidant utilities with recycling capacities (Mitchell et al.,

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“…For example, a structural motif based on alternating aromatic and basic amino acid residues (i.e., Dmt-D-Arg-Phe-Lys-NH 2 and D-Arg-Dmt-LysPhe-NH 2 ) can be employed. 7 These peptide conjugates are cell-permeable in a passive manner and concentrate up to 1000 fold in the inner mitochondrial membrane, 8 thereby allowing the use of lower drug concentrations. We have developed an alternative strategy by taking advantage of the naturally occurring membrane-active antibiotic, gramicidin S (GS).…”

Section: Introductionmentioning

confidence: 99%

Mitochondrial targeting of radioprotectants using peptidyl conjugates

et al. 2007

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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.

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Selective targeting of synthetic antioxidants to mitochondria: towards a mitochondrial medicine for neurodegenerative diseases?

Cited by 79 publications

References 12 publications

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Superoxide Dismutase Mimics: Chemistry, Pharmacology, and Therapeutic Potential

Structural Requirements for Optimized Delivery, Inhibition of Oxidative Stress, and Antiapoptotic Activity of Targeted Nitroxides

Mitochondrial targeting of radioprotectants using peptidyl conjugates

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