Designing Inhibitors of Cytochrome c/Cardiolipin Peroxidase Complexes: Mitochondria-Targeted Imidazole-Substituted Fatty Acids

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• Alternative Title:
  Free Radic Biol Med
• Personal Author:
  Jiang, Jianfei ; Bakan, Ahmet ; Kapralov, Alexandr A. ; Silva, K. Ishara ; Huang, Zhentai ; Amoscato, Andrew A. ; Peterson, James ; Garapati, Venkata Krishna ; Saxena, Sunil ; Bayir, Hülya ; Atkinson, Jeffrey ; Bahar, Ivet ; Kagan, Valerian E.
• Description:
  Mitochondria have emerged as the major regulatory platform responsible for the coordination of numerous metabolic reactions as well as cell death processes, whereby the execution of intrinsic apoptosis includes the production of reactive oxygen species fueling oxidation of cardiolipin (CL) catalyzed by cytochrome (Cyt) c. As this oxidation occurs within the peroxidase complex of Cyt c with CL, the latter represents a promising target for the discovery and design of drugs with antiapoptotic mechanisms of action. In this work, we designed and synthesized a new group of mitochondria-targeted imidazole-substituted analogs of stearic acid TPP-n-ISAs with various positions of the attached imidazole group on the fatty acid (n = 6, 8, 10, 13, and 14). By using a combination of absorption spectroscopy and EPR protocols (continuous wave electron paramagnetic resonance and electron spin echo envelope modulation) we demonstrated that TPP-n-ISAs indeed were able to potently suppress CL-induced structural rearrangements in Cyt c, paving the way to its peroxidase competence. TPP-n-ISA analogs preserved the low-spin hexa-coordinated heme-iron state in Cyt c/CL complexes whereby TPP-6-ISA displayed a significantly more effective preservation pattern than TPP-14-ISA. Elucidation of these intermolecular stabilization mechanisms of Cyt c identified TPP-6-ISA as an effective inhibitor of the peroxidase function of Cyt c/CL complexes with a significant antiapoptotic potential realized in mouse embryonic cells exposed to ionizing irradiation. These experimental findings were detailed and supported by all-atom molecular dynamics simulations. Based on the experimental data and computation predictions, we identified TPP-6-ISA as a candidate drug with optimized antiapoptotic potency.
• Keywords:
  All-atom Molecular Dynamics Simulation Animals Apoptosis Cardiolipin Peroxidation Cardiolipins Cytochrome C Cytochromes C Drug Design Electron Paramagnetic Resonance Embryonic Stem Cells Enzyme Inhibitors Gamma Rays Horses Imidazole-substituted Stearic Acid Imidazoles Mice Mitochondria, Heart Mitochondria Targeting Molecular Dynamics Simulation Organophosphorus Compounds Peroxidase Peroxidase Inhibitors Phosphatidylcholines Reactive Intermediates Ricinoleic Acids Stearic Acids Structure-Activity Relationship

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• Source:
  Free Radic Biol Med. 2014; 71:221-230
• Pubmed ID:
  24631490
• Pubmed Central ID:
  PMC4216591
• Document Type:
  Journal Article
• Funding:
  R01 ES020693/ES/NIEHS NIH HHSUnited States/ ; U19 AI068021/AI/NIAID NIH HHSUnited States/ ; ES021068/ES/NIEHS NIH HHSUnited States/ ; R01 NS076511/NS/NINDS NIH HHSUnited States/ ; ES020693/ES/NIEHS NIH HHSUnited States/ ; GM099738-02/GM/NIGMS NIH HHSUnited States/ ; P01HL114453/HL/NHLBI NIH HHSUnited States/ ; OH008282/OH/NIOSH CDC HHSUnited States/ ; R01 NS061817/NS/NINDS NIH HHSUnited States/ ; P01 HL114453/HL/NHLBI NIH HHSUnited States/ ; R01 GM099738/GM/NIGMS NIH HHSUnited States/ ; R01 NS084604/NS/NINDS NIH HHSUnited States/ ; R21 ES021068/ES/NIEHS NIH HHSUnited States/
• Volume:
  71
• Collection(s):
  CDC Public Access
• Main Document Checksum:
  urn:sha256:7fa7462e628e55bb494492f6f1a12b911d981e3519350b4c24eb603b002933c2
• Download URL:
  https://stacks.cdc.gov/view/cdc/30160/cdc_30160_DS1.pdf
• File Type:
  [PDF - 1.49 MB ]