Research Synopsis

The Lawrence research program is multifaceted, encompassing the fields of organic and peptide synthesis, photochemistry, enzymology, cell biology, and microscopy. This research team is engaged in the synthesis, characterization, and cell-based application of light-responsive agents (inhibitors, sensors, activators, proteins, and gene expression system), which are designed to manipulate and probe the biochemical pathways that control cell behavior. Disease states under investigation include cancer, disorders of metabolism, and Third World diseases (e.g., tuberculosis and malaria).

Profile

David Lawrence works to understand the biochemical processes of the cell by studying them as they happen in the cell as opposed to studying them in vitro. He currently focuses on applying his discoveries to cancer detection and treatment and, to a more limited extent, diseases of the developing world. Lawrence is a Fred Eshelman Distinguished Professor of Medicinal Chemistry and holds joint appointments in the Department of Chemistry and the Department of Pharmacology and is a member of the UNC Lineberger Comprehensive Cancer Center. Before joining the School in 2007, Lawrence spent eleven years as a professor of biochemistry at the Albert Einstein College of Medicine at Yeshiva University in New York. Before that, he was at the State University of New York at Buffalo for ten years.

Research Summary

Living cells have been referred to as the test tubes of the twenty-first century. The design and synthesis of molecules that inhibit, probe, or alter the biochemistry of the cell lies at the nexus between chemistry and biology. The field of chemical biology seeks to correlate the underlying chemistry of life with the behavior of cells, tissues, and organisms. By revealing the nature of the molecular engine that drives cellular behavior chemical biology provides the molecular foundation upon which innovative therapies can be created for the entire spectrum of human afflictions. The projects underway in the Lawrence Lab have biological implications, particularly in the area of cancer detection and treatment. Organic synthesis, solid phase peptide synthesis, and photochemistry all play a key role in the creation of the compounds under study.

Inhibitors and Drug Development

Lawrence's team has developed a combinatorial library strategy that creates extraordinarily potent and selective inhibitors for specific signaling proteins. We have constructed compounds that activate the insulin pathway (diabetes), the leptin pathway (obesity) (Endocrinology, 2007, 148, 433-40) and inhibit various cancer-causing pathways (Biochemistry, 2008, 47, 986-96; J. Amer. Chem. Soc. 2009, 131, 13072 - 3; ChemBioChem, 2008, 9, 507-9).

Enzyme Sensors

The Lawrence Lab has synthesized fluorescent sensors that allow us to visualize intracellular enzymatic activity, including biochemical behavior responsible for division (Chem. & Biol., 2007, 14, 1254-60), digestion of old and ineffective proteins (J. Amer. Chem. Soc., 2010, 132, in press), and uncontrolled cell growth (J. Amer. Chem. Soc., 2007, 129, 2742-3).

In collaboration with Professor Nancy Allbritton, we are developing an array of sensors that will be used to detect breast, pancreatic, and prostate cancer. In collaboration with Professor Lee Graves, the Lawrence lab constructed a pair of sensors that distinguishes between cells that resistant or sensitive to Gleevec, and anticancer drug used to treat chronic myelogenous leukemia (ACS Chemical Biology 2010, 5, 887).

Light-Activated Inhibitors, Sensors, and Signaling Proteins

An array of compounds have been prepared that undergo dramatic chemical changes in response to light (ACS Chemical Biology 2009, 4, 409-27). These light sensitive agents can be switched on or off at any time or place inside living cells, thereby allowing the chemistry of the cell to be controlled wherever and whenever we so desire. Issues currently under study include identifying the role that key proteins play in controlling the stages of cell division, motility, and death. Examples include light-controlled proteins (Science, 2004, 303, 743-6), inhibitors (Organic Lett., 2007, 9, 2249-52), and sensors (J. Amer. Chem. Soc., 2006, 128, 14016-7; J. Amer. Chem. Soc., 2010, 132, in press).

Light-Induced Gene Expression

A strategy has been developed for using light to activate the expression of any gene of interest. This furnishes a direct means to examine the biological consequences of gene expression within the context of specific tissue microenvironments. This technology is being applied to living animals in collaboration with a group at the Albert Einstein College of Medicine (J. Biomed. Optics 2005, 10, 0514061 -9).

Third World Diseases

Almost one million people a year die from malaria, most in sub-Saharan Africa. Nearly two million people a year die from tuberculosis, most in developing countries. A simple easy-to-use test is required to detect the presence of these diseases, which are often in a latent stage, so that treatment can be started while the individual is still healthy. A strategy has been developed, in collaboration with Professor Vyas Sharma, which uses plant seeds in combination with a chemically modified natural product to detect whether a person is infected. Spit on the seed and, if germination occurs, then treatment is required.

Ten Most Recent Publications

1. Dual wavelength photoactivation of cAMP- and cGMP-dependent protein kinase signaling pathways. Priestman MA, Sun L, Lawrence DS. ACS Chem Biol. 2011 Apr 15;6(4):377-84. doi: 10.1021/cb100398e. Epub 2011 Jan 26. PMID: 21218856 [PubMed - indexed for MEDLINE]
2. Construction of a photoactivatable profluorescent enzyme via propinquity labeling. Lee HM, Xu W, Lawrence DS. J Am Chem Soc. 2011 Mar 2;133(8):2331-3. Epub 2011 Feb 8. PMID: 21302921 [PubMed - indexed for MEDLINE]
3. A new trick (hydroxyl radical generation) for an old vitamin (B12). Shell TA, Lawrence DS. J Am Chem Soc. 2011 Feb 23;133(7):2148-50. Epub 2011 Jan 28. PMID: 21275391 [PubMed - indexed for MEDLINE]
4. Multicolor monitoring of dysregulated protein kinases in chronic myelogenous leukemia. Wang Q, Zimmerman EI, Toutchkine A, Martin TD, Graves LM, Lawrence DS. ACS Chem Biol. 2010 Sep 17;5(9):887-95. PMID: 20583816 [PubMed - indexed for MEDLINE]
5. Suborganelle sensing of mitochondrial cAMP-dependent protein kinase activity.
6. Agnes RS, Jernigan F, Shell JR, Sharma V, Lawrence DS. J Am Chem Soc. 2010 May 5;132(17):6075-80. PMID: 20380406 [PubMed - indexed for MEDLINE] Free PMC Article
7. Light-mediated remote control of signaling pathways. Priestman MA, Lawrence DS.Biochim Biophys Acta. 2010 Mar;1804(3):547-58. Epub 2009 Sep 16. Review. PMID: 19765679 [PubMed - indexed for MEDLINE] Free PMC Article
8. Light-mediated spatial control via photolabile fluorescently quenched peptide cassettes. Lee HM, Priestman MA, Lawrence DS. J Am Chem Soc. 2010 Feb 10;132(5):1446-7. PMID: 20073458 [PubMed - indexed for MEDLINE] Free PMC Article
9. Simultaneous fluorescent monitoring of proteasomal subunit catalysis. Wakata A, Lee HM, Rommel P, Toutchkine A, Schmidt M, Lawrence DS. J Am Chem Soc. 2010 Feb 10;132(5):1578-82. PMID: 20078037 [PubMed - indexed for MEDLINE] Free PMC Article
10. Acquisition of a potent and selective TC-PTP inhibitor via a stepwise fluorophore-tagged combinatorial synthesis and screening strategy. Zhang S, Chen L, Luo Y, Gunawan A, Lawrence DS, Zhang ZY. J Am Chem Soc. 2009 Sep 16;131(36):13072-PMID: 19737019 [PubMed - indexed for MEDLINE] Free PMC Article
11. Uber-responsive peptide-based sensors of signaling proteins. Sharma V, Lawrence DS. Angew Chem Int Ed Engl. 2009;48(40):7290-2. No abstract available. PMID: 19739174 [PubMed - indexed for MEDLINE] Free PMC Article