Aberrant proteolysis, a hallmark of many pathologies, is often localized to certain organs and tissues. Unfortunately, basic studies to understand spatial aspects of aberrant proteolysis in human disease models are difficult to carry out, because current inhibitors lack the ability to be activated in a location- and time-specific fashio. Furthermore, even though small molecule inhibitors are available to target aberrant proteolysis, inhibition in non-target tissues can be a significant cause of side effects and toxicity during chemotherapeutic interventions. In general, we must be able to not only measure, but also inhibit proteolysis in a spatially controlled fashion in human disease models, in order to study spatial aspects of aberrant protease activity. Towards this goal we have developed an exciting new method that gives spatial and temporal control over enzyme inhibition using light. Our photoactivated approach works against isolated enzymes and in live cells, and targets an important class of cysteine proteases associated with inflammation and cancer progression. We developed an effective caging method based on neutralizing nitrile warheads of protease inhibitors through metal binding, where fast inhibitor release and activation occur with visible light, without causing deleterious toxicity. During this grant period, we propose to make a significant step towards our long-term goal, to develop and apply a complete toolkit of light-activated inhibitors to investigate the role of cysteine proteases in inflammation and cancer in live animal models.
Specific Aims are 1) to develop new, potent versions of caged cathepsin and caspase inhibitors, 2) to understand the photochemistry of caged protease inhibitors and tune the wavelength of release;3) to characterize the behavior of caged complexes in living cells;4) to achieve local inhibition of cathepsin and caspase enzymes in a murine model of bone tumor growth. We have assembled a highly complementary and interdisciplinary research team for this project that has a proven track record of working and publishing together. Targeting of bone tumors was chosen, because bone is the primary site of metastasis for prostate cancer and most patients with advanced disease experience complications from bone lesions that are incurable. This proposal aims to develop and validate light-activated cysteine protease inhibitors as basic research tools, and potential therapeutics in metastatic bone disease. Literature data confirm that photodynamic therapy is effective against bone tumors in live animal models, which strongly supports our studies.

Public Health Relevance

The proposed research is relevant to human health because its aim is to develop inhibitors of enzymes associated with cancer and inflammation, which are spatially controlled using light. This proposal will address current unmet needs because aberrant proteolysis is difficult to control spatially with current enzyme inhibitors. Special emphasis is placed on development of new chemical tools to study aberrant proteolysis in bone tumor metastasis and experimental validation of this new therapeutic approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Biomedical Imaging and Bioengineering (NIBIB)
Type
Research Project (R01)
Project #
1R01EB016072-01A1
Application #
8529017
Study Section
Synthetic and Biological Chemistry A Study Section (SBCA)
Program Officer
Tucker, Jessica
Project Start
2013-04-15
Project End
2017-03-31
Budget Start
2013-04-15
Budget End
2014-03-31
Support Year
1
Fiscal Year
2013
Total Cost
$383,701
Indirect Cost
$92,574
Name
Wayne State University
Department
Chemistry
Type
Schools of Arts and Sciences
DUNS #
001962224
City
Detroit
State
MI
Country
United States
Zip Code
48202
Loftus, Lauren M; White, Jessica K; Albani, Bryan A et al. (2016) New Ru(II) Complex for Dual Activity: Photoinduced Ligand Release and (1) O2 Production. Chemistry 22:3704-8
Li, Ao; White, Jessica K; Arora, Karan et al. (2016) Selective Release of Aromatic Heterocycles from Ruthenium Tris(2-pyridylmethyl)amine with Visible Light. Inorg Chem 55:10-2
Huisman, Matthew; White, Jessica K; Lewalski, Veronica G et al. (2016) Caging the uncageable: using metal complex release for photochemical control over irreversible inhibition. Chem Commun (Camb) 52:12590-12593
Arora, Karan; White, Jessica K; Sharma, Rajgopal et al. (2016) Effects of Methyl Substitution in Ruthenium Tris(2-pyridylmethyl)amine Photocaging Groups for Nitriles. Inorg Chem 55:6968-79
Palmer, Alycia M; Knoll, Jessica D; Turro, Claudia (2015) Photoinduced interactions of two dirhodium complexes with d(GTCGAC)2 probed by 2D NOESY. Dalton Trans 44:3640-6
Tu, Yi-Jung; Mazumder, Shivnath; Endicott, John F et al. (2015) Selective Photodissociation of Acetonitrile Ligands in Ruthenium Polypyridyl Complexes Studied by Density Functional Theory. Inorg Chem 54:8003-11
Knoll, J D; Albani, B A; Turro, C (2015) Excited state investigation of a new Ru(II) complex for dual reactivity with low energy light. Chem Commun (Camb) 51:8777-80
Knoll, Jessica D; Turro, Claudia (2015) Control and utilization of ruthenium and rhodium metal complex excited states for photoactivated cancer therapy. Coord Chem Rev 282-283:110-126
Sharma, Rajgopal; Knoll, Jessica D; Ancona, Nicholas et al. (2015) Solid-phase synthesis as a platform for the discovery of new ruthenium complexes for efficient release of photocaged ligands with visible light. Inorg Chem 54:1901-11
Ramalho, Suelem D; Sharma, Rajgopal; White, Jessica K et al. (2015) Imaging Sites of Inhibition of Proteolysis in Pathomimetic Human Breast Cancer Cultures by Light-Activated Ruthenium Compound. PLoS One 10:e0142527

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