TARGETING MITOCHONDRIA DESIGN, SYNTHESIS AND APPLICATION OF GS-NITROXIDES. Tanja Krainz Wipf Group Research Topic Seminar 16 th May, 2015
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1 TARGETING MITOCHONDRIA DESIGN, SYNTHESIS AND APPLICATION OF GS-NITROXIDES Tanja Krainz Wipf Group Research Topic Seminar 16 th May, 2015 Tanja Wipf Group Page 1 of 26 5/20/2015
2 Mitochondria as a Target in Drug Discovery Mitochondria play an essential role in cellular life and death Aging is the greatest risk factor for neurodegenerative disease due to accumulation of mtdna mutations, oxidative stress Escaping ROS damage many intracellular targets in vicious cycle Radiation, Traumatic Brain Injury induce ROS generation There is strong evidence to support the hypothesis that the source of pathogenesis in age-related neurodegeneration is oxidative stress caused by overproduction of ROS as a result of mitochondrial dysfunction Nature 2006, 443, Tanja Wipf Group Page 2 of 33 May 16, 2015 Tanja Wipf Group Page 2 of 26 5/20/2015
3 Mitochondria The Energy Powerhouse Discreet organelles in most eukaryotic cells 80-90% of ATP is produced in mitochondria via oxidative phosphorylation (OXPHOS) Other Roles of Mitochondria: Ion Homeostasis Regulation of Apoptotic Cell Death Biochemical pathways (Krebs Cycle, β- Oxidation, Lipid Cholesterol Synthesis) Calcium Regulation Mitochondria Morphology Porous outer membrane (< 5kDa) Intermembrane space Innermitochondrial membrane Mitochondrial Matrix Curr. Biol. 2006, 16, R551 Biomol. Therap. 2010, 18, Tanja Wipf Group Page 3 of 33 May 16, 2015 Tanja Wipf Group Page 3 of 26 5/20/2015
4 ATP Production and Oxidative Stress In 1956 Harman proposed free radical theory of aging and related diseases the reaction of active free radicals, normally produced in the organism, with cellular constituents initiates the changes associated with aging Ca. 0.2% of cellular O 2 is converted to ROS Trends Biochem Sci, 2010, 35, Biochem J. 2009, 417, 1-13 Tanja Wipf Group Page 4 of 33 May 16, 2015 Tanja Wipf Group Page 4 of 26 5/20/2015
5 The Role of Cardiolipin Cardiolipin (CL) is exclusively expressed in the IMM Ø Ø Ø Roles: Cristae Formation Organization of complexes into supercomplexes for optimal OXPHOS Interaction with Cyt c for optimal electron transfer Br J Pharmacol. 2014, 171, Tanja Wipf Group Page 5 of 33 May 16, 2015 Tanja Wipf Group Page 5 of 26 5/20/2015
6 Consequences of Cardiolipin (CL) Oxidation CL is particularly vulnerable to oxidation due to unsaturated fatty acid chains Located at ROS production site Reduction of CL affinity to cyt c leading to cyt c unfolding and enhances cyt c peroxidase activity Oxidized CL synergizes with Ca 2+ to induce opening of the mitochondrial permeability transition pore (MPT) Br. J. Pharmacol. 2014, 171, Tanja Wipf Group Page 6 of 33 May 16, 2015 Tanja Wipf Group Page 6 of 26 5/20/2015
7 Harmful Activities of ROS Apoptotic and necrotic cell death Mitochondrial diseases Neurodegenerative disease (Huntington's, Alzheimer s, Parkinson s) Neuromuscular Obesity Diabetes Cardiovascular Cancer Biochem. J. 2009, 417, 1-13 Tanja Wipf Group Page 7 of 33 May 16, 2015 Tanja Wipf Group Page 7 of 26 5/20/2015
8 Natural Antioxidants Superoxide dismutase (SOD) Catalase Vitamin C Vitamin E Thioredoxin (Trx) Glutathione peroxidase Environ. Mol. Mutagen, 2010, 51, 462 Tanja Wipf Group Page 8 of 33 May 16, 2015 Tanja Wipf Group Page 8 of 26 5/20/2015
9 Strategies in Mitochondrial Targeting Environ. Mol. Mutagen. 2010, 51, 462 Tanja Wipf Group Page 9 of 33 May 16, 2015 Tanja Wipf Group Page 9 of 26 5/20/2015
10 Gramicidin S based Conjugates Gramicidin S Scaffold for Subcellular Targeting Probes Cyclic Peptide (Bacillus brevis) Disrupts bacterial inner membrane Type II β turn ( D Phe-Pro) E-alkene isostere Payload TEMPO Vehicle (hemi GS) Replacement of amide bond with alkene à extended bioavailability due to increased resistance against protease action Acc. Chem. Res. 2008, 41, 87 Tanja Wipf Group Page 10 of 33 May 16, 2015 Tanja Wipf Group Page 10 of 26 5/20/2015
11 Cyclic Nitroxides ROS scavengers and SOD mimetics Cyclic Nitroxides are stable free radicals Nitroxides with α-hs are unstable due to dismutation to nitrones Very efficient radical scavengers Inhibit lipid peroxidation Cyclic Nitroxides in therapeutic applications: TEMPOL: completed phase I in radiation oncology Challenges: High dosage necessary due to poor cellular partitioning J. Org. Chem, 2008, 73, 6763 Tanja Wipf Group Page 11 of 33 May 16, 2015 Tanja Wipf Group Page 11 of 26 5/20/2015
12 Synthetic Route to XJB Tanja Wipf Group Page 12 of 33 May 16, 2015 Tanja Wipf Group Page 12 of 26 5/20/2015
13 Monte Carlo Simulation Effective partitioning of nitroxide is necessary but not sufficient for the protection against oxidative stress XJB Cardiolipin Positioning of the nitroxide at the polar/nonpolar interface of the lipid membrane is essential for activity to allow successful competition with O 2 for electrons from ETC. Accomplished by the intact β-turn motif J. Pharmacol. Exp. Ther. 2007, 320, Tanja Wipf Group Page 13 of 33 May 16, 2015 Tanja Wipf Group Page 13 of 26 5/20/2015
14 XJB Delivery into Mitochondria EPR monitoring of mitochondrial uptake of XJB in Mouse Embryonic Cells (MECs) à incubation with 10 µm XJB Mitochondrial enrichment of XJB and reduction of nitroxide to hydroxylamine J. Am. Chem. Soc. 2005, 127, Tanja Wipf Group Page 14 of 33 May 16, 2015 Tanja Wipf Group Page 14 of 26 5/20/2015
15 Fluorescent Labelling of XJB Mitochondrial Localization of labelled XJB Overlay XJB-BODIPY-FL MitoTrackCMXROS Tanja Wipf Group Page 15 of 33 May 16, 2015 Tanja Wipf Group Page 15 of 26 5/20/2015
16 Independent studies with XJB Anti-inflammatory properties Radioprotection Lethal Haemorrhagic Shock Protection against gamma irradiation Huntington s disease Ischemia reperfusion Traumatic Brain Injury Tanja Wipf Group Page 18 of 33 May 16, 2015 Tanja Wipf Group Page 16 of 26 5/20/2015
17 In Vivo Studies: Lethal Haemorrhagic Shock Leading cause of death of people under 45 years of age. Current Treatment: controlling of bleeding and restoring intravascular volume 0h 55% blood removal 1h Post bleeding observation 6h 16 rats 3 rats died i.v. injection of XJB (total dose 2 µmol/kg) XJB prolongs survival of rats with lethal haemorrhagic shock Ann. Surg. 2007, 245, 305 Biochem. Pharmacol. 2007, 74, 801 Tanja Wipf Group Page 19 of 33 May 16, 2015 Tanja Wipf Group Page 17 of 26 5/20/2015
18 Traumatic Brain Injury (TBI) Leading cause of death and disability in children and young adults Ca. 1.7 million people/year in US alone sustain acute brain injury ~52,000 deaths ~85,000 suffer from long term disabilities. No specific therapy standard treatment remains supportive care Nat. Neuro. 2012, 15, Tanja Wipf Group Page 20 of 33 May 16, 2015 Tanja Wipf Group Page 18 of 26 5/20/2015
19 XJB Partitioning in the Brain Imaging of XJB in the brain by L-B and EPR spectroscopy Dose and time-dependent distribution of XJB in naïve rat brain after interperitoneal injection Tanja Wipf Group Page 21 of 33 May 16, 2015 Tanja Wipf Group Page 19 of 26 5/20/2015
20 Cytochrome C Release Triggers Apoptosis Accumulation of H 2 O 2 during TBI leads to unfolding of Cyt c Enhancement of Cyt c peroxidase activity targeting side chains of CL Oxidation of CL weakens interaction with Cyt c Release of Cyt c to cytosol via transition pore Nat. Neurosc. 2012, 15, Tanja Wipf Group Page 22 of 33 May 16, 2015 Tanja Wipf Group Page 20 of 26 5/20/2015
21 Traumatic Brain Injury 2D-LCMS assessment of molecular species of CL and its oxidation products trauma +XJB XJB substantially reduces neuronal death in both in vitro and in vivo, and markedly reduced behavioural deficits and cortical lesion volume. Tanja Wipf Group Page 23 of 33 May 16, 2015 Tanja Wipf Group Page 21 of 26 5/20/2015
22 Huntington s Disease Huntington s disease is a progressive brain disorder that causes uncontrolled movements, cognitive difficulties and emotional disturbance Disease more prevalent in people of European ancestry 3-7 out of 100,000 in Europe have HD 30,000 cases in US Only 1-3% of HD cases are not inherited This study: Mouse Model of HD harbouring disease length 150CAG tract knocked into both alleles of the mouse HD gene homologue. HD150Kl mice treated up to 57 weeks with XJB (1 mg/kg up to 3 times/ week) Tanja Wipf Group Page 24 of 33 May 16, 2015 Tanja Wipf Group Page 22 of 26 5/20/2015
23 In Vivo Studies: Huntington s Disease Early signs of HD: Weight loss Motor Abnormalities XJB supresses weight loss in HD mice and significantly improves motor performance Cell Rep. 2012, 2,1137 Tanja Wipf Group Page 25 of 33 May 16, 2015 Tanja Wipf Group Page 23 of 26 5/20/2015
24 Huntington s Disease: XJB Enhances Neuronal Survival B. MtT=Mitotracker co-labelled in primary striatal neurons from embryonic day 17 HD150KI mice. C. XJB treatment (1 µm) for 1 week does not induce measurable changes in the number of MT as quantified after Mitotracker intensity. D. XJB treatment protects survival of primary striatal neurons after 7 days in culture Tanja Wipf Group Page 26 of 33 May 16, 2015 Tanja Wipf Group Page 24 of 26 5/20/2015
25 Conclusion and Future Outlook Demonstrated effectiveness of XJB in: Traumatic Brain Injury Lethal Haemorrhagic Shock Huntington's Disease BODIPY - analogues for visualization and co-localization in mitochondria Challenges: More concise synthesis of XJB Metabolic stability Solubility Tanja Wipf Group Page 33 of 33 May 16, 2015 Tanja Wipf Group Page 25 of 26 5/20/2015
26 Acknowledgements Prof Peter Wipf CMCR Wipf Group Collaborators Prof Hülya Bayir Prof Cynthia McMurray Prof Joel Greenberger Prof Laura Niedernhofer Prof Louis Falo Tanja Wipf Group Page 33 of 33 May 16, 2015 Tanja Wipf Group Page 26 of 26 5/20/2015
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