Hoye, AT and Davoren, JE and Wipf, P and Fink, MP and Kagan, VE
(2008)
Targeting mitochondria.
Accounts of Chemical Research, 41 (1).
87 - 97.
ISSN 0001-4842
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Abstract
(Figure Presented) Reactive oxygen spedes (ROS) and reactive nitrogen spedes (RNS) are closely linked to degenerative diseases such as Alzheimer's disease, Parkinson's, neuronal death induding ischemic and hemorrhagic stroke, acute and chronic degenerative cardiac myocyte death, and cancer. As a byproduct of oxidative phosphorylation, a steady stream of reactive spedes emerge from our cellular energy plants, the mitochondria. ROS and RNS potentially cause damage to all cellular components. Structure alteration, biomolecule fragmentation, and oxidation of side chains are trade-offs of cellular energy production. ROS and RNS escape results in the activation of cytosolic stress pathways, DNA damage, and the upregulation of JNK, p38, and p53. Incomplete scavenging of ROS and RNS particularly affects the mitochondrial lipid cardiolipin (CL), triggers the release of mitochondrial cytochrome c, and activates the intrinsic death pathway. Due to the active redox environment and the excess of NADH and ATP at the inner mitochondrial membrane, a broad range of agents including electron acceptors, electron donors, and hydride acceptors can be used to influence the biochemical pathways. The key to therapeutic value is to enrich selective redox modulators at the target sites. Our approach is based on conjugating nitroxides to segments of natural products with relatively high affinity for mitochondrial membranes. For example, a modified gramicidin S segment was successfully used for this purpose and proven to be effective in preventing superoxide production in cells and CL oxidation in mitochondria and in protecting cells against a range of pro-apoptotic triggers such as actinomycin D, radiation, and staurosporine. More importantly, these mitochondria-targeted nitroxide/gramicidin conjugates were able to protect against apoptosis in vivo by preventing CL oxidation induced by intestinal hemorrhagic shock. Optimization of nitroxide carriers could lead to a new generation of effective antiapoptotic agents acting at an early mitochondrial stage. Alternative chemistry-based approaches to targeting mitochondria include the use of proteins and peptides, as well as the attachment of payloads to lipophilic cationic compounds, sulfonylureas, anthracyclines, and other agents with proven or hypothetical affinities for mitochondria. Manganese superoxide dismutase (MnSOD), SS tetrapeptides with 2′,6′-dimethyltyrosine (Dmt) residues, rhodamine, triphenylphosphonium salts, nonopioid analgesics, adriamycin, and diverse electron-rich aromatics and stilbenes were used to influence mitochondrial biochemistry and the biology of aging. Some general structural principles for effective therapeutic agents are now emerging. Among these are the presence of basic or positively charged functional groups, hydrophobic substructures, and, most promising for future selective strategies, classes of compounds that are actively shuttled into mitochondria, bind to mitochondria-specific proteins, or show preferential affinity to mitochondria-specific lipids. © 2008 American Chemical Society.
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Details
| Item Type: |
Article
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| Status: |
Published |
| Creators/Authors: |
|
| Date: |
1 January 2008 |
| Date Type: |
Publication |
| Journal or Publication Title: |
Accounts of Chemical Research |
| Volume: |
41 |
| Number: |
1 |
| Page Range: |
87 - 97 |
| DOI or Unique Handle: |
10.1021/ar700135m |
| Schools and Programs: |
Dietrich School of Arts and Sciences > Chemistry |
| Refereed: |
Yes |
| ISSN: |
0001-4842 |
| MeSH Headings: |
Animals; Antioxidants--chemical synthesis; Antioxidants--chemistry; Antioxidants--pharmacology; Apoptosis--drug effects; Drug Design; Free Radical Scavengers--chemical synthesis; Free Radical Scavengers--chemistry; Free Radical Scavengers--pharmacology; Humans; Mitochondria--chemistry; Mitochondria--drug effects; Mitochondria--metabolism; Mitochondrial Membranes--chemistry; Mitochondrial Membranes--drug effects; Mitochondrial Membranes--metabolism; Reactive Nitrogen Species--antagonists & inhibitors; Reactive Nitrogen Species--metabolism; Reactive Oxygen Species--antagonists & inhibitors; Reactive Oxygen Species--metabolism |
| PubMed ID: |
18193822 |
| Date Deposited: |
01 Jul 2014 17:19 |
| Last Modified: |
02 Feb 2019 14:57 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/20679 |
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