Our First Specific Aim further develops the concept that sequences of the membrane-active antibiotic Gramicidin S (GS) can be used to deliver biologically active payloads to mitochondria. Specifically, we will construct hybrid molecules with higher catalytic activity than 4-amino-Tempo linked JP4-039 and XJB-5-131. The Second Specific Aim provides molecules linked to NOS inhibitors such as AMT (GS-NOS-I), which will test the hypothesis of Project 1 that mitochondrial targeted small NOS inhibitors will be effective alone and when added to GS-nitroxides as radiation damage mitigators. The Third Specific Aim tests the hypothesis that additive and synergistic effects in radiation mitigation can be accomplished by nanoparticle conjugation of GS-nitroxide and GS-NOS-1 as well as other combination therapeutics. The Fourth Specific Aim will support Project 4 and provide proof-of-principle that hydrogen peroxide (H202) releasing small molecules can induce the formation of high molecular weight oligomers of human (rh)MnSOD with intact activity. This effect of H202 on MnSOD activity is likely due to the oligomerization-induced stabilization of the enzyme's structure. Therefore, it can be used as a protective strategy to replenish irradiation induced MnSOD deficiency. The Fifth Specific Aim is directed toward the synthesis of triphenylphosphonium (TPP)-derived oximes, nitroxides, salen-Mn and porphyrin-Mn complexes and thus employs a charge-driven delivery strategy of radioprotective agents to mitochondria. The Sixth Specific Aim is focused on the synthesis of general analogs of Project lead structures, the development of structure-activity relationships of all drug and lead candidates, and the gram-level scaleup of any other synthetic compounds in any ofthe Projects and non-synthetic Cores ofthe Pittsburgh CMCR. Specifically, Core D will optimize PUMA inhibitors in collaboration with Project 5, and optimize delivery systems in collaboration with Cores C and E.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program--Cooperative Agreements (U19)
Project #
5U19AI068021-09
Application #
8515301
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2013-09-01
Budget End
2014-08-31
Support Year
9
Fiscal Year
2013
Total Cost
$253,817
Indirect Cost
$76,997
Name
University of Pittsburgh
Department
Type
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Huang, Zhentai; Epperly, Michael; Watkins, Simon C et al. (2016) Necrostatin-1 rescues mice from lethal irradiation. Biochim Biophys Acta 1862:850-6
Anthonymuthu, Tamil Selvan; Kenny, Elizabeth Megan; Bayır, Hülya (2016) Therapies targeting lipid peroxidation in traumatic brain injury. Brain Res 1640:57-76
Mao, Gaowei; Qu, Feng; St Croix, Claudette M et al. (2016) Mitochondrial Redox Opto-Lipidomics Reveals Mono-Oxygenated Cardiolipins as Pro-Apoptotic Death Signals. ACS Chem Biol 11:530-40
Tejero, Jesús; Kapralov, Alexandr A; Baumgartner, Matthew P et al. (2016) Peroxidase activation of cytoglobin by anionic phospholipids: Mechanisms and consequences. Biochim Biophys Acta 1861:391-401
Scott, Melanie J; Billiar, Timothy R; Stoyanovsky, Detcho A (2016) N-tert-butylmethanimine N-oxide is an efficient spin-trapping probe for EPR analysis of glutathione thiyl radical. Sci Rep 6:38773
Chen, Dongshi; Yu, Jian; Zhang, Lin (2016) Necroptosis: an alternative cell death program defending against cancer. Biochim Biophys Acta 1865:228-36
Kagan, V E; Jiang, J; Huang, Z et al. (2016) NDPK-D (NM23-H4)-mediated externalization of cardiolipin enables elimination of depolarized mitochondria by mitophagy. Cell Death Differ 23:1140-51
Zou, Chunbin; Synan, Matthew J; Li, Jin et al. (2016) LPS impairs oxygen utilization in epithelia by triggering degradation of the mitochondrial enzyme Alcat1. J Cell Sci 129:51-64
Lazo, John S; Sharlow, Elizabeth R (2016) Drugging Undruggable Molecular Cancer Targets. Annu Rev Pharmacol Toxicol 56:23-40
Stern, Andrew M; Schurdak, Mark E; Bahar, Ivet et al. (2016) A Perspective on Implementing a Quantitative Systems Pharmacology Platform for Drug Discovery and the Advancement of Personalized Medicine. J Biomol Screen 21:521-34

Showing the most recent 10 out of 159 publications