Department of Chemistry

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Alexander Deiters

Professor

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1305 Chevron
Chevron Science Center
219 Parkman Avenue

Pittsburgh, PA 15260
412-624-5515

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Research Overview

Chemical Biology, Chemical Genetics, Synthetic Chemistry, Synthetic Biology, Photochemistry

Our group consists of students and postdocs with a diverse set of backgrounds in synthetic organic chemistry, nucleic acid chemistry, biochemistry, analytical chemistry, chemical engineering, and functional genomics. We are developing novel chemical tools to elucidate biological processes in an area broadly defined as Chemical Biology. Our multidisciplinary research program involves small molecule synthesis, medicinal and organometallic chemistry, cell and molecular biology, protein engineering, nucleic acid chemistry, amino acid chemistry, natural product chemistry, as well as photochemistry. A summary of some of our research directions and links to selected publications is provided below.

Biologically Active Small Molecules – Synthesis and Methodology Development

We are developing synthetic approaches to a wide range of natural and unnatural molecules. The chemical synthesis of new compounds is the enabling technology for all biological discoveries and methodology developments in the lab. Being able to synthesize molecules with novel functions and architectures allows us to create tools and molecular probes tailored to the biological problems that we are addressing.

We have developed microwave-mediated [2+2+2] cyclotrimerization reactions that enable the rapid construction of carbo- and heterocyclic molecules. We are applying this methodology to the assembly of several structures found in nature and to the discovery of new small molecule modifiers of important cellular pathways.

fig 1

We are developing synthetic routes to new monomeric building blocks of biological macromolecules in order to engineer DNA, RNA, and proteins with new functions and new chemistries. Our synthetic efforts led to the multistep assembly of light-activated phosphoramidites and unnatural amino acids. These molecules represent essential parts for our projects in developing novel optochemical tools.

fig 2

Drug Discovery through Small Molecule Targeting of Cellular Pathways

Several of our projects involve the discovery of small molecule inhibitors and activators of specific biological pathways that are implicated in human diseases, including cancer and viral infection. Besides representing novel chemical biology tools for the investigation of those pathways, the discovered molecules also have significant potential as fundamentally new therapeutic agents. We reported the first small molecule inhibitors of the microRNA pathway, specifically inhibiting miR-21, which is overexpressed in a wide range of cancers. We are currently using the small molecules as probes to investigate miR-21 biogenesis and we are also testing their therapeutic potential in cellular models of cancer. Another miRNA that we are targeting with small molecule inhibitors is miR-122. This miRNA is highly expressed in the liver and has been shown to be required for the replication of the hepatitis C virus. Importantly, the small molecule inhibitors discovered in our lab significantly reduce HCV levels in treated human liver cells.

fig 3

Optochemical Tools for the Investigation of Biological Processes

Biological processes are regulated with high spatial and temporal resolution in Nature. In order to investigate such processes and their involvement in human disease, molecular tools need to be developed that enable external control with a similar level of spatio-temporal resolution. In this context, light represents an ideal regulatory element. We are developing a wide range of methods that enable the photochemical activation and deactivation of protein function and gene function. We are applying the developed methodologies to the dissection of complex biological mechanisms in single cells and multicellular organisms.

For the development of light-activated proteins, we are using a Synthetic Biology approach by expanding the genetic code of cells to enable the site-specific incorporation of unnatural amino acids into proteins. The genetic encoding of light-activated proteins allows for the investigation of dynamic changes in protein activity, folding, and translocation, as well as the engineering of protein structure and function with atomic precision.

fig 4

Besides using synthetic biology approaches to the development of cellular light-switches, we are extensively applying our photocaged oligonucleotide chemistry to control gene function with high spatial and temporal resolution via antisense and DNA decoy approaches in mammalian tissue culture. This methodology has proven to be very robust and applicable to a wide range of biological targets.

fig 5

If you would like to learn more about any of these projects or if you are interested in collaborating on the application of any of these methods to your research problem, please email alexdeiters@gmail.com.

Awards

  • Charles E. Kaufman Foundation – New Initiative Research Grant (2014)
  • North Carolina State University – Alumni Association Outstanding Research Award (2011)
  • American Cancer Society – Research Scholar Award (2011)

  • Thieme Chemistry Journals Award (2010)

  • American Chemical Society – Teva USA Scholar Award (2009)

  • National Science Foundation – Faculty Early Career Development (CAREER) Award (2009)

  • Arnold and Mabel Beckman Foundation – Beckman Young Investigator Award (2007)

  • Research Corporation – Cottrell Scholar Award (2007)

  • Sigma Xi Faculty Research Award (2007)

  • CEM Corporation – MJ Collins Award (2007)

  • March of Dimes Foundation – Basil O’Connor Starter Scholar Research Award (2006)

  • The Scripps Society of Fellows Fall Symposium Lecture Award (2003)

  • Postdoctoral Fellowship of the German Research Foundation (2002)

  • Best Dissertation Award in the College for Natural Sciences, Mathematics, and Computer Science University of Münster (2001)
  • Feodor-Lynen Postdoctoral Fellowship of the Alexander von Humboldt-Foundation (2001)
  • German Chemical Society – Research Prize for Young Chemists (1999)
  • Predoctoral Fellowship of the Fund of the Chemical Industry (1998)
  • Fellowship of the German National Academic Foundation (1996)

Publications

“Genetic Code Expansion in Zebrafish Embryos and Its Application to Optical Control of Cell Signaling,” Liu, J., Hemphill, J.; Samanta, S.; Tsang, M.; Deiters, A. , J Am Chem Soc., Vol. 139, 2017, Pages 9100–9103
“Small-molecule control of protein function through Staudinger reduction,” Luo, J.; Liu, Q.; Morihiro, K.; Deiters, A. , Nat Chem., Vol. 8, 2016, Pages 1027–1034
“Conditional Control of Alternative Splicing through Light-Triggered Splice-Switching Oligonucleotides,” Hemphill, J.; Liu, Q.; Uprety, R.; Juliano, R. J.; Tsang, M.; Deiters, A. , J. Am. Chem. Soc., Vol. 137, 2015, Pages 3656-3662
“Optical Control of CRISPR/Cas9 Gene Editing,” Hemphill, J.; Borchardt, E. K.; Asokan, A.; Deiters, A , J. Am. Chem. Soc, Vol. 137, 2015, Pages 5642-5645
“Genetically Encoded Optochemical Probes for Simultaneous Fluorescence Reporting and Light-Activation of Protein Function with Two-Photon Excitation,” Luo, J.: Uprety, R.; Naro, Y.; Chou, C.; Chin, J. W.; Deiters, A. , J. Am. Chem. Soc., Vol. 136, 2014, Pages 15551-15558
“Interfacing Synthetic DNA Logic Operations with Protein Outputs,” Prokup, A.; Deiters, A., Angew. Chem. Int. Ed., Vol. 53, 2014, Pages 13192–13195
“Sequential Gene Silencing Using Wavelength-Selective Caged Morpholino Oligonucleotides,” Yamazoe, S.; Liu, Q.; McQuade, L. E.; Deiters, A.; Chen, J. K., Angew. Chem. Int. Ed., Vol. 53, 2014, Pages 10114–10118
“Site-Specific Promoter Caging Enables Optochemical Gene Activation in Cells and Animals,” Hemphill, J.; Govan, J.; Uprety, R.; Tsang, M.; Deiters, A., J. Am. Chem. Soc., Vol. 136, 2014, Pages 7152–7158
“Genetically Encoded Light-Activated Transcription for Spatiotemporal Control of Gene Expression and Gene Silencing in Mammalian Cells,” Hemphill, J.; Chou, C.; Chin, J. W.; Deiters, A., J. Am. Chem. Soc., Vol. 135, 2013, Pages 13433–13439
“DNA Computation in Mammalian Cells: MicroRNA Logic Operations,” Hemphill, J.; Deiters, A., J. Am. Chem. Soc., Vol. 135, 2013, Pages 10512–10518
“Hydrogen Peroxide Induced Activation of Gene Expression in Mammalian Cells using Boronate Estrone Derivatives,” Govan, J. M.; McIver, A. L.; Riggsbee, C.; Deiters, A., Angew. Chem. Int. Ed., Vol. 51, 2012, Pages 9066–9070
“DNA Computation: A Photochemically Controlled AND Gate,” Prokup, A.; Hemphill, J.; Deiters, A., J. Am. Chem. Soc., Vol. 134, 2012, Pages 3810-3815
“Genetically Encoded Norbornene Directs Site-Specific Cellular Protein Labeling via a Rapid Bioorthogonal Reaction,” Lang, K.; Davis, L.; Torres-Kolbus, J.; Chou, C., Deiters, A.; Chin, J., Nature Chem., Vol. 4, 2012, Pages 298-304