Teaching
Research Interests
Current Funding
Publications and Presentations
Student Research Projects
Other Interesting Links
Teaching
Fall 2006:
Biochemistry, Biochemistry Lab, FYEC: The Drug Trade, Senior Seminar
Spring 2006:
FYEC: The Drug Trade, General Chemistry, Introduction to Research
Research Interests
The Synthesis of Organic Molecules to Control Protein Conformation and Function
I am interested in preventing Dengue Virus infections by controlling the conformation and function of the Dengue envelope glycoprotein with small organic molecules. The Dengue Virus is one of approximately 70 flaviviruses which have been identified. Half of these flaviviruses are capable of causing disease in humans. From a public health standpoint, the most important of these viruses include Dengue, West Nile, yellow fever, Japanese encephalitis, and tick-borne encephalitis. Vaccines have been developed for yellow fever, Japanese encephalitis, and tick-borne encephalitis; however, there is currently no known treatment or vaccine for dengue and West Nile viruses.
Both the dengue and West Nile viruses are transmitted to humans through the bite of an infected mosquito. Dengue virus has four antigenically distinct virus serotypes that cause dengue fever, dengue hemmorhagic fever (DHF), and dengue hemmorhagic shock syndrome (DHSS). The symptoms of dengue fever may persist for up to ten days and include a sudden high fever, joint and muscle pain, headaches, nausea, and a mild rash. The symptoms of DHF and DHSS are more severe and are characterized by capillary frailty, potential hemorrhage, and collapse of the cardiovascular system. The dengue virus is endemic in more than 100 countries in Africa, South America, the Eastern Mediterranean, Southeast Asia, and the Western Pacific, while in the 1970s, dengue fever was found in only nine countries. The World Health Organization estimates that up to two-fifths of the world's population (2.5 billion people) are at risk of acquiring the virus. There are 50 million infections per year, and at least 500,000 hospitalizations due to dengue hemmorhagic fever. According to the World Health Organization, the fatality rate is usually 2.5%; however, rates of up to 20% have been reported during some epidemics.
X-Ray Crystal Structure of the Dengue Envelope Protein
The positive-stranded RNA genome of the dengue virus is packaged in a lipid bilayer with three structural proteins: the core nucleocapsid protein (C), the membrane protein (M) and the envelope glycoprotein (E). The envelope protein is responsible for mediating both receptor binding and fusion with the host cell. The protein is organized into three domains and is found as a metastable head-to-tail dimer that lies flat on the surface of the virus. When the virus is exposed to the low pH (6.0) environment of the endosome after receptor-mediated endocytosis, an irreversible conformational change is initiated that reorganizes the envelope protein into a more stable trimeric species and exposes the fusion peptide.
Schematic Representation of the Low pH Conformational Change
Nutraceuticals for drug discovery
Nutraceuticals are biologically active organic compounds which have disease-preventing or medicinal properties and are found naturally in plants. These compounds have also been referred to as phytochemicals or functional foods. The use of these natural compounds to fight diseases can be traced back to ancient oriental herbal medicine. The drug discovery process is lengthy and it usually takes between 10-15 years for a new drug to come to market. The time this process takes can be drastically reduced if a compound found in a common plant with known toxicity data is found to have nutraceutical properties. This is a particularly attractive option in the case of orphan diseases (where pharmaceutical companies can't recuperate discovery costs) or diseases like the Dengue virus which primarily affect third world countries (where people can't afford expensive drugs).
My 2005 Schapiro Undergraduate Research Fellowship students at the symposium on August 4, 2005. From left to right: Ted Shaner, Kerisa Harriott, Robert Culley IV, and Ashley A. Ford
Current Research Funding
The Camille and Henry Dreyfus Start-Up Grant for Undergraduate Institutions
Randolph-Macon College Faculty Start-Up
Publications
Green, N. S.; Foss, T. Kelly, J. W. "Is Soy Mother Nature's Miracle Worker? Genistein as an Effective Inhibitor of Transthyretin Amyloidosis." Proc. Natl. Acad. Sci. USA. 2005, 102, 14545-14550.
Kelly, J. W.; Green, N. S. "Genistein Inhibibition of Transthyretin Amyloidosis." U.S. Patent Application 11/504,134, 2005. International patent application September 2006.
Johnson, S. J.; Wiseman, R. L; Sekijima, Y; Green, N. S.; Adamski-Werner, S. L.; Kelly, J. W. "Native State Kinetic Stabilization as a Strategy to Ameliorate Protein Misfolding Diseases: A Focus on the Transthyretin Amyloidoses." Acc. Chem. Res. 2005, 38, 911-921.
Wiseman, R. L.; Green, N. S.; Kelly, J. W. ""Kinetic Stabilization of an Oligomeric Protein under Physiological Conditions Demonstrated by a Lack of Subunit Exchange: Implications for Transthyretin Amyloidosis" Biochemistry 2005, 44, 9265-9274.
Green, N. S.; Palaninathan, S. K.; Sacchettini, J. C.; Kelly, J. W. Synthesis and Characterization of Potent Bivalent Inhibitors of Amyloidosis that Bind Prior to Transthyretin Tetramerization. J. Am. Chem. Soc. 2003, 13404-13414.
Green, N. S.; Reisler, E.; Houk, K. N. Quantitative Evaluation of the Lengths of Homobifunctional Protein Cross-linking Reagents Used as Molecular Rulers. Protein Science 2001, 10, 1293-1304.
Behnam, S. M.; Behnam, S. E.; Ando, K.; Green, N. S.; Houk, K. N. Stereoelectronic, Steric, and Torsional Effects on the Rates of Enolization of Ketones. J. Org. Chem. 2000, 65, 8970-8978.
Green, N. S.; Miller, M. M.; Houk, K. N. Evaluation of Isoprenoid Conformation in Solution and in the Active Site of Protein-Farnesyl Transferase Using Carbon-13 Labeling in Conjunction with Solution- and Solid-State NMR. Chemtracts 2000, 13, 749-756.
Green, N. S.; Houk K. N. Structures of Enzymes involved in Terpenoid Biosynthesis. Chemtracts 2000, 13, 844-852.
Ando, K.; Green, N. S.; Li, Y.; Houk, K. N. Torsional and Steric Effects Control the Stereoselectivities of Alkylations of Pyrrolidinone Enolates. J. Am. Chem. Soc. 1999, 121, 5334-5335.
Green, N. S.; Houk K. N. Structures of Enzymes involved in Terpenoid Biosynthesis. Chemtracts 1998, 11, 537-545.
Presentations
Green, N. S. “Teaching Medicinal Chemistry at a Small Liberal Arts College” American Chemical Society 232nd National Meeting, San Francisco, CA. September 12, 2006, COMP 187 (Invited talk).
Green, N. S. “Crossing Boundries: From Hartree Fock-Up to Protein Chemist” University of California, Los Angeles Chemistry and Biology Interface Symposium, Los Angeles, CA. July 21, 2006. (Invited talk)
Green N. S. "Purification of transthyretin: An experiment for project-based biochemistry laboratories." American Chemical Society 231st National Meeting, Atlanta, GA. March 26, 2006, CHED 112.
Shaner, Ted V.; Green, Nora S. "Stabilization of envelope protein in Dengue virus." American Chemical Society 231st National Meeting, Atlanta, GA. March 27, 2006, CHED 784.
Green, N. S.; Foss, T.; Kelly, J. W. " Genistein, a Natural Product from Soy, is a Potent Iinhibitor of Transthyretin Amyloidosis" American Chemical Society 229th National Meeting, San Diego, CA March 13, 2005, MEDI-197.
Green, N. S.; Houk, K. N. The Design and Synthesis of Novel Gated Host-Guest Systems. American Chemical Society 219th National Meeting, San Francisco, CA. March 26, 2000, ORGN 080.
Student Research Projects
Nelia Kranitzky, SURF 2006 "Synthesis of Benzimidazole, Benzathiazole, and Indole Diarginine Mimics as Inhibitors of the Dengue Virus NS3 Protease."
Perry Kennedy, Fall 2005-Spring 2006 "Nutraceuticals in the Search for a Dengue Virus NS3 Protease Inhibitor."
Robert Culley IV, SURF 2005, Spring 2006, SURF 2006 "Development of a New Gel Filtration Assay to Probe Small Molecule Conformational Control of the Dengue Virus Envelope Glycoprotein."
Ashley A. Ford, SURF 2005 "Synthesis of Heterocyclic Alpha Amino Acid Arginine Mimics as Potential Inhibitors of the Dengue Virus."
Kerisa Harriott, SURF 2005, Spring 2006 "Synthesis of Disubstituted Urea Compounds for the Inhibition of the Dengue Virus NS3 Protease"
Ted Shaner, SURF 2005-present "Stabilization of the Envelope Protein in Dengue Fever."
Diana Wright, Spring 2006 "Flourescent Studies on Transthyretin."
Ellen Sakell, January 2005-Spring 2005 "Solid Phase Peptide Synthesis of a Chromogenic Peptide Substrate for the Dengue Virus NS3 Protease."
Other Interesting Links
Biochemistry Tools
The Protein Data Bank
Visual Molecular Dynamics Webpage
Pymol webpage
ExPASy proteomics tools
UCLA Online Resources in Chemistry and Biochemistry
The American Chemical Society
The American Chemical Society Publications Home
Dengue Virus
The World Health Organization
The Center for Disease Control
Flavivirus links
The Big Picture Book of Viruses
Links of Personal Interest:
The Breast Cancer 3-Day
The Breast Cancer Site
The Animal Rescue Site
The Hunger Site
The Association for Women in Science
The Council on Undergraduate Research
Circle K International
My dog Abby:
