Qisheng Zhang, Ph.D.
Associate Professor, UNC Department of Pharmacology
Associate Professor, Division of Chemical Biology and Medicinal Chemistry
4108 Marsico Hall, Eshelman School Of Pharmacy, CB# 7363, Chapel Hill, NC, 27599
ACCEPTING DOCTORAL STUDENTS
The Zhang lab studies lipid signaling pathways that are involved in development and diseases by developing novel chemical probes and technologies. As key components of cellular membranes, lipids also serve as signaling molecules and modify functions of proteins through either covalent or non-covalent interactions. Dys-regulation of lipid signaling has been correlated with various diseases including cancer, diabetes, and neurodegenerative diseases. Consequently, many lipid-related proteins or processes have been used as therapeutic targets. However, lipids are dynamically metabolized and transported, making it difficult to illustrate the roles of lipids in development and diseases with limited availability of probes and technologies for lipid studies.
The active projects in the lab include
- developing novel technologies to synthesize complex lipids, particularly phosphatidylinositides, and to identify their interacting proteins in live cells;
- developing new small-molecule sensors and inhibitors for lipid metabolic enzymes such as PI3K and PLC; and
- investigating cellular functions of lipids on different processes, particularly those regulated by small GTPases.
Research in the Zhang lab is focused on understanding the roles of endogenous small molecules, particularly phospholipids, in cell signaling events that are responsible for both normal development and diseases. Phospholipids play essential roles in all living organisms. Other than being major membrane constituents in cells, many phospholipids function as signaling molecules. Consequently, abnormal levels of phospholipids and aberrant regulation of their metabolizing enzymes have been associated with onset and progression of various diseases. However, how phospholipid signaling pathways regulate normal development and diseases is still poorly understood, largely due to their dynamic metabolism in the cells and the lack of available reagents and assays for phospholipids and their metabolic enzymes. I am interested in three different approaches to profile and understand phospholipids: 1) develop small molecule sensors and inhibitors for different phospholipid metabolizing enzymes; 2) develop efficient methods and technologies to profile phospholipids and use the resulting data for precision medicine and identification of new signaling molecules; and 3) investigate cellular functions of known and unknown phospholipids, particularly their synergistic actions with small GTPases ADP-ribosylation factors in regulating protein trafficking in signaling transduction. More recently, we have also extended our efforts to drug discovery towards diseases where phospholipid metabolizing enzymes are dysregulated. Toward this end, we are constructing library of small molecules with unique structures and functions.
4/2018 – present Director of Graduate Studies, Division of Chemical Biology and Medicinal Chemistry, UNC-Chapel Hill
9/2014 – present Associate Professor of Pharmacology, UNC-Chapel Hill
1/2013 – present Associate Professor of Chemical Biology and Medicinal Chemistry, UNC-Chapel Hill
1/2007 – 1/2013 Assistant Professor of Chemical Biology and Medicinal Chemistry, UNC-Chapel Hill
2015 PY2 Instructor of the Year, UNC Eshelman School of Pharmacy
2007 Junior Faculty R. J. Reynolds Fund Award
Chemical probes for phosphatidylinositide signaling pathway
Phosphatidylinositides (PIs) play diverse roles in various cellular processes. Every enzyme that is involved in PI metabolism, when mutated, deleted, or abnormally amplified, is linked to at least one type of human diseases. However, the roles of PIs in disease development are poorly understood due to their dynamic metabolism in the cells, complex chemical structures and cellular localizations, and the lack of available reagents and assays for PIs and their metabolic enzymes. We have developed a novel fluorogenic reporter, WH-15 that enables the development of the first high-throughput screen to identify small molecule inhibitors for mammalian phospholipase C isozymes. We have also developed fluorescent PtdIns(4,5)P2 derivatives, when coupled with capillary electrophoresis that enables simultaneously measuring activity of multiple PI metabolic enzymes.
1. Huang, W.; Hicks, S. N.; Sondek, J.; Zhang, Q. A Fluorogenic, Small Molecule Reporter for Mammalian Phospholipase C Isozymes. ACS Chem. Biol. 2011, 6, 223-228. PMCID: PMC3312000.
2. Wang, X.; Barrett, M.; Sondek, J.; Harden, T. K.; Zhang, Q. Fluorescent Phosphatidylinositol 4,5- Bisphosphate Derivatives with Modified 6-Hydroxy Group as Novel Substrates for Phospholipase C. Biochemistry 2012, 51, 5300-5306. PMCID: PMC3603374.
3. Charpentier, T. H.; Waldo, G. L.; Barrett, M. O.; Huang, W.; Zhang, Q.; Harden, T. K.; Sondek, J. Membrane-induced Allosteric Control of Phospholipase C-β Isozymes. J. Biol. Chem. 2014, 289,29545- 29547. PMCID: PMC4207972.
4. Waybright, J.; Huang, W.; Proctor, A.; Wang, X.; Allbritton, N. L.; Zhang, Q. Required Hydrophobicity of Fluorescent Reporters for Phosphatidylinositol Family of Lipid Enzymes. Anal. Bioanal. Chem. 2017, 409, 6781-6789.
5. Huang, W.; Wang, X.; Endo-Streeter, S.; Barrett, M.; Waybright, J.; Wohlfeld, C.; Hajcek, N.; Harden, T. K.; Sondek, J.; Zhang, Q. A Membrane-associated, Fluorogenic Reporter for Mammalian Phospholipase C Isozymes. J. Biol. Chem. 2017, in press. DOI: 10.1074/jbc.RA117.000926.
Regulation of small GTPases ADP-ribosylation factors (ARFs)
While working as a postdoctoral fellow in Dr. Peter Schultz’s lab at Scripps, I have established chemical and genetic screens to identify novel modulators of the canonical Wnt/β-catenin signaling pathway. One small molecule, QS11 synergistically activates the Wnt/β-catenin pathway through interacting with ARFGAP1 and thereby activating small GTPase ARFs. Several groups have since followed up our initial discovery to illustrate how ARFs crosstalk with the Wnt/β-catenin signaling. Realizing that synergy between ARFs and PIs is one of the major mechanisms to regulate membrane trafficking, I continue to study ARFs by illustrating how QS11 interacts with ARFGAP1/ARF1. I have also developed the first high-throughput screen assay of ARFGAP enzymatic activity. In collaboration with the NIH screening center at Scripps Florida, we have completed a screen of over 370,000 compounds and are working on 3 promising chemical series to develop potent and selective ARFGAP inhibitors. These compounds represent the first set of ARFGAP inhibitors. We have also developed a chemical biology approach to selectively modify and regulate ARFs.
1. Zhang, Q.; Major, B.; Takanashi, S.; Camp, N. D.; Nishiya, N.; Peters, E. C.; Ginsberg, M.; Schultz, P. G.; Moon, R. T.; Ding, S. A Small Molecule Synergist of the Wnt/β-catenin Signaling Pathway. Proc. Natl. Acad. Sci. U. S. A. 2007, 104, 7444–7448. PMCID: PMC1863490.
2. Jones, C. A.; Nishiya, N.; London, N. R.; Zhu, W.; Sorensen, L. K.; Chan, A.; Lim, C. J.; Chen, H.; Zhang, Q.; Schultz, P. G.; Hayallah, A. M.; Thomas, K. R.; Famulok, M.; Zhang, K.; Ginsberg, M. H.; Li, D. Y. Slit2-Robo4 Signaling Promotes Vascular Stability by Blocking Arf6 Activity. Nature Cell Biol. 2009, 11, 1325-1331. PMCID: PMC2854659.
3. Sun, W.; Vanhooke, J.; Sondek, J.; Zhang, Q. High Throughput Fluorescence Polarization Assay for the Enzymatic Activity of GTPase-activating Protein of ADP-ribosylation Factor (ARFGAP). J. Biomol. Screen. 2011, 16, 717-723. [PMC journal- in process].
4. Gao, H.; Sun, W.; Song, Z.; Yu, Y.; Wang, L.; Chen, X.; Zhang, Q. A Method to Generate and Analyze Modified Myristoylated Proteins. Chembiochem 2017, 18, 324-330.
Drug discovery through targeting trafficking processes
Phospholipids and small GTPases are major regulators of trafficking events. Many diseases, particularly infectious diseases, have close association with aberrant trafficking processes. We used both target-based and phenotype-based approaches to identify small molecules that inhibit growth of virus, pathogenic bacteria, and malaria.
1. Huang, W.; Barrett, M.; Hajicek, N.; Hicks, S.; Harden, T. K.; Sondek, J.; Zhang, Q. Small Molecule Inhibitors of Phospholipase C from a Novel High-throughput Screen. J. Biol. Chem. 2013, 288, 5840- 5848. PMCID: PMC3581404.
2. Singh, M. H.; Gao, H.; Sun, W.; Song, Z.; Schmalzigaug, R.; Premont, R. T.; Zhang, Q. Structure-activity Relationship Studies of QS11, a Small Molecule Wnt Synergistic Agonist. Bioorg. Med. Chem. Lett. 2015, 25, 4838-4842. PMCID: PMC4607626.
3. Singh, M. K.; Waybright, J.; Zhang, Q. A Facile Method to Enable a Model Phospholipid Cell-permeable and Photoactivatable. Tetrahedron 2017, 73, 3677-3683.
4. Tan, L.; Zhou, T.; Cederquist, G.; Mukherjee, S.; Kristen, B.; Zhang, Q.; Schwartz, R.; Evans, T. R.; Chen, S. High Content Screening in hESC-Neural Progenitors Identifies Drug Candidates that Inhibit Zika Virus Infection in Fetal-like Organoids and Adult Brain. Cell Stem Cell 2017, 21, 274-283.
Fluorous chemistry in biological applications
I was trained as a synthetic organic chemist in graduate school under Dr. Dennis Curran’s guidance at the University of Pittsburgh. As the major contributor to the technique “fluorous quasiracemic synthesis”, I developed the strategy to synthesize multiple natural products simultaneously by tagging different starting materials with distinct fluorous tags and subsequently separating products based on tags. The power of using fluorous tags to separate products from complex reaction mixtures prompted me to further develop fluorous techniques in my independent research, but in biological applications rather than chemical synthesis. We have introduced “fluorous enzymatic profiling” and “fluorous enzymatic synthesis” techniques to identify new targets of small molecule drugs and to generate endogenous, complex signaling molecules such as PIs.
1. Song, Z. and Zhang, Q. Fluorous Aryl Diazirine Photoaffinity Labeling Reagents. Org. Lett. 2009, 11, 4883-4885. [PMC journal- in process].
2. Song, Z.; Zhang, Q. Design, Synthesis, and Incorporation of Fluorous 5-Methylcytosines into Oligonucleotides. J. Org. Chem. 2011, 76, 10263-10268. [PMC journal- in process].
3. Song, Z.; Huang, W.; Zhang, Q. Isotope-coded, Fluorous Photoaffinity Labeling Reagents. Chem. Commun. 2012, 48, 3339-3341. [PMC journal- in process].
4. Huang, W.; Proctor, A.; Sims, C. E.; Allbritton, N. L.; Zhang, Q. Fluorous Enzymatic Synthesis of Phosphatidylinositides. Chem. Commun. 2014, 50, 2928-2931. PMCID: PMC3993006.
R01CA177993-01A1. (Allbritton) NIH 08/15/2014-07/31/2019
Single-cell Measurement of Lipid Signaling in Colorectal Cancer
The goal of this application is to develop a technology platform to readily measure phosphatidylinositide lipid signaling in single cells of colorectal cancer cell lines or patient samples. My lab is responsible for design, synthesis, and characterization of various phosphatidylinositide derivatives.
R1030 (Zhang) EII 06/01/2016-05/31/2018
“Clickable” Assays of Metabolic Enzymes for Precision Medicine
Role: Principal investigator
The goal of this application is to develop “clickable” assay to analyze metabolic enzymes and profile endogenous small molecules.
Not numbered (Chen) Daedalus Fund 07/01/2017-06/30/2018
Developing Novel Anti-Zika Virus Drugs
The goal of this application is to develop novel anti-Zika virus drugs based on the two hit compounds identified from a high throughput screen.
Completed research support R01GM086558-01A1 (Zhang) NIH 09/01/2011-08/31/2017
Developing Small Molecule ARFGAP Regulators to Dissect Cell Signaling
Role: Principal Investigator
The goal of this grant is to develop small molecule ARFGAP regulators from QS11, a Wnt synergistic agonist, to probe cell signaling, particularly the role of ARFGAP-regulated processes for the Wnt/-catenin signaling pathway
R01GM098894-01 (MPI: Sondek/Zhang) NIH 09/26/2011/-08/31/2015
High-throughput Screens to Identify Modulators of Phospholipase C Isozymes
Role: Principal Investigator
The goal of this grant is to develop integrated screening strategies for the identification of modulators of PLCs.
R01ES013611-01S1 (Jaspers) NIH 08/01/2013-06/30/2015
Diesel-induced Alterations of Influenza Infectivity
The overall goal of this grant is to develop novel technologies and complementary experimental approaches to investigate how exposures to diesel exhaust modify innate immune responses in humans.
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