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.
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.
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).
