Alex Lippert
CD4 Projects
Triggered Energy Transfer Chemiluminescence for In Vivo Imaging
Funding: NSF CHE1653474
PI: Alexander R. Lippert
Chemiluminescence is the direct generation of light from a chemical reaction and does not require an excitation light source, which eliminates autofluorescence and light scattering that is endemic to fluorescence imaging. Our lab is developing the fundamental chemistry of triggered energy transfer chemiluminescence for imaging a range of molecular markers and photophysical properties ideally suited for whole animal imaging. These chemical agents consist of a dioxetane ring as the chemiluminescent core, which is stabilized by the appendage of the spiroadamantane group. An acrylic group red-shifts emission and increases quantum yield, and chemical reaction-based triggers can be modularly installed to translate disease markers such as hypoxia, pH, and oxygen metabolites into an observable optical response. In collaboration with the Department of Radiology at the University of Texas Southwestern Medical Center, we have validated a number of chemiluminescence imaging agents for pre-clinical application and are currently setting the stage to apply these imaging techniques to the develop new types of therapies for cancer and other diseases.
Chemical Probes for Reactive Sulfur, Oxygen, and Nitrogen Species
Funding: NIGMS R15GM114792
PI: Alexander R. Lippert
Life has evolved to harness small reactive molecules like nitric oxide, hydrogen sulfide, and reactive oxygen species to mediate intra- and intercellular communications. This super family of reactive sulfur, oxygen, and nitrogen (RSON) species are small and diffusible, can easily cross cellular membranes, and signal by direct reaction with proteins. Because of their ubiquity in health and disease, targeting RSON species signaling, particularly that of nitric oxide, has been of great interest in drug development efforts. Drugs such as PDEi5 inhibitors (Viagra), soluble guanylyl cyclase aactivators/stimulators (Adempas), and organic nitrates (Nitroglycerin, Isordil) all rely on the reactive signaling of nitric oxide and its metabolites. This reactive nature leads to a diverse and complex set of interacting reactive species, which are difficult to study in a reaction flask, and even more challenging in living systems. Our approach is to design small molecules that react with these analytes with high specificity and sensitivity to give an chemiluminescent or other type of optical response. Recently, we have endeavored to develop a technique to quantify the concentrations of these species using an innovative kinetics-based approach. Many of our efforts are in the process of being commercialized for disease monitoring and drug development applications by the start-up company BioLum Sciences, LLC.
CD4 Recent Publications (2019–2020)
Li, B.; Haris, U.; Aljowni, M.; Nakatsuka, A.; Patel, S. K.; Lippert, A. R. “Tuning the Photophysical Properties of Spirolactam Rhodamine Photoswitches.” Isr. J. Chem. 2020, online publication.
Bunton, C. B.; Bassampour, Z. M.; Boothby, J. M.; Smith, A. N.; Rose, J. V.; Nguyen, D. M.; Ware, T. H.; Csaky, K. G.; Lippert, A. R.; Tsarevsky, N. V.; Son, D. Y. “Degradable Silyl Ether–Containing Networks from Trifunctional Thiols and Acrylates.” Macromolecules 2020, Article ASAP.
Quimbar, M. E.; Davis, S. Q.; Al-Farra, S. T.; Hayes, A.; Jovic, V.; Masuda, M.; Lippert, A. R. “Chemiluminescent Measurement of Hydrogen Peroxide in Exhaled Breath Condensate of Healthy and Asthmatic Adults.” Anal. Chem. 2020, 92, 14594–14600.
Ryan, L. S.; Gerberich, J.; Haris, U.; Nguyen, D.; Mason, R. P.; Lippert, A. R. “Ratiometric pH Imaging Using a 1,2-Dioxetane Chemiluminescence Resonance Energy Transfer Sensor in Live Animals.” ACS Sens. 2020, 5, 2925–2932.
Bezner, B. J.; Ryan, L. S.; Lippert, A. R. “Reaction-Based Luminescent Probes for Reactive Sulfur, Oxygen, and Nitrogen Species: Analytical Techniques and Recent Progress.” Anal. Chem. 2020, 92, 309–326.
Wise, J. G.; Nanayakkara, A. M.; Aljowni, M.; Chen, G.; De Oliveira, M. C.; Ammerman, L.; Olengue, K.; Lippert, A. R.; Vogel, P. D. “Optimizing Targeted Inhibitors of P-Glycoprotein Using Computational and Structure-Guided Approaches.” J. Med. Chem. 2019, 62, 10645–10663.
Worth, R. C.; Mizrachi, A.; Li, H.; Markovsky, E.; Enyedi, B.; Jacobi, J.; Brodsky, O.; Cao, J.; Lippert, A. R.; Incrocci, L.; Mulhall, J. P.; Haimovitz-Friedman, A. “Sildenafil Protects Endothelial Cells from Radiation-Induced Oxidative Stress.” J. Sex. Med. 2019, 16, 1721–1733.
Jones, K. A.; Kentala, K.; Beck, M. W.; An. W.; Lippert, A. R.; Lewis, J. C.; Dickinson, B. C. “Development of a Split Esterase for Protein-Protein Interaction-Dependent Small-Molecule Activation.” ACS Cent. Sci. 2019, 5, 1768–1776.
Ryan, L. S.; Gerberich, J. L.; Cao, J.; An, W.; Jenkins, B. A.; Mason, R. P.; Lippert, A. R. “Kinetics-Based Measurement of Hypoxia in Living Cells and Animals Using an Acetoxymethyl Ester Chemiluminescent Probe.” ACS Sens. 2019, 4, 1391–1398.
An, W.; Ryan, L. S.; Reeves, A. G.; Bruemmer, K. J.; Mouhaffel, M.; Gerberich, J. L.; Winters, A.; Mason, R. P.; Lippert, A. R. “A Chemiluminescent Probe for HNO Quantification and Real-time Monitoring in Living Cells.” Angew. Chem. Int. Edit. 2019, 58, 1361–1365.